Evaluating Dendritic Cell Vaccination Therapy for Multiple Myeloma: A Systematic Review

Evaluating Dendritic Cell Vaccination Therapy for Multiple Myeloma: A Systematic Review | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Evaluating Dendritic Cell Vaccination Therapy for Multiple Myeloma: A Systematic Review Jamal Motallebzadeh Khanmiri, Mohammad Khani-Eshratabadi, Mahdis Helmi Oskouei, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5347479/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Multiple myeloma (MM) presents significant challenges in treatment, necessitating the exploration of innovative therapeutic strategies. Standard treatments, such as chemotherapy and stem cell transplantation, have limitations, particularly regarding adverse effects and relapse rates. This systematic review aims to evaluate the potential of dendritic cell (DC) vaccination therapy as a promising approach in MM management, contributing to the expanding range of therapeutic options for this complex hematologic malignancy. Methods A systematic search was conducted across PubMed, Scopus, ProQuest, and Web of Science databases to identify relevant studies. Strict inclusion criteria were applied to select studies within the review’s scope, and a rigorous quality assessment was performed using Cochrane risk-of-bias tools. Evaluation parameters included remission rates, survival outcomes, and immunological impacts. Results From an initial pool of 2,923 studies, 15 were deemed eligible for inclusion. The analysis revealed that DC vaccination therapy demonstrated efficacy in inducing both complete and partial remissions and showed potential in enhancing immune responses. Significant improvements were observed in various immune cell populations and cytokine levels, indicating a multifaceted therapeutic mechanism. Conclusion This review highlights the potential of DC vaccination therapy as a viable treatment option for MM. While the observed outcomes are promising, further research is necessary to refine administration protocols, optimize treatment efficacy, and ensure long-term safety and sustainability. Advancing our understanding and application of DC vaccination therapy could significantly impact MM management and improve patient outcomes by offering more effective and personalized treatment strategies. Multiple Myeloma Dendritic Cells Immunotherapy Vaccination Neoplasm Vaccines Figures Figure 1 Figure 2 Introduction Multiple Myeloma (MM) is a rare neoplastic disorder caused by the clonal proliferation of bone marrow plasma cells, disrupting normal hematopoiesis. MM is associated with various complications such as anemia, hypercalcemia, renal dysfunction, and osteolytic lesions. Despite the advent of novel therapeutic agents, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, the disease remains incurable, and frequent relapses or drug resistance is noted ( 1 , 2 ). Therefore, investigating new therapeutic strategies seems to be crucial. Dendritic cell (DC) vaccines are novel and innovative strategies in cancer immunotherapy. DCs are potent antigen-presenting cells capable of initiating and modulating immune responses. They can capture, process, and present antigens to T cells, establishing a solid connection between innate and adaptive immunity ( 3 , 4 ). Regarding this ability, DC vaccines are ideal candidates for cancer prevention strategies. They can be modified ex vivo and subsequently utilized to stimulate strong anti-tumor responses by presenting tumor antigens. DCs are categorized into several subsets based on their distinct functions and characteristics, including myeloid DCs (mDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). mDCs are particularly effective in inducing T-cell responses due to their high expression of co-stimulatory molecules and cytokines. Alternatively, pDCs can produce a significant amount of type I interferons in response to viral infections. moDCs, derived from monocytes in-vitro, are commonly used in DC vaccination studies due to their ease of generation and functional properties ( 5 , 6 ). The process of DC vaccine generation consists of isolating monocytes from peripheral blood mononuclear cells (PBMCs) and subsequent differentiation into DCs in-vitro using cytokines such as GM-CSF and IL-4. Then, these DCs are fused with tumor cells or loaded with tumor antigens employing various techniques, such as pulsing with peptides, RNA, or tumor lysates. Antigen-loaded DCs are then matured using stimuli such as TNF-α, IL-1β, and poly I to enhance their immunogenicity before being administered back to the patient ( 7 , 8 ). The efficacy of DC vaccines has been investigated in melanoma, prostate cancer, and glioblastoma. Sipuleucel-T, an autologous DC vaccine, has also been approved by the FDA to treat metastatic castration-resistant prostate cancer, highlighting the clinical potential of this approach ( 9 , 10 ). DC vaccines can induce immune responses against hematologic malignancies, improving clinical outcomes. Our recent systematic review on DC vaccination for acute myeloid leukemia (AML) highlighted its potential to induce remission and enhance immune responses, providing a strong rationale for exploring similar strategies in MM ( 11 ). The immunosuppressive microenvironment of MM poses a significant challenge to effective immune-based therapies. Myeloma cells and the surrounding stromal cells release various cytokines and growth factors to inhibit immune system function and promote tumor growth. TGF-β, IL-10, and VEGF suppress DC maturation and function, leading to an ineffective anti-tumor response ( 12 , 13 ). Therefore, strategies that can overcome this immunosuppression can ensure the efficacy of DC vaccination in MM. Recent advancements in DC vaccine development have focused on enhancing the immunogenicity of DCs and overcoming the immunosuppressive tumor microenvironment. When compared to immature DCs, mature leukemia-derived DCs (DCleu) have been demonstrated to elicit more significant immune responses. Additionally, co-transfection of DCs with mRNAs encoding immunostimulatory ligands such as CD40L and OX40L has been explored to enhance their ability to activate T cells ( 14 , 15 ). Another innovative strategy is using DC-derived small extracellular vesicles (DCsEVs). These vesicles can effectively present tumor antigens and deliver immunostimulatory signals to T cells, providing a cell-free alternative to traditional DC vaccines. DCsEVs have demonstrated a promising potential to induce anti-tumor immune responses ( 16 , 17 ). Furthermore, the combination of DC vaccine with other immunotherapeutic approaches such as checkpoint inhibitors and CAR-T cell therapy has been investigated to improve the overall outcome. Checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 antibodies can amplify the anti-tumor response. When combined with DC vaccines, these agents synergistically enhance both activation and expansion of tumor-specific T cells ( 18 , 19 ). Despite these advancements, several challenges remain in the clinical translation of DC vaccines for MM. The heterogeneity of the disease, the complexity of the tumor microenvironment, and the need for personalized vaccine formulations are some of the obstacles that need to be addressed. Additionally, standardized protocols for DC generation, antigen loading, and maturation are essential to ensure the consistency and reproducibility of clinical outcomes ( 8 ). This systematic review evaluates the current evidence on the efficacy and safety of DC vaccination therapy for MM. By synthesizing data from various studies, we hope to provide insights into the potential of DC vaccines as a therapeutic strategy for MM and identify areas for future research. Our findings from the AML study underscore the importance of personalized approaches and the potential benefits of integrating DC vaccination with other immunotherapeutic modalities ( 11 ). Methods Search strategy This study systematically searched online databases including Web of Science (WOS), PubMed, Scopus, and ProQuest to identify the relevant articles published before April 16, 2024. The search strategy incorporated keywords such as “lymphoma,” “leukemia,” “myeloma,” “vaccination,” “immunization,” “immunotherapy,” and “dendritic cell,” targeting these terms in the title and abstract sections. Additionally, the reference lists and 'cited by' papers of the selected articles were examined to include any potentially relevant studies. Study selection Duplicates were removed. Then, to check for eligibility, two independent reviewers (N. Seddighi and M. Haddadi) screened the titles and abstracts of the retrieved articles. The same reviewers investigated full texts, where necessary. Discrepancies were resolved by discussion with a third researcher (J. M. Khanmiri). We considered all English publications that meet the inclusion criteria, including clinical trials (phases I, II, and III) involving diagnosed MM patients planning for vaccination and treatment with dendritic cells, with or without chemotherapy. Exclusion criteria were as follows: i) unclear results or presence of errors in methodology and/or analyses; ii) imprecise results resulting in low reproducibility; iii) unavailable full text unless the abstracts provided adequate data; iv) review articles; v) Inappropriate study designs such as case reports and letters to the editor; vi) Incorrect interventions; v) conference abstracts; and vi) non-English publications. Data extractions and quality assessment Data collection was performed independently by two researchers (J. M. Khanmiri and M. Khani-Eshratabadi). When discrepancies arose, a third researcher (B. Baradaran) provided additional evaluation. The extracted data from various studies comprised the first author, date of publication, study type, number of cases and demographics, intervention for test and control group, administration route/dosage, outcome, and possible side effects. Quality of the studies was assessed using the Cochrane risk-of-bias tool based on five critical criteria, including selection bias, performance bias, detection bias, attrition bias, and reporting bias, rated as a 'low,' 'high,' or 'unclear' risk of bias. Discrepancies among the data collectors were resolved through discussion or consulting a third reviewer (B. Baradaran). Statistical analysis R software version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org ) was used for statistical analysis. The frequency of clinical and immunological responses associated with DC vaccination was evaluated using proportion analysis. A pooled prevalence analysis was performed utilizing the inverse variance method. Heterogeneity was assessed through Cochrane’s Q test and calculation of the I² statistic. If the P-value from the heterogeneity test was below 0.05 or I² exceeded 50%, the random-effects model was utilized; otherwise, the common-effects model was applied. Results Initially, we identified 2923 articles through a search in four databases; after removing duplicates, 2163 relevant articles were screened by title and abstract. 1930 articles were excluded and the full text of 233 papers were assessed. Finally, 15 relevant articles were included in this study (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34). Figure 1 illustrates the screening process. Study Characteristics Table 1 summarizes the comprehensive information on the 15 clinical trials included in the study. Four were phase I trials (24, 28, 30, 33), three were phase I/II trials (26, 32, 34), and one was a phase II trial (29), and the remaining seven articles did not mention the trial phase (20, 21, 22, 23, 25, 27, 31). Treatment Results The primary and secondary outcomes of the included papers are shown in Table 2. Table1 . The overview of the included studies. First author (Reference) Trial Phase Characteristics No. of Cases (Male/Female) Age in years Intervention methods Administration Route/dose G. Cull (20) ND advanced refractory myeloma 2 (2/0) 53 Autologous idiotype protein pulsed dendritic cells plus adjuvant with GM-CSF SQ Patient 1 received 4 × 106, 4 × 106, 2·5 × 107 and 2·5 × 107 DCs over four vaccinations; However, patient 2 received 2·5 × 10 7 , 2·5 × 10 7 , 4 × 10 7 and 4 × 10 7 for the four vaccinations Seah H. LIM (21) ND MM patients 6 (1/5) 67.66 Pulsed DC with the autologous Id and a control vaccine, KLH, and re infused i.v. back to the patients on 3 separate occasions IV 47.5×10 6 (Patient 1), 34.4×10 6 (Patient 2), 38×10 6 (Patient3, 3.5×10 6 (Patient4), 40×10 6 (Patient5) and 89×10 6 (Patient6) SANDRA TITZER (22) ND MM patients with stage III (but one I) 11 (5/6) 62.81 CD34 stem cell-derived DCs pulsed with Id peptides SC 1×10 6 (patients 1, 2 and 10), 1×10 7 (patients 3,4,5 and 8), 2.5×10 6 (patient 9), 2×10 7 (patients 7, 11 and 12) Qing Yi (23) ND Stable partial remission of MM after high-dose chemotherapy 5 (3/2) 62 Idiotype protein-pulsed DCs vaccination IV/SC 20 × 10 6 Volker l. Reichardt (24) I MM patients responsive to HDT and PBSCT 12 (5/7) 52.41 autologous idiotype pulsed DC vaccines followed by Id/keyhole limpet hemocyanin (Id/KLH) boosters immunizations co-injected with GM-CSF . IV 4.5 × 10 6 Maurizio Bendandi (25) ND Relapsed/progressed MM after decreased intensity conditioning (RIC) alloSCT and failure to rescue therapy with donor lymphocyte infusion or chemotherapy 4 (2/2) 49 Id-pulsed alloDC oupled with the traditional, soluble protein-based Id vaccine formulation ID 5–10 × 10 8 Antonio Curti (26) I/II MM patients with progression and stable disease 15 (11/4) 57.33 loaded CD14+-derived DCs with the autologous Id as whole protein or Id-derived class I-restricted peptides and KLH SC/IV 50 × 10 6 Qing Yi (27) ND patients with smouldering or stable MM without treatment 9 (5/4) 57.4 idiotype (Id) protein-pulsed DC Intranodal injection 5×10 5 cells Jacalyn Rosenblatt (28) I Patients with active disease who had received ≥1 prior treatment, and stage I myeloma patients under observation without needing therapy 18 (12/ 6 ) 57 DCs (generated from adherent mononuclear cells) loaded with Myeloma Cells SQ 1 × 10 6 , 2×10 6 , 4 × 10 6 × 3 L. ZAHRADOVA (29) II relapsed MM patients 11 (4/7) 63.8 DCs loaded with autologous Id-protein ID 0.5x10 6 Willemijn Hobo (30) I treatment for MRD in MM after SCT 12 (11/1) 60.58 Mature moDCs were pulsed with KLH and electroporated with MAGE3, Survivin or B-cell maturation antigen mRNA IV: 5–22 × 10 6 ID: 4–11 × 10 6 Xia Zhao (31) ND MM patients 50* (14/12) 57.14 Two groups of patients, including 24 on simple chemotherapy and 26 on chemotherapy plus DC/CIK immunotherapy 2.0-5.0×10 9 R Oostvogels (32) I/II MM patients who failed to respond to a first DLI 15 (10/5) 58.2 moDCs (autologous) isolated from autologous leukapheresis products collected and cryopreserved before allo-SCT IV/ID 90×10 6 (administered in one to three courses of maximally 30 × 10 6 DCs per infusion) Sung-Hoon Jung (33) I Relapsed/refractory MM patients 12 (5/7) 62.5 DCs loaded with autologous myeloma cells irradiated with ultraviolet B (VAX-DC/MM) ID 5 × 10 6 or 10 × 10 6 LE Franssen (34) I/II Persistent or relapsed MM following allo SCT and a previous DLI 9 (6/3) 55.77 donor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI IV/ID 45–90 × 10 6 * 26: chemotherapy plus DC/CIK immunotherapy Abbreviations: GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor, SC: Subcutaneous, MM: Multiple Myeloma, DC: Dendritic Cells, Id: Idiotype, KLH: Keyhole Limpet Hemocyanin, IV: Intravenous, ID: Intradermal, DLI: Donor Lymphocyte Infusion, VAX-DC/MM: Vaccine Dendritic Cells for Multiple Myeloma, CIK: Cytokine-Induced Killer, moDCs: Monocyte-Derived Dendritic Cells, High-dose chemotherapy: HDT, Peripheral blood stem cell transplantation: PBSCT Table 2 . Primary and secondary outcomes of included studies. First Author (year) No. of Cases Response (n) Adverse events (n) G. Cull (1999) 2 Immune responses: KLH-specific T-cell proliferation: (2), gamma-interferon production: (1) humoral response to KLH: anti-KLH IgM and IgG antibodies (2) CTL assay: No idiotype-specific killing of antigen-loaded DC by effector cells subject Mild flu-like symptoms and fever (1) Seah H. LIM (1999) 6 Immune responses: PBMC proliferative responses to Id (5), Poduction of IFN-g (2), cytotoxic T-cell precursor frequencies for Id-pulsed autologous targets (3) anti-Id IgM (3), anti-Id IgG (4); Clinical responses: SD observed in all patients during the vaccination period, (1) patient showed a consistent 25% reduction in serum Id levels ND SANDRA TITZER (1999) 11 Immune responses: (3) out of 10 analyzed patients showed increased anti-idiotype antibody serum titres, The idiotype-specific T-cell response, was increased in (4) out of 10 analyzed patients; Clinical responses: SD (1), PD (10) ND Qing Yi (2001) 5 Immune responses: anti-idiotypic B-cell responses (4), Idiotypespecific T-cell responses (4) proliferation assays (2) positive IFN-g response (3); Clinical Response: defined as a 50% reduction in serum M-component, in (1) patient who received the vaccination. This reduction persisted for 6 months, SD for 6 months was observed in (3) other patients ND Volker l. Reichardt (2003) 12 Immune responses: (2) patients developed Id-specific T-cell proliferative responses, (1) patient showed Id-specific cytotoxic T lymphocyte (CTL) response, (1) patient had Id-specific TH1 cytokine secretion, Delayed KLH-specific antibody responses (7) Clinical responses: PR (9), SD (1), PD(2) ND Maurizio Bendandi (2006) 4 Immune responses: Humoral response (4), Proliferative response (4) Clinical responses: SD (2) ND Antonio Curti (2007) 15 Immune responses: Id-specific T-cell proliferative response (8) Id specific IFN-g secreting T cell (8) Id-positive DTH test (4) KLH-specific antibody response (15) KLH-specific T-cell proliferative response (10) KLH specific IFN-g secreting T cell (9) KLH-positive DTH test (10) Clinical responses: PR (1), SD (7), PD (7) ND Qing Yi (2010) 9 Immune responses: Interleukin-4 response (2) skin delayed-type hypersensitivity reaction (7) Id-specific cytotoxic T-cell responses (5) Id-specific B cells responses (9) Clinical response: SD(6), PD(3) ND Jacalyn Rosenblatt (2010) 18 Immune responses: Increase in the percentage of CD4 or CD81 tumor-reactive T cells (11), Antibody response against BRCA1-associated protein (1); Clinical response: SD (11) Without evidence of dose-limiting toxicity. One patient who had a previous history of deep vein thrombosis (DVT) developed DVT and pulmonary embolus while on study. injection-site reactions (13) L. ZAHRADOVA (2012) 11 Immune Responses: ELISpot: (3), DTH Skin Test: Positive in ( 8) Clinical response: SD (10), PD (1) No serious toxicities, Fever (1), Willemijn Hobo (2013) 12 Immune responses: KLH-specific T-cell responses (12), induration and erythema at the DTH sites (6), KLH specific IFN-g production (5) Clinical response: SD (5), PD (5), fever, chills, malaise and muscular pain (10) Xia Zhao (2015) 50 Immunological responses: CD3+CD8+ ratio decreased and CD3+CD4+/CD3+CD8+ ratio increased significantly in the combined therapy group compared to the simple chemotherapy group (P<0.05), Peripheral blood CD4+CD25+/CD4+ and CD4+CD25+FoxP3+/CD4+CD25+ ratios were significantly lower in the combined therapy group (P<0.05), Positive rate of NKG2D was significantly higher in the combined therapy group (P<0.05); Clinical response: PS scores, percentage of MM cells, β2-MG, serum M protein, 24-hour urinary light chain content, and Scr improved significantly in the combined therapy group compared to the simple chemotherapy group (P<0.05), transient chills and fever (2), nerve terminal injury (5), R Oostvogels (2016) 15 Immunological response: Objective T-cell responses against KLH (15), Anti-host T-cell responses in 6/10 evaluable patients, mHag peptide-loaded DCs induced an objective T-cell response in 1/4 patients; Clinical response: SD (7), PD (7), PR (1) Injection site (12) Sung-Hoon Jung (2017) 12 Immunological response: in 7 out of 9 patients (77.8%) receiving 10 × 10^6 cells, Clinical response: SD (5), PD (3), MR (1) injection site and infusion-related reactions myalgia (4), fever (2), and chills (2) lymphocytopenia and thrombocytopenia (2) subclinical hypothyroidism (2) LE Franssen (2017) 9 Immunological response: anti-KLH responses (9), induction of mHag-specific CD8+ T cells (5), Clinical response: SD (5), PD (3) intradermal injection site (9), severe adverse events (5) Abbreviations: SD: Stable Disease, PD: Progressive Disease, PR: Partial Response, CR: Complete Response, MR: Minimal Response, KLH: Keyhole Limpet Hemocyanin, IgM: Immunoglobulin M, IgG: Immunoglobulin G, CTL: Cytotoxic T Lymphocyte, PBMC: Peripheral Blood Mononuclear Cell Clinical Response We assessed and investigated all clinical responses from previous studies on DC therapy in multiple myeloma (MM). Disease stabilization was reported in 69 out of 139 cases across 13 studies (pooled prevalence [95% CI] = 50.31 [41.01%; 59.58%], I2= 42.6%) (21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 34). Additionally, progressive disease (PD) was developed in 41 out of 112 cases across ten studies (pooled prevalence [95% CI] = 36.84% [27.47%; 47.33%], I2= 44.2%) (21, 22, 24, 26, 27, 29, 30, 32, 33, 34). G. CULL et al. studied two patients with MM treated by autologous idiotype protein-pulsed dendritic cells plus adjuvant GM-CSF. The results showed that in one patient, the paraprotein level increased slowly during the vaccination but increased sharply one month after the last vaccination, requiring treatment with dexamethasone. In another patient, the paraprotein level remained steady during treatment and follow-up (20). Seah H. LIM et al. reported six patients who had received dendritic cell vaccination with idiotypic protein. One patient died after the second dose due to chest pain and could not be evaluated for clinical response. Among the remaining patients, one showed a minor decrease in idiotypic (Id) protein levels, two had steady serum Id levels during follow-up, and disease progression was observed in two patients after treatment. Additionally, the disease did not progress after vaccination in five patients (21). A clinical trial by SANDRA TITZER et al. evaluated ten MM patients who were treated with idiotype-pulsed dendritic cells. The results showed a reduction in plasma cells after vaccination in one, while the remaining cases experienced progressive disease (22). Qing Yi et al. reported no side effects during the vaccination of five patients, followed for one year. Two patients showed increasing M-protein levels by week 26, while one patient exhibited a reduction in M-protein from 9 g/dL at week 2 to 4 g/dL at week 4, remaining stable thereafter. Other patients showed no significant changes (23). Volker L. Reichardt et al. observed that among 12 patients who received autologous idiotype-pulsed DC vaccines followed by Id/keyhole limpet hemocyanin (Id/KLH) booster immunizations co-injected with GM-CSF, one patient was excluded during the vaccination phase due to disease progression. Another patient completed the vaccination protocol phase but progressed. Two patients achieved partial improvement during follow-up, while eight patients experienced disease progression, four of whom died, and the remaining four were alive with salvage therapy (24). Similarly, in another trial by Maurizio Bendandi et al., two patients died during the protocol, and two patients withdrew from the study, opting for other treatments (25). Antonio Curti et al. enrolled 15 patients for the trial. Seven achieved stable responses, one achieved partial response, and the remaining seven progressed (26). Another study by Qing Yi et al. reported that none of the nine patients showed significant side effects during vaccination. However, during the one-year follow-up, one patient showed a reduction in M-protein, five illustrated no significant changes, and three showed progression (27). Jacalyn Rosenblatt et al. conducted a study on dendritic cell/tumor fusion cell vaccination in 16 MM patients, among whom 13 presented injection-site reactions, and stable disease during several months of follow-up was reported in 11 (28). In a trial by ZAHRADOVA et al., involving Id-protein-loaded dendritic cell vaccines in MM patients, stable disease was noted in 73% of patients, and the others showed disease progression during one-year follow-up. Patients did not receive specific treatment during the protocol phase (29). Additionally, Willemijn Hobo et al., studied MM patients who received intensive chemotherapy and autologous SCT. These patients received DC vaccinations pulsed with MAGE3, Survivin, and B-cell maturation antigen mRNA. At the last follow-up, ten out of twelve patients were still alive. Of these, five had stable disease, while the other five had progressive disease, with four receiving additional treatment. Several patients were diagnosed with secondary cancers (two with acute myeloid leukemia, one with prostate cancer, and one with plasma cell leukemia) (30). Xia Zhao et al. investigated MM patients treated with DC/CIK combined with chemotherapy. Two out of 26 patients showed transient chills and fever a few hours after combined treatment, and none of the patients died during the study (31). In the study by R Oostvogels et al., patients underwent DC vaccination combined with donor lymphocyte infusion. Out of 15 patients, 11 were observed for clinical response; five showed a good response (two had objective clinical benefits, and three had possible clinical benefits), while six patients experienced disease progression (32). Sung-Hoon Jung et al. conducted a clinical study on MM patients who received autologous dendritic cell therapy. The patients were followed for approximately 16 months, during which eight showed disease progression, five of whom received salvage therapy (33). LE Franssen et al. evaluated the efficacy and safety of dendritic cell vaccination in MM patients who received donor lymphocyte infusion (DLI). Five patients maintained stable disease in a median of seven months after vaccination, one achieved complete molecular remission, and three showed ongoing disease progression after vaccination (34). Immune response The immune responses are shown in Table 2. The prevalence of six treatment-associated was calculated. The induction of KLH antibodies was revealed in 33 out of 38 patients across four studies (pooled prevalence [95% CI] = 84.98% [53.80; 88.54], I2= 50.5%) (20, 24, 26, 34). In the G. CULL study, these strong humoral responses were maximal for IgM at week 5 and for IgG at week 7 (20). Another study conducted by Volker L. Reichardt et al. detected KLH antibodies in all patients, with these antibodies being detected in three patients following the second immunization and in four patients after the third immunization (24). Additionally, Antonio Curti et al. observed KLH-specific antibody responses; they detected KLH antibodies following the first vaccination and reported maximum concentration after the third vaccination (26). Furthermore, the induction of KLH T cells was reported in 39 out of 44 cases across four studies (pooled prevalence [95% CI] = 78.80% [60.12%; 90.17%]; I2= 42.8%) (20, 26, 30, 32). G.CULL et al. showed the proliferation of KLH-specific T-cells after the first vaccination in one patient and after the first vaccine administration in the other one. This response was dose-dependent during vaccination. They could detect the immune response at the latest follow-up assessment (20–26 weeks) (20). In a study by Antonio Curti et al., the concentration of circulating KLH-specific IFN-γ secreting T cells was significantly increased following the third vaccination course in almost half of patients (26). Willemijn Hobo et al. evaluated KLH-specific T-cell responses after the first vaccination; overall, four patients had a moderate response, four had a good response, and four illustrated an excellent T-cell response to KLH. Some patients showed increased responses after subsequent vaccinations, but most showed no change or a decrease (30). Additionally, IFN-γ responses were investigated in 19 out of 38 patients across four studies (pooled prevalence [95% CI] = 50.11% [34.37%; 65.84%]; I2= 0.0%) (21, 23, 26, 30). In the study by Seah H. LIM et al., IFN-γ production in the supernatant culture was detectable in two out of six patients after the third vaccination (21). Qing Yi et al. also observed that DC vaccination induced an IFN-γ response in four patients, with one showing an enhanced response (23). Antonio Curti et al. demonstrated that the concentration of KLH-specific IFN-γ secreting T cells in circulation increased in 60% of patients (9/15) after the third vaccination (26). In the Willemijn Hobo et al. study, five out of six patients produced KLH-specific IFN-γ (30). The Id T cell response in six studies revealed 26 out of 58 cases (pooled prevalence [95% CI] = 45.99% [32.83; 59.73%]; I2 = 23.2) (22, 23, 24, 26, 27). Table 2 presents the other results of immune responses collected from the included papers. Adverse events The prevalence of delayed-onset hypersensitive reaction in 31 out of 47 cases across four studies was assessed (pooled prevalence [95% CI] = 65.37% [50.45%; 77.78%], I2= 0.0%) (26, 27, 29, 30). The adverse events are summarized in Table 2. Sandra Titzer et al. identified five patients with new osteolytic lesions about two months after vaccination. It should be noted that six patients had osteolytic lesions before vaccination therapy (22). Qing Yi et al. reported that one out of five patients showed an erythema without induration after the second vaccination (23). Volker L. Reichardt et al. reported that with an increase in booster injections, all patients exhibited moderate to severe local reactions such as erythema, local soreness, and swelling (24). In the Maurizio Bendandi et al. study, two patients showed side effects: one experienced an elevated number of osteolytic bone lesions and progressive renal failure, and the other exhibited hypercalcemia and cranial plasmacytoma (25). The results of Jacalyn Rosenblatt et al. reported transient adverse events in stages 1 and 2, with the most common being injection-site reactions in the form of erythema with or without pain. Additionally, one patient with a history of deep vein thrombosis experienced a pulmonary embolism during the study. Other side effects included edema, myalgia, arthralgia, pruritus, diarrhea, stiffness, fatigue, fever, chills, eye swelling, decreased appetite, rash, abdominal pain, lightheadedness, night sweats, and dyspnea (28). L. Zahradova et al. documented no serious side effects during the study; 43.3% of vaccinated individuals showed local redness, and 44.8% experienced induration. One patient exhibited a mild increase in temperature, nearly 37.2 degrees, after each vaccine injection. Other toxicities were in grades 1 and 2 and probably unrelated to vaccination. Additionally, patients did not show signs of autoimmune diseases (29). Similarly, Willemijn Hobo et al. reported no severe toxicities during treatment, and temporary reactions in grades 1-2 were observed (30). Xia Zhao et al. discovered adverse events in the study; in the simple chemotherapy group, five out of 24 patients reported symptoms of nerve terminal injury, such as mild numbness in the limbs, and out of 26 patients in the case group, two reported transient chills and fever after blood cell transfusion (31). All patients in the study by R Oostvogels et al. demonstrated mild and temporary vaccination-site local induration. Additionally, other toxicity reactions in stages 2 and 3, including back and leg pain, self-limiting diarrhea, and alkaline phosphatase elevation, were observed in some patients. One patient with a history of mild chronic GvHD in the skin developed a slight escalation of GvHD in the oral mucosa with a transitory elevation in liver enzymes after joining the research (32). In the Sung-Hoon Jung et al. study, all patients experienced injection site reactions (including erythema and itching). Other adverse events included myalgia in 33.3%, fever in 16.6%, chills in 16.6%, pruritus in 8.3%, neutropenia in 8.3%, lymphocytopenia in 16.6%, and thrombocytopenia in 16.6% of patients (33). L.E. Franssen et al. reported that all patients experienced induration, erythema, and grade 2 fever following the second and third vaccinations. In addition, five adverse events were documented, four of which were potentially related to the vaccinations. These included a case of high fever and abdominal pain after the second vaccination, which resolved spontaneously, and three cases of pneumonia. Other observed adverse events in grade II or III included diarrhea, hypophosphatemia, flu-like symptoms, liver enzyme elevation, herpes simplex infection, and basal cell carcinoma of the skin (34). Discussion MM is the second most prevalent hematological neoplastic disorder, characterized by uncontrolled proliferation and formation of differentiated BM B-lymphocytes as the primary cause of advanced stages. Diagnostic clinical hallmarks included anemia, renal failure, and hypercalcemia associated with osteolytic bone lesions (1). M-protein containing specific antigenic determinants, known as the Id, is released by MM cells and is considered a tumor-associated antigen (TAA) (35). The age of diagnosis is usually between 65 and 70, with 37% of patients detected at a lower age. The majority of patients eventually expire due to progressive disease, with an average lifespan of 5-7 years (36, 37). Our major goal is to assess how effectively DC vaccine therapy applies to the treatment of MM. This research revealed a range of outcomes, such as a crucial rise, constant and slight decline in Id protein levels, and a reduction in plasma cells following immunization. In the investigations, complete molecular relief, partial improvement, and disease stabilization were observed during the treatment, in addition to a few drawbacks. Additionally, it was determined that the treatment boosted immunity as evidenced by increased IFN-γ, noteworthy humoral responses (IgM, IgG), generation of KLH antibody, and KLH-specific T-cell responses. DCs are antigen-presenting cells that represent a potential therapeutic approach in cancer therapy due to their proficiency and triggers of tumor-specific immune responses. Several DC-based approaches have been investigated in preclinical and clinical MM. Nevertheless, there were few long-lasting and robust responses in MM patients, which may have been caused by the immunosuppressive BM microenvironment and the source of mo-derived DCs (38). The review's findings shed light on the potential for therapy of DC vaccines, consistent with our earlier study on AML (11) and other cancer types, such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, melanoma, prostate cancer, and glioblastoma (9, 10, 15, 38, 39, 40, 41). Similarly, DC vaccination is a key in managing autoimmune diseases, degenerative disorders, and viral infections (42, 43). We aim to emphasize the therapeutic potential of DC vaccines in MM and suggest directions for further investigation by integrating data from various studies. Over time, several generations of DC vaccinations have been developed—the first, second, and emerging next generation. Various protocols and approaches are available for producing and manufacturing the first and second generations of DC-based immunizations (44). Generally, CD14+ monocytes isolated from PBMCs can differentiate into immature moDCs (first-generation DC vaccines) and mature moDCs (second-generation DC vaccines) in response to GM-CSF, IL-4, and TNF-α, IL-13, SCF, TGF-β1, FLT3L, or CD40L, respectively (45) (Figure 2). Studies indicate that DC vaccination therapy improves the health-related quality of life among MM patients. Despite these promising results, the clinical application of DC vaccines in MM is still challenging. Addressing disease heterogeneity, the complexity of the tumor microenvironment, and tailored vaccine formulations is crucial for consistent clinical outcomes. Additionally, standardized techniques for DC production, antigen loading, and maturation are essential (46, 47). Various strategies can be used to deal with these issues. It was reviewed that DCs can be loaded with Id-proteins, pulsed with MM-AA mRNA (MAGE3, BCMA, and Survivin), or fused with whole tumor MM cells as MM-specific TAA to evoke particular immune responses. We compare the efficient immunization of these three TAA, as previously discussed. Clinical trials show poor immunization of DC-based vaccines without boosters, which could not excite crucial responses (20, 22, 24, 48, 49). However, in the advanced stage of MM, DC-based therapy followed by three boosters has shown encouraging outcomes, such as adequate humoral and cellular responses and declined MM cell permeation. The disease stage may also account for the weak immunity (22). Moreover, studies found that subcutaneous and intranodal administration of mature DCs and TAA mRNA-loaded DC vaccinations resulted in specific responses in MM patients (23, 27). Despite the low level of induced immunity by Id-proteins, the TAA mRNA-loaded DC immunization induced a TAA-specific CTL response in MM patients and was well tolerated. Importantly, it has been demonstrated that loading DC with the entire MM-antigen is a method that allows for a polyvalent immune response and the chance to target unique neoantigens, thereby circumventing the drawbacks of employing a single TAA. Researchers also noted that DC vaccination efficacy in MM patients may be significantly increased by combination therapy with immunomodulatory drugs and checkpoint inhibitors that target the immunosuppressive milieu (50, 51, 52, 53, 54, 55) (Figure 2). Investigations clarified that although the DC-based strategies provide anti-tumor immunity, long-term clinical responses are limited. Notably, the included studies differ widely based on study design, patient age, illness stage, combination therapy, the significance of DC dosage for immune responses, and DC vaccine manufacturing and delivery procedures. These factors impacted the various post-DC vaccination complications. Consequently, the findings of the included trials must be clarified in light of their unique design, and further research must be conducted to determine the best DC vaccination plan for individuals with MM. Finally, this systematic review demonstrated that DC-based immunotherapy is affordable and effective for individuals with MM. Results support the safety with consistent responses and remission. However, more research in a broad population and with other combination therapies should be considered due to the necessity for long-term and protected immunity by this therapeutic method. With fewer side effects and more advanced perspectives, DC immunotherapy may become a vital treatment for many cancer types, such as MM. Declarations Conflict of Interest The authors declare that they have no conflict of interest. Author Contribution Behzad Baradaran and Jamal Motallebzadeh Khanmiri: Study conception and design, acquisition of data, analysis, and interpretation of data, writing the manuscript, and critical revision. Mohammad Khani-Eshratabadi, Mahdis Helmi Oskouei, Narjes Seddighi, Maryam Haddadi, Sina Esmaeili: Acquisition of data, analysis, and interpretation of data, writing the manuscript, and critical revision. Alireza Khanahmad, Mohsen Alizadeh, Amir Baghbanzadeh, Nazila Alizadeh: Writing the manuscript, review, and critical revision. References Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. American journal of hematology. 2020;95(5):548–67. Mahindra A, Laubach J, Raje N, Munshi N, Richardson PG, Anderson K. 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Recent advances in experimental dendritic cell vaccines for cancer. Frontiers in oncology. 2021;11:730824. Palma M, Adamson L, Hansson L, Kokhaei P, Rezvany R, Mellstedt H, et al. Development of a dendritic cell-based vaccine for chronic lymphocytic leukemia. Cancer Immunology, Immunotherapy. 2008;57:1705–10. Wang X, Guan F, Miller H, Byazrova MG, Candotti F, Benlagha K, et al. The role of dendritic cells in COVID-19 infection. Emerging Microbes & Infections. 2023;12(1):2195019. Brezovakova V, Valachova B, Hanes J, Novak M, Jadhav S. Dendritic cells as an alternate approach for treatment of neurodegenerative disorders. Cellular and Molecular Neurobiology. 2018;38:1207–14. Hopewell EL, Cox C. Manufacturing dendritic cells for immunotherapy: monocyte enrichment. Molecular Therapy-Methods & Clinical Development. 2020;16:155–60. Sabado RL, Balan S, Bhardwaj N. Dendritic cell-based immunotherapy. Cell research. 2017;27(1):74–95. Del Prete A, Salvi V, Soriani A, Laffranchi M, Sozio F, Bosisio D, et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cellular & molecular immunology. 2023;20(5):432–47. De Kouchkovsky I, Abdul-Hay M. Acute myeloid leukemia: a comprehensive review and 2016 update. Blood cancer journal. 2016;6(7):e441-e. Reichardt VL, Okada CY, Liso A, Benike CJ, Stockerl-Goldstein KE, Engleman EG, et al. Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma—a feasibility study. Blood, The Journal of the American Society of Hematology. 1999;93(7):2411–9. Wen Y-J, Ling M, Bailey-Wood R, Lim SH. Idiotypic protein-pulsed adherent peripheral blood mononuclear cell-derived dendritic cells prime immune system in multiple myeloma. Clinical cancer research: an official journal of the American Association for Cancer Research. 1998;4(4):957–62. Li R, Qian J, Zhang W, Fu W, Du J, Jiang H, et al. Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma. British journal of haematology. 2014;166(5):690–701. Hume DA, Mabbott N, Raza S, Freeman TC. Can DCs be distinguished from macrophages by molecular signatures? Nature immunology. 2013;14(3):187–9. Anderson LD, Cook DR, Yamamoto TN, Berger C, Maloney DG, Riddell SR. Identification of MAGE-C1 (CT-7) epitopes for T-cell therapy of multiple myeloma. Cancer Immunology, Immunotherapy. 2011;60:985–97. Ocadlikova D, Kryukov F, Mollová K, Kovarova L, Buresdova I, Matejkova E, et al. Generation of myeloma-specific T cells using dendritic cells loaded with MUC1-and hTERT-drived nonapeptides or myeloma cell apoptotic bodies. Neoplasma. 2010;57(5):455–64. Batchu RB, Moreno AM, Szmania SM, Bennett G, Spagnoli GC, Ponnazhagan S, et al. Protein transduction of dendritic cells for NY-ESO-1-based immunotherapy of myeloma. Cancer Research. 2005;65(21):10041–9. Lim SH, Wang Z, Chiriva-Internati M, Xue Y. Sperm protein 17 is a novel cancer-testis antigen in multiple myeloma. Blood, The Journal of the American Society of Hematology. 2001;97(5):1508–10. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5347479","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":375241175,"identity":"cdbab525-4120-482a-bcff-d6c7e67ba8a3","order_by":0,"name":"Jamal Motallebzadeh Khanmiri","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Jamal","middleName":"Motallebzadeh","lastName":"Khanmiri","suffix":""},{"id":375241176,"identity":"8921d42b-cafa-4811-a189-0d310a57aeb7","order_by":1,"name":"Mohammad Khani-Eshratabadi","email":"","orcid":"","institution":"Mashhad University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"","lastName":"Khani-Eshratabadi","suffix":""},{"id":375241177,"identity":"e2b06db0-d8c4-47c4-a3ed-2bb5f0767fb5","order_by":2,"name":"Mahdis Helmi Oskouei","email":"","orcid":"","institution":"Islamic Azad University","correspondingAuthor":false,"prefix":"","firstName":"Mahdis","middleName":"Helmi","lastName":"Oskouei","suffix":""},{"id":375241178,"identity":"aed40cab-2fda-4b8c-9f9a-410546af424b","order_by":3,"name":"Narjes Seddighi","email":"","orcid":"","institution":"Tabriz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Narjes","middleName":"","lastName":"Seddighi","suffix":""},{"id":375241179,"identity":"17e14379-042d-40a0-956b-2404262fbb71","order_by":4,"name":"Maryam Haddadi","email":"","orcid":"","institution":"Guilan University of Medical Science","correspondingAuthor":false,"prefix":"","firstName":"Maryam","middleName":"","lastName":"Haddadi","suffix":""},{"id":375241180,"identity":"37abb1ab-8c3b-4a81-a7e1-7281a02f7d5f","order_by":5,"name":"Sina Esmaeili","email":"","orcid":"","institution":"Shahed University","correspondingAuthor":false,"prefix":"","firstName":"Sina","middleName":"","lastName":"Esmaeili","suffix":""},{"id":375241181,"identity":"8b26fc85-1750-40ef-961e-25b944f2baf7","order_by":6,"name":"Alireza Khanahmad","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Alireza","middleName":"","lastName":"Khanahmad","suffix":""},{"id":375241182,"identity":"2200b73d-572b-49e3-b4d2-95c7dc46e4f2","order_by":7,"name":"Mohsen Alizadeh","email":"","orcid":"","institution":"Tabriz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Mohsen","middleName":"","lastName":"Alizadeh","suffix":""},{"id":375241183,"identity":"66bb7f53-5f5f-4ad6-8562-300405cbbf3e","order_by":8,"name":"Amir Baghbanzadeh","email":"","orcid":"","institution":"Tabriz University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Amir","middleName":"","lastName":"Baghbanzadeh","suffix":""},{"id":375241184,"identity":"6b0040ce-f378-46d6-9d25-dd3971c834e5","order_by":9,"name":"Behzad Baradaran","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYBACAxDBAyIkmA8wg4UOwMUJamFLbCZVC48hkhY8wJz97MMPb2ruyZtL93x/XPBnmxzfAeaHHxgK7uHUYtmTbiw551ix4c45Zzc2z+C5bSx5gM1YgsGgGLfDDqQxSPOwJTBuuJG7sZlH4nbihgMMZkDxBNxazj9j/s3zL8F+w42ch808BrfrNxxg/4Zfy400NmnetoREoBbGZp6E2wkGB3jw22I54xmb5dy+hOQNd44Zzp5x4LbhzMM8xRIJeLSY86cx33jzLcF2w+3mB58L/tyW5zvevvHDhz+4tWABoDRAkoZRMApGwSgYBRgAANGxWKlzQbd0AAAAAElFTkSuQmCC","orcid":"","institution":"Tabriz University of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Behzad","middleName":"","lastName":"Baradaran","suffix":""}],"badges":[],"createdAt":"2024-10-28 13:23:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5347479/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5347479/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":69462080,"identity":"f5caf3b5-9298-4621-9de8-3a39bdf0b0cc","added_by":"auto","created_at":"2024-11-20 15:00:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":148178,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flowchart illustrates the search results at each stage, including the primary and secondary screenings. It also provides a count of duplicate studies and those deemed irrelevant to the research topic.\u003c/p\u003e","description":"","filename":"floatimage167.png","url":"https://assets-eu.researchsquare.com/files/rs-5347479/v1/d44e1568847343106497726f.png"},{"id":69462081,"identity":"cd4a8ca7-8d62-447a-bb09-e167b8e68715","added_by":"auto","created_at":"2024-11-20 15:00:16","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":243487,"visible":true,"origin":"","legend":"\u003cp\u003eDendritic cell (DC) vaccine therapy used in clinical trials for multiple myeloma (MM) patients. Monocytes are collected via leukapheresis from the peripheral blood of the patient. The collected monocytes are then differentiated into dendritic cells in the laboratory. Upon maturation, these DCs are loaded with tumor-specific antigens to generate potent, activated DCs capable of stimulating a targeted immune response. The efficacy of DC vaccination is enhanced through combination therapies, which include adjuvants, immunomodulatory drugs, and checkpoint inhibitors, to bolster the tumor antigen-specific cytotoxic T lymphocyte (CTL) response. For sustained clinical benefits, optimizing the dosage, delivery method, and use of booster doses is crucial.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5347479/v1/83be275ea24e9f43ec8e49f1.jpeg"},{"id":69463761,"identity":"8797964e-0dfe-412c-a224-d89684b19420","added_by":"auto","created_at":"2024-11-20 15:16:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":974106,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5347479/v1/67d57dc7-aa31-4ddc-b3ab-a46864148ac2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Evaluating Dendritic Cell Vaccination Therapy for Multiple Myeloma: A Systematic Review","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMultiple Myeloma (MM) is a rare neoplastic disorder caused by the clonal proliferation of bone marrow plasma cells, disrupting normal hematopoiesis. MM is associated with various complications such as anemia, hypercalcemia, renal dysfunction, and osteolytic lesions. Despite the advent of novel therapeutic agents, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, the disease remains incurable, and frequent relapses or drug resistance is noted (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Therefore, investigating new therapeutic strategies seems to be crucial.\u003c/p\u003e \u003cp\u003eDendritic cell (DC) vaccines are novel and innovative strategies in cancer immunotherapy. DCs are potent antigen-presenting cells capable of initiating and modulating immune responses. They can capture, process, and present antigens to T cells, establishing a solid connection between innate and adaptive immunity (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). Regarding this ability, DC vaccines are ideal candidates for cancer prevention strategies. They can be modified ex vivo and subsequently utilized to stimulate strong anti-tumor responses by presenting tumor antigens.\u003c/p\u003e \u003cp\u003eDCs are categorized into several subsets based on their distinct functions and characteristics, including myeloid DCs (mDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). mDCs are particularly effective in inducing T-cell responses due to their high expression of co-stimulatory molecules and cytokines. Alternatively, pDCs can produce a significant amount of type I interferons in response to viral infections. moDCs, derived from monocytes in-vitro, are commonly used in DC vaccination studies due to their ease of generation and functional properties (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe process of DC vaccine generation consists of isolating monocytes from peripheral blood mononuclear cells (PBMCs) and subsequent differentiation into DCs in-vitro using cytokines such as GM-CSF and IL-4. Then, these DCs are fused with tumor cells or loaded with tumor antigens employing various techniques, such as pulsing with peptides, RNA, or tumor lysates. Antigen-loaded DCs are then matured using stimuli such as TNF-α, IL-1β, and poly I to enhance their immunogenicity before being administered back to the patient (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe efficacy of DC vaccines has been investigated in melanoma, prostate cancer, and glioblastoma. Sipuleucel-T, an autologous DC vaccine, has also been approved by the FDA to treat metastatic castration-resistant prostate cancer, highlighting the clinical potential of this approach (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). DC vaccines can induce immune responses against hematologic malignancies, improving clinical outcomes. Our recent systematic review on DC vaccination for acute myeloid leukemia (AML) highlighted its potential to induce remission and enhance immune responses, providing a strong rationale for exploring similar strategies in MM (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe immunosuppressive microenvironment of MM poses a significant challenge to effective immune-based therapies. Myeloma cells and the surrounding stromal cells release various cytokines and growth factors to inhibit immune system function and promote tumor growth. TGF-β, IL-10, and VEGF suppress DC maturation and function, leading to an ineffective anti-tumor response (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Therefore, strategies that can overcome this immunosuppression can ensure the efficacy of DC vaccination in MM.\u003c/p\u003e \u003cp\u003eRecent advancements in DC vaccine development have focused on enhancing the immunogenicity of DCs and overcoming the immunosuppressive tumor microenvironment. When compared to immature DCs, mature leukemia-derived DCs (DCleu) have been demonstrated to elicit more significant immune responses. Additionally, co-transfection of DCs with mRNAs encoding immunostimulatory ligands such as CD40L and OX40L has been explored to enhance their ability to activate T cells (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnother innovative strategy is using DC-derived small extracellular vesicles (DCsEVs). These vesicles can effectively present tumor antigens and deliver immunostimulatory signals to T cells, providing a cell-free alternative to traditional DC vaccines. DCsEVs have demonstrated a promising potential to induce anti-tumor immune responses (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurthermore, the combination of DC vaccine with other immunotherapeutic approaches such as checkpoint inhibitors and CAR-T cell therapy has been investigated to improve the overall outcome. Checkpoint inhibitors like anti-PD-1 and anti-CTLA-4 antibodies can amplify the anti-tumor response. When combined with DC vaccines, these agents synergistically enhance both activation and expansion of tumor-specific T cells (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite these advancements, several challenges remain in the clinical translation of DC vaccines for MM. The heterogeneity of the disease, the complexity of the tumor microenvironment, and the need for personalized vaccine formulations are some of the obstacles that need to be addressed. Additionally, standardized protocols for DC generation, antigen loading, and maturation are essential to ensure the consistency and reproducibility of clinical outcomes (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis systematic review evaluates the current evidence on the efficacy and safety of DC vaccination therapy for MM. By synthesizing data from various studies, we hope to provide insights into the potential of DC vaccines as a therapeutic strategy for MM and identify areas for future research. Our findings from the AML study underscore the importance of personalized approaches and the potential benefits of integrating DC vaccination with other immunotherapeutic modalities (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003eThis study systematically searched online databases including Web of Science (WOS), PubMed, Scopus, and ProQuest to identify the relevant articles published before April 16, 2024. The search strategy incorporated keywords such as \u0026ldquo;lymphoma,\u0026rdquo; \u0026ldquo;leukemia,\u0026rdquo; \u0026ldquo;myeloma,\u0026rdquo; \u0026ldquo;vaccination,\u0026rdquo; \u0026ldquo;immunization,\u0026rdquo; \u0026ldquo;immunotherapy,\u0026rdquo; and \u0026ldquo;dendritic cell,\u0026rdquo; targeting these terms in the title and abstract sections. Additionally, the reference lists and 'cited by' papers of the selected articles were examined to include any potentially relevant studies.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy selection\u003c/h3\u003e\n\u003cp\u003eDuplicates were removed. Then, to check for eligibility, two independent reviewers (N. Seddighi and M. Haddadi) screened the titles and abstracts of the retrieved articles. The same reviewers investigated full texts, where necessary. Discrepancies were resolved by discussion with a third researcher (J. M. Khanmiri).\u003c/p\u003e \u003cp\u003eWe considered all English publications that meet the inclusion criteria, including clinical trials (phases I, II, and III) involving diagnosed MM patients planning for vaccination and treatment with dendritic cells, with or without chemotherapy. Exclusion criteria were as follows: i) unclear results or presence of errors in methodology and/or analyses; ii) imprecise results resulting in low reproducibility; iii) unavailable full text unless the abstracts provided adequate data; iv) review articles; v) Inappropriate study designs such as case reports and letters to the editor; vi) Incorrect interventions; v) conference abstracts; and vi) non-English publications.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eData extractions and quality assessment\u003c/h3\u003e\n\u003cp\u003eData collection was performed independently by two researchers (J. M. Khanmiri and M. Khani-Eshratabadi). When discrepancies arose, a third researcher (B. Baradaran) provided additional evaluation. The extracted data from various studies comprised the first author, date of publication, study type, number of cases and demographics, intervention for test and control group, administration route/dosage, outcome, and possible side effects.\u003c/p\u003e \u003cp\u003eQuality of the studies was assessed using the Cochrane risk-of-bias tool based on five critical criteria, including selection bias, performance bias, detection bias, attrition bias, and reporting bias, rated as a 'low,' 'high,' or 'unclear' risk of bias. Discrepancies among the data collectors were resolved through discussion or consulting a third reviewer (B. Baradaran).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eR software version 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria; \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.R-project.org\u003c/span\u003e\u003cspan address=\"http://www.R-project.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was used for statistical analysis. The frequency of clinical and immunological responses associated with DC vaccination was evaluated using proportion analysis. A pooled prevalence analysis was performed utilizing the inverse variance method. Heterogeneity was assessed through Cochrane\u0026rsquo;s Q test and calculation of the I\u0026sup2; statistic. If the P-value from the heterogeneity test was below 0.05 or I\u0026sup2; exceeded 50%, the random-effects model was utilized; otherwise, the common-effects model was applied.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eInitially, we identified 2923 articles through a search in four databases; after removing duplicates, 2163 relevant articles were screened by title and abstract. 1930 articles were excluded and the full text of 233 papers were assessed. Finally, 15 relevant articles were included in this study\u0026nbsp;(20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34). Figure 1 illustrates the screening process.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 summarizes the comprehensive information on the 15 clinical trials included in the study. Four were phase I trials\u0026nbsp;(24, 28, 30, 33), three were phase I/II trials\u0026nbsp;(26, 32, 34), and one was a phase II trial\u0026nbsp;(29), and the remaining seven articles did not mention the trial phase\u0026nbsp;(20, 21, 22, 23, 25, 27, 31).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Results\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary and secondary outcomes of the included papers are shown in Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable1\u003c/strong\u003e. The overview of the included studies.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"964\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst author\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Reference)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrial\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePhase\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of Cases\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(Male/Female)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge in years\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntervention methods\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdministration Route/dose\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eG. Cull\u003c/p\u003e\n \u003cp\u003e(20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eadvanced refractory myeloma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e(2/0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eAutologous idiotype protein pulsed dendritic cells plus adjuvant with GM-CSF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eSQ\u003c/p\u003e\n \u003cp\u003ePatient 1 received 4 \u0026times; 106, 4 \u0026times; 106, 2\u0026middot;5 \u0026times; 107 and 2\u0026middot;5 \u0026times; 107 \u0026nbsp;DCs over four vaccinations; However, patient 2 received 2\u0026middot;5 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e, 2\u0026middot;5 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e, 4 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e and 4 \u0026times; 10\u003csup\u003e7\u003c/sup\u003e for the four vaccinations\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eSeah H. LIM\u003c/p\u003e\n \u003cp\u003e(21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eMM patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e(1/5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e67.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003ePulsed DC with the autologous Id and a control vaccine, KLH, and re infused i.v. back to the patients on 3 separate occasions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003cp\u003e47.5\u0026times;10\u003csup\u003e6\u003c/sup\u003e(Patient 1), 34.4\u0026times;10\u003csup\u003e6\u003c/sup\u003e(Patient 2), 38\u0026times;10\u003csup\u003e6\u003c/sup\u003e(Patient3, 3.5\u0026times;10\u003csup\u003e6\u003c/sup\u003e(Patient4), 40\u0026times;10\u003csup\u003e6\u003c/sup\u003e (Patient5) and 89\u0026times;10\u003csup\u003e6\u003c/sup\u003e(Patient6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eSANDRA TITZER\u003c/p\u003e\n \u003cp\u003e(22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eMM patients with stage III (but one I)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e(5/6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e62.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eCD34 stem cell-derived DCs pulsed with Id peptides\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eSC\u003c/p\u003e\n \u003cp\u003e1\u0026times;10\u003csup\u003e6\u003c/sup\u003e(patients 1, 2 and 10), 1\u0026times;10\u003csup\u003e7\u003c/sup\u003e(patients 3,4,5 and 8), 2.5\u0026times;10\u003csup\u003e6\u003c/sup\u003e (patient 9), 2\u0026times;10\u003csup\u003e7\u003c/sup\u003e(patients 7, 11 and 12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eQing Yi\u003c/p\u003e\n \u003cp\u003e(23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eStable partial remission of MM after high-dose chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e(3/2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eIdiotype protein-pulsed DCs vaccination\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eIV/SC\u003c/p\u003e\n \u003cp\u003e20 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eVolker l. Reichardt\u003c/p\u003e\n \u003cp\u003e(24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eMM patients responsive to HDT and PBSCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e(5/7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e52.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eautologous idiotype pulsed DC vaccines followed by Id/keyhole limpet hemocyanin (Id/KLH) boosters immunizations co-injected with GM-CSF\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003cp\u003e4.5 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eMaurizio Bendandi\u003c/p\u003e\n \u003cp\u003e(25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eRelapsed/progressed MM after decreased intensity conditioning (RIC) alloSCT and failure to rescue therapy with donor lymphocyte infusion or chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003cp\u003e(2/2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eId-pulsed alloDC oupled with the traditional, soluble protein-based Id vaccine formulation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003cp\u003e5\u0026ndash;10 \u0026times; 10\u003csup\u003e8\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eAntonio Curti\u003c/p\u003e\n \u003cp\u003e(26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eI/II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eMM patients with progression and stable disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(11/4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e57.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eloaded CD14+-derived DCs with the autologous Id as whole protein or Id-derived class I-restricted peptides and KLH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eSC/IV\u003c/p\u003e\n \u003cp\u003e50 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eQing Yi\u003c/p\u003e\n \u003cp\u003e(27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003epatients with smouldering or stable MM without treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(5/4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e57.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eidiotype (Id) protein-pulsed DC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eIntranodal injection\u003c/p\u003e\n \u003cp\u003e5\u0026times;10\u003csup\u003e5\u003c/sup\u003e cells\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eJacalyn Rosenblatt\u003c/p\u003e\n \u003cp\u003e(28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003ePatients with active disease who had received \u0026ge;1 prior treatment, and stage I myeloma patients under observation without needing therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e(12/\u003cspan dir=\"RTL\"\u003e6\u003c/span\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eDCs\u0026nbsp;(generated from adherent mononuclear cells)\u0026nbsp;loaded with Myeloma Cells\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eSQ\u003c/p\u003e\n \u003cp\u003e\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e1 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e, 2\u0026times;10\u003csup\u003e6\u003c/sup\u003e, 4 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e \u0026times; 3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eL. ZAHRADOVA\u003c/p\u003e\n \u003cp\u003e(29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003erelapsed MM patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003cp\u003e(4/7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e63.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eDCs loaded with autologous Id-protein\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003cp\u003e0.5x10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eWillemijn Hobo\u003c/p\u003e\n \u003cp\u003e(30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003etreatment for MRD in MM after SCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e(11/1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e60.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eMature moDCs were pulsed with KLH and electroporated with MAGE3, Survivin or B-cell maturation antigen mRNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eIV: 5\u0026ndash;22 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eID: 4\u0026ndash;11 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eXia Zhao\u003c/p\u003e\n \u003cp\u003e(31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eMM patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e50*\u003c/p\u003e\n \u003cp\u003e(14/12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e57.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eTwo groups of patients, including 24 on simple chemotherapy and 26 on chemotherapy plus DC/CIK immunotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003e2.0-5.0\u0026times;10\u003csup\u003e9\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eR Oostvogels\u003c/p\u003e\n \u003cp\u003e(32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eI/II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eMM patients who failed to respond to a first DLI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003cp\u003e(10/5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e58.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003emoDCs (autologous) isolated from autologous leukapheresis products collected and cryopreserved before allo-SCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eIV/ID\u003c/p\u003e\n \u003cp\u003e90\u0026times;10\u003csup\u003e6\u0026nbsp;\u003c/sup\u003e(administered in one to three courses of maximally 30 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e DCs per infusion)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eSung-Hoon Jung\u003c/p\u003e\n \u003cp\u003e(33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003eRelapsed/refractory MM patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003cp\u003e(5/7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e62.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003eDCs loaded with autologous myeloma cells irradiated with ultraviolet B (VAX-DC/MM)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003cp\u003e5 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e or 10 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.0332%;\"\u003e\n \u003cp\u003eLE Franssen\u003c/p\u003e\n \u003cp\u003e(34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.0166%;\"\u003e\n \u003cp\u003eI/II\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17.2199%;\"\u003e\n \u003cp\u003ePersistent or relapsed MM following allo SCT and a previous DLI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.9959%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003cp\u003e(6/3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6.74274%;\"\u003e\n \u003cp\u003e55.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.6639%;\"\u003e\n \u003cp\u003edonor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 31.3278%;\"\u003e\n \u003cp\u003eIV/ID\u003c/p\u003e\n \u003cp\u003e45\u0026ndash;90 \u0026times; 10\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* 26:\u0026nbsp;chemotherapy plus DC/CIK immunotherapy\u003c/p\u003e\n\u003cp\u003eAbbreviations: GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor, SC: Subcutaneous, MM: Multiple Myeloma, DC: Dendritic Cells, Id: Idiotype, KLH: Keyhole Limpet Hemocyanin, IV: Intravenous, ID: Intradermal, DLI: Donor Lymphocyte Infusion, VAX-DC/MM: Vaccine Dendritic Cells for Multiple Myeloma, CIK: Cytokine-Induced Killer, moDCs: Monocyte-Derived Dendritic Cells, High-dose chemotherapy: HDT, Peripheral blood stem cell transplantation: PBSCT\u0026nbsp;\u003cbr\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e. Primary and secondary outcomes of included studies.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"945\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFirst Author (year)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of Cases\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eResponse (n)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdverse events (n)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eG. Cull\u003c/p\u003e\n \u003cp\u003e(1999)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: KLH-specific T-cell proliferation: (2),\u003c/p\u003e\n \u003cp\u003egamma-interferon production: (1)\u003c/p\u003e\n \u003cp\u003ehumoral response to KLH: anti-KLH IgM and IgG antibodies (2)\u003c/p\u003e\n \u003cp\u003eCTL assay: No idiotype-specific killing of antigen-loaded DC by effector cells subject\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eMild flu-like symptoms and fever (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eSeah H. LIM\u003c/p\u003e\n \u003cp\u003e(1999)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: PBMC proliferative responses to Id (5),\u003c/p\u003e\n \u003cp\u003ePoduction of IFN-g\u0026nbsp;(2),\u003c/p\u003e\n \u003cp\u003ecytotoxic T-cell precursor frequencies for Id-pulsed autologous targets (3)\u003c/p\u003e\n \u003cp\u003eanti-Id IgM (3), anti-Id IgG (4);\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eClinical responses: SD observed in all patients during the vaccination period,\u003c/p\u003e\n \u003cp\u003e(1) patient showed a consistent 25% reduction in serum Id levels\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eSANDRA TITZER\u003c/p\u003e\n \u003cp\u003e(1999)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses:\u0026nbsp;(3) out of 10 analyzed patients showed increased anti-idiotype antibody serum titres,\u0026nbsp;The idiotype-specific T-cell response, was increased in (4) out of 10 analyzed patients;\u003c/p\u003e\n \u003cp\u003eClinical responses: SD (1), PD (10)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eQing Yi\u003c/p\u003e\n \u003cp\u003e(2001)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: anti-idiotypic B-cell responses (4), Idiotypespecific T-cell responses (4)\u003c/p\u003e\n \u003cp\u003eproliferation assays (2)\u003c/p\u003e\n \u003cp\u003epositive IFN-g\u0026nbsp;response (3);\u003c/p\u003e\n \u003cp\u003eClinical Response: defined as a 50% reduction in serum M-component, in (1) patient who received the vaccination. This reduction persisted for 6 months, SD for 6 months was observed in (3) other patients\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eVolker l. Reichardt (2003)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: (2) patients developed Id-specific T-cell proliferative responses, (1) patient showed Id-specific cytotoxic T lymphocyte (CTL) response, (1) patient had Id-specific TH1 cytokine secretion, Delayed KLH-specific antibody responses (7)\u003c/p\u003e\n \u003cp\u003eClinical responses: PR (9), SD (1), PD(2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eMaurizio Bendandi (2006)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: Humoral response (4), Proliferative response (4)\u003c/p\u003e\n \u003cp\u003eClinical responses: SD (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eAntonio Curti (2007)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: Id-specific T-cell proliferative response (8)\u003c/p\u003e\n \u003cp\u003eId specific IFN-g\u0026nbsp;secreting T cell (8)\u003c/p\u003e\n \u003cp\u003eId-positive DTH test\u0026nbsp;(4)\u003c/p\u003e\n \u003cp\u003eKLH-specific antibody response (15)\u003c/p\u003e\n \u003cp\u003eKLH-specific T-cell proliferative response (10)\u003c/p\u003e\n \u003cp\u003eKLH specific IFN-g\u0026nbsp;secreting T cell (9)\u003c/p\u003e\n \u003cp\u003eKLH-positive DTH test (10)\u003c/p\u003e\n \u003cp\u003eClinical responses: PR (1), SD (7), PD (7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eQing Yi\u003c/p\u003e\n \u003cp\u003e(2010)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: Interleukin-4 response (2)\u003c/p\u003e\n \u003cp\u003eskin delayed-type hypersensitivity reaction (7)\u003c/p\u003e\n \u003cp\u003eId-specific cytotoxic T-cell responses (5)\u003c/p\u003e\n \u003cp\u003eId-specific B cells responses (9)\u003c/p\u003e\n \u003cp\u003eClinical response: SD(6), PD(3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eJacalyn Rosenblatt\u003c/p\u003e\n \u003cp\u003e(2010)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: Increase in the percentage of CD4 or CD81 tumor-reactive T cells (11),\u003c/p\u003e\n \u003cp\u003eAntibody response against BRCA1-associated protein (1);\u003c/p\u003e\n \u003cp\u003eClinical response: SD (11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eWithout evidence of dose-limiting toxicity.\u003c/p\u003e\n \u003cp\u003eOne patient who had a previous history of deep vein thrombosis (DVT) developed DVT and pulmonary embolus while on study.\u003c/p\u003e\n \u003cp\u003einjection-site reactions (13)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eL. ZAHRADOVA\u003c/p\u003e\n \u003cp\u003e(2012)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eImmune Responses:\u003c/span\u003e\u003cspan dir=\"LTR\"\u003e\u0026nbsp;\u003c/span\u003e\u003cspan dir=\"LTR\"\u003eELISpot: (3), DTH Skin Test: Positive in ( 8)\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eClinical response: SD (10), PD (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eNo serious toxicities, Fever (1),\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eWillemijn Hobo\u003c/p\u003e\n \u003cp\u003e(2013)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmune responses: KLH-specific T-cell responses (12), induration and erythema at the DTH sites (6), KLH specific IFN-g\u0026nbsp;production (5)\u003c/p\u003e\n \u003cp\u003eClinical response: SD (5), PD (5),\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003efever, chills, malaise and muscular pain (10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eXia Zhao\u003c/p\u003e\n \u003cp\u003e(2015)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmunological responses: CD3+CD8+ ratio decreased and CD3+CD4+/CD3+CD8+ ratio increased significantly in the combined therapy group compared to the simple chemotherapy group (P\u0026lt;0.05), Peripheral blood CD4+CD25+/CD4+ and CD4+CD25+FoxP3+/CD4+CD25+ ratios were significantly lower in the combined therapy group (P\u0026lt;0.05), Positive rate of NKG2D was significantly higher in the combined therapy group (P\u0026lt;0.05);\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eClinical response: PS scores, percentage of MM cells, \u0026beta;2-MG, serum M protein, 24-hour urinary light chain content, and Scr improved significantly in the combined therapy group compared to the simple chemotherapy group (P\u0026lt;0.05),\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003etransient chills and fever (2), nerve terminal injury (5),\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eR Oostvogels\u003c/p\u003e\n \u003cp\u003e(2016)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmunological response: Objective T-cell responses against KLH (15),\u003c/p\u003e\n \u003cp dir=\"RTL\"\u003e\u003cspan dir=\"LTR\"\u003eAnti-host T-cell responses in 6/10 evaluable patients,\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003emHag peptide-loaded DCs induced an objective T-cell response in 1/4 patients;\u003c/p\u003e\n \u003cp\u003eClinical response: SD (7), PD (7), PR (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eInjection site (12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eSung-Hoon Jung\u003c/p\u003e\n \u003cp\u003e(2017)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmunological response: \u0026nbsp; \u0026nbsp; in 7 out of 9 patients (77.8%) receiving 10 \u0026times; 10^6 cells,\u003c/p\u003e\n \u003cp\u003eClinical response: SD (5), PD (3), MR (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003einjection site and infusion-related reactions\u003c/p\u003e\n \u003cp\u003emyalgia (4), fever (2), and chills (2)\u003c/p\u003e\n \u003cp\u003elymphocytopenia and thrombocytopenia (2)\u003c/p\u003e\n \u003cp\u003esubclinical hypothyroidism (2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12.2751%;\"\u003e\n \u003cp\u003eLE Franssen\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e(2017)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.3439%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 48.3598%;\"\u003e\n \u003cp\u003eImmunological response: \u0026nbsp; \u0026nbsp; anti-KLH responses (9), induction\u003c/p\u003e\n \u003cp\u003eof mHag-specific CD8+ T cells (5),\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eClinical response: SD (5), PD (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 24.0212%;\"\u003e\n \u003cp\u003eintradermal injection site (9), severe adverse events (5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: SD: Stable Disease, PD: Progressive Disease, PR: Partial Response, CR: Complete Response, MR: Minimal Response, KLH: Keyhole Limpet Hemocyanin, IgM: Immunoglobulin M, IgG: Immunoglobulin G, CTL: Cytotoxic T Lymphocyte, PBMC: Peripheral Blood Mononuclear Cell\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe assessed and investigated all clinical responses from previous studies on DC therapy in multiple myeloma (MM). Disease stabilization was reported in 69 out of 139 cases across 13 studies (pooled prevalence [95% CI] = 50.31 [41.01%; 59.58%], I2= 42.6%)\u0026nbsp;(21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 34). Additionally, progressive disease (PD) was developed in 41 out of 112 cases across ten studies (pooled prevalence [95% CI] = 36.84% [27.47%; 47.33%], I2= 44.2%)\u0026nbsp;(21, 22, 24, 26, 27, 29, 30, 32, 33, 34).\u003c/p\u003e\n\u003cp\u003eG. CULL et al. studied two patients with MM treated by autologous idiotype protein-pulsed dendritic cells plus adjuvant GM-CSF. The results showed that in one patient, the paraprotein level increased slowly during the vaccination but increased sharply one month after the last vaccination, requiring treatment with dexamethasone. In another patient, the paraprotein level remained steady during treatment and follow-up\u0026nbsp;(20).\u003c/p\u003e\n\u003cp\u003eSeah H. LIM et al. reported six patients who had received dendritic cell vaccination with idiotypic protein. One patient died after the second dose due to chest pain and could not be evaluated for clinical response. Among the remaining patients, one showed a minor decrease in idiotypic (Id) protein levels, two had steady serum Id levels during follow-up, and disease progression was observed in two patients after treatment. Additionally, the disease did not progress after vaccination in five patients\u0026nbsp;(21).\u003c/p\u003e\n\u003cp\u003eA clinical trial by SANDRA TITZER et al. evaluated ten MM patients who were treated with idiotype-pulsed dendritic cells. The results showed a reduction in plasma cells after vaccination in one, while the remaining cases experienced progressive disease\u0026nbsp;(22).\u003c/p\u003e\n\u003cp\u003eQing Yi et al. reported no side effects during the vaccination of five patients, followed for one year. Two patients showed increasing M-protein levels by week 26, while one patient exhibited a reduction in M-protein from 9 g/dL at week 2 to 4 g/dL at week 4, remaining stable thereafter. Other patients showed no significant changes\u0026nbsp;(23).\u003c/p\u003e\n\u003cp\u003eVolker L. Reichardt et al. observed that among 12 patients who received autologous idiotype-pulsed DC vaccines followed by Id/keyhole limpet hemocyanin (Id/KLH) booster immunizations co-injected with GM-CSF, one patient was excluded during the vaccination phase due to disease progression. Another patient completed the vaccination protocol phase but progressed. Two patients achieved partial improvement during follow-up, while eight patients experienced disease progression, four of whom died, and the remaining four were alive with salvage therapy\u0026nbsp;(24). Similarly, in another trial by Maurizio Bendandi et al., two patients died during the protocol, and two patients withdrew from the study, opting for other treatments\u0026nbsp;(25).\u003c/p\u003e\n\u003cp\u003eAntonio Curti et al. enrolled 15 patients for the trial. Seven achieved stable responses, one achieved partial response, and the remaining seven progressed\u0026nbsp;(26). Another study by Qing Yi et al. reported that none of the nine patients showed significant side effects during vaccination. However, during the one-year follow-up, one patient showed a reduction in M-protein, five illustrated no significant changes, and three showed progression\u0026nbsp;(27). Jacalyn Rosenblatt et al. conducted a study on dendritic cell/tumor fusion cell vaccination in 16 MM patients, among whom 13 presented injection-site reactions, and stable disease during several months of follow-up was reported in 11\u0026nbsp;(28).\u003c/p\u003e\n\u003cp\u003eIn a trial by ZAHRADOVA et al., involving Id-protein-loaded dendritic cell vaccines in MM patients, stable disease was noted in 73% of patients, and the others showed disease progression during one-year follow-up. Patients did not receive specific treatment during the protocol phase\u0026nbsp;(29).\u003c/p\u003e\n\u003cp\u003eAdditionally, Willemijn Hobo et al., studied MM patients who received intensive chemotherapy and autologous SCT. These patients received DC vaccinations pulsed with MAGE3, Survivin, and B-cell maturation antigen mRNA. At the last follow-up, ten out of twelve patients were still alive. Of these, five had stable disease, while the other five had progressive disease, with four receiving additional treatment. Several patients were diagnosed with secondary cancers (two with acute myeloid leukemia, one with prostate cancer, and one with plasma cell leukemia)\u0026nbsp;(30). Xia Zhao et al. investigated MM patients treated with DC/CIK combined with chemotherapy. Two out of 26 patients showed transient chills and fever a few hours after combined treatment, and none of the patients died during the study\u0026nbsp;(31).\u003c/p\u003e\n\u003cp\u003eIn the study by R Oostvogels et al., patients underwent DC vaccination combined with donor lymphocyte infusion. Out of 15 patients, 11 were observed for clinical response; five showed a good response (two had objective clinical benefits, and three had possible clinical benefits), while six patients experienced disease progression\u0026nbsp;(32). Sung-Hoon Jung et al. conducted a clinical study on MM patients who received autologous dendritic cell therapy. The patients were followed for approximately 16 months, during which eight showed disease progression, five of whom received salvage therapy\u0026nbsp;(33).\u003c/p\u003e\n\u003cp\u003eLE Franssen et al. evaluated the efficacy and safety of dendritic cell vaccination in MM patients who received donor lymphocyte infusion (DLI). Five patients maintained stable disease in a median of seven months after vaccination, one achieved complete molecular remission, and three showed ongoing disease progression after vaccination (34).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmune response\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe immune responses are shown in Table 2. The prevalence of six treatment-associated was calculated. The induction of KLH antibodies was revealed in 33 out of 38 patients across four studies (pooled prevalence [95% CI] = 84.98% [53.80; 88.54], I2= 50.5%)\u0026nbsp;(20, 24, 26, 34). In the G. CULL study, these strong humoral responses were maximal for IgM at week 5 and for IgG at week 7\u0026nbsp;(20). Another study conducted by Volker L. Reichardt et al. detected KLH antibodies in all patients, with these antibodies being detected in three patients following the second immunization and in four patients after the third immunization\u0026nbsp;(24). Additionally, Antonio Curti et al. observed KLH-specific antibody responses; they detected KLH antibodies following the first vaccination and reported maximum concentration after the third vaccination\u0026nbsp;(26).\u003c/p\u003e\n\u003cp\u003eFurthermore, the induction of KLH T cells was reported in 39 out of 44 cases across four studies (pooled prevalence [95% CI] = 78.80% [60.12%; 90.17%]; I2= 42.8%)\u0026nbsp;(20, 26, 30, 32). G.CULL et al. showed the proliferation of KLH-specific T-cells after the first vaccination in one patient and after the first vaccine administration in the other one. This response was dose-dependent during vaccination. They could detect the immune response at the latest follow-up assessment (20\u0026ndash;26 weeks)\u0026nbsp;(20). In a study by Antonio Curti et al., the concentration of circulating KLH-specific IFN-\u0026gamma; secreting T cells was significantly increased following the third vaccination course in almost half of patients\u0026nbsp;(26). Willemijn Hobo et al. evaluated KLH-specific T-cell responses after the first vaccination; overall, four patients had a moderate response, four had a good response, and four illustrated an excellent T-cell response to KLH. Some patients showed increased responses after subsequent vaccinations, but most showed no change or a decrease\u0026nbsp;(30).\u003c/p\u003e\n\u003cp\u003eAdditionally, IFN-\u0026gamma; responses were investigated in 19 out of 38 patients across four studies (pooled prevalence [95% CI] = 50.11% [34.37%; 65.84%]; I2= 0.0%) (21, 23, 26, 30). In the study by Seah H. LIM et al., IFN-\u0026gamma; production in the supernatant culture was detectable in two out of six patients after the third vaccination (21). Qing Yi et al. also observed that DC vaccination induced an IFN-\u0026gamma; response in four patients, with one showing an enhanced response (23). Antonio Curti et al. demonstrated that the concentration of KLH-specific IFN-\u0026gamma; secreting T cells in circulation increased in 60% of patients (9/15) after the third vaccination (26). In the Willemijn Hobo et al. study, five out of six patients produced KLH-specific IFN-\u0026gamma; (30). The Id T cell response in six studies revealed 26 out of 58 cases (pooled prevalence [95% CI] = 45.99% [32.83; 59.73%]; I2 = 23.2) (22, 23, 24, 26, 27). Table 2 presents the other results of immune responses collected from the included papers.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdverse events\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe prevalence of delayed-onset hypersensitive reaction in 31 out of 47 cases across four studies was assessed (pooled prevalence [95% CI] = 65.37% [50.45%; 77.78%], I2= 0.0%)\u0026nbsp;(26, 27, 29, 30). The adverse events are summarized in Table 2.\u003c/p\u003e\n\u003cp\u003eSandra Titzer et al. identified five patients with new osteolytic lesions about two months after vaccination. It should be noted that six patients had osteolytic lesions before vaccination therapy\u0026nbsp;(22). Qing Yi et al. reported that one out of five patients showed an erythema without induration after the second vaccination\u0026nbsp;(23). Volker L. Reichardt et al. reported that with an increase in booster injections, all patients exhibited moderate to severe local reactions such as erythema, local soreness, and swelling\u0026nbsp;(24). In the Maurizio Bendandi et al. study, two patients showed side effects: one experienced an elevated number of osteolytic bone lesions and progressive renal failure, and the other exhibited hypercalcemia and cranial plasmacytoma\u0026nbsp;(25). The results of Jacalyn Rosenblatt et al. reported transient adverse events in stages 1 and 2, with the most common being injection-site reactions in the form of erythema with or without pain. Additionally, one patient with a history of deep vein thrombosis experienced a pulmonary embolism during the study. Other side effects included edema, myalgia, arthralgia, pruritus, diarrhea, stiffness, fatigue, fever, chills, eye swelling, decreased appetite, rash, abdominal pain, lightheadedness, night sweats, and dyspnea\u0026nbsp;(28).\u003c/p\u003e\n\u003cp\u003eL. Zahradova et al. documented no serious side effects during the study; 43.3% of vaccinated individuals showed local redness, and 44.8% experienced induration. One patient exhibited a mild increase in temperature, nearly 37.2 degrees, after each vaccine injection. Other toxicities were in grades 1 and 2 and probably unrelated to vaccination. Additionally, patients did not show signs of autoimmune diseases\u0026nbsp;(29). Similarly, Willemijn Hobo et al. reported no severe toxicities during treatment, and temporary reactions in grades 1-2 were observed\u0026nbsp;(30). Xia Zhao et al. discovered adverse events in the study; in the simple chemotherapy group, five out of 24 patients reported symptoms of nerve terminal injury, such as mild numbness in the limbs, and out of 26 patients in the case group, two reported transient chills and fever after blood cell transfusion\u0026nbsp;(31).\u003c/p\u003e\n\u003cp\u003eAll patients in the study by R Oostvogels et al. demonstrated mild and temporary vaccination-site local induration. Additionally, other toxicity reactions in stages 2 and 3, including back and leg pain, self-limiting diarrhea, and alkaline phosphatase elevation, were observed in some patients. One patient with a history of mild chronic GvHD in the skin developed a slight escalation of GvHD in the oral mucosa with a transitory elevation in liver enzymes after joining the research (32). In the Sung-Hoon Jung et al. study, all patients experienced injection site reactions (including erythema and itching). Other adverse events included myalgia in 33.3%, fever in 16.6%, chills in 16.6%, pruritus in 8.3%, neutropenia in 8.3%, lymphocytopenia in 16.6%, and thrombocytopenia in 16.6% of patients (33). L.E. Franssen et al. reported that all patients experienced induration, erythema, and grade 2 fever following the second and third vaccinations. In addition, five adverse events were documented, four of which were potentially related to the vaccinations. These included a case of high fever and abdominal pain after the second vaccination, which resolved spontaneously, and three cases of pneumonia. Other observed adverse events in grade II or III included diarrhea, hypophosphatemia, flu-like symptoms, liver enzyme elevation, herpes simplex infection, and basal cell carcinoma of the skin (34).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMM is the second most prevalent hematological neoplastic disorder, characterized by uncontrolled proliferation and formation of differentiated BM B-lymphocytes as the primary cause of advanced stages. Diagnostic clinical hallmarks included anemia, renal failure, and hypercalcemia associated with osteolytic bone lesions\u0026nbsp;(1). M-protein containing specific antigenic determinants, known as the Id, is released by MM cells and is considered a tumor-associated antigen (TAA)\u0026nbsp;(35). The age of diagnosis is usually between 65 and 70, with 37% of patients detected at a lower age. The majority of patients eventually expire due to progressive disease, with an average lifespan of 5-7 years\u0026nbsp;(36, 37). Our major goal is to assess how effectively DC vaccine therapy applies to the treatment of MM. This research revealed a range of outcomes, such as a crucial rise, constant and slight decline in Id protein levels, and a reduction in plasma cells following immunization. In the investigations, complete molecular relief, partial improvement, and disease stabilization were observed during the treatment, in addition to a few drawbacks. Additionally, it was determined that the treatment boosted immunity as evidenced by increased IFN-\u0026gamma;, noteworthy humoral responses (IgM, IgG), generation of KLH antibody, and KLH-specific T-cell responses.\u003c/p\u003e\n\u003cp\u003eDCs are antigen-presenting cells that represent a potential therapeutic approach in cancer therapy due to their proficiency and triggers of tumor-specific immune responses. Several DC-based approaches have been investigated in preclinical and clinical MM. Nevertheless, there were few long-lasting and robust responses in MM patients, which may have been caused by the immunosuppressive BM microenvironment and the source of mo-derived DCs\u0026nbsp;(38).\u003c/p\u003e\n\u003cp\u003eThe review\u0026apos;s findings shed light on the potential for therapy of DC vaccines, consistent with our earlier study on AML\u0026nbsp;(11)\u0026nbsp;and other cancer types, such as non-Hodgkin lymphoma, chronic lymphocytic leukemia, melanoma, prostate cancer, and glioblastoma\u0026nbsp;(9, 10, 15, 38, 39, 40, 41). Similarly, DC vaccination is a key in managing autoimmune diseases, degenerative disorders, and viral infections\u0026nbsp;(42, 43). We aim to emphasize the therapeutic potential of DC vaccines in MM and suggest directions for further investigation by integrating data from various studies.\u003c/p\u003e\n\u003cp\u003eOver time, several generations of DC vaccinations have been developed\u0026mdash;the first, second, and emerging next generation. Various protocols and approaches are available for producing and manufacturing the first and second generations of DC-based immunizations\u0026nbsp;(44). Generally, CD14+ monocytes isolated from PBMCs can differentiate into immature moDCs (first-generation DC vaccines) and mature moDCs (second-generation DC vaccines) in response to GM-CSF, IL-4, and TNF-\u0026alpha;, IL-13, SCF, TGF-\u0026beta;1, FLT3L, or CD40L, respectively\u0026nbsp;(45)\u0026nbsp;(Figure 2). Studies indicate that DC vaccination therapy improves the health-related quality of life among MM patients. Despite these promising results, the clinical application of DC vaccines in MM is still challenging. Addressing disease heterogeneity, the complexity of the tumor microenvironment, and tailored vaccine formulations is crucial for consistent clinical outcomes. Additionally, standardized techniques for DC production, antigen loading, and maturation are essential\u0026nbsp;(46, 47).\u003c/p\u003e\n\u003cp\u003eVarious strategies can be used to deal with these issues. It was reviewed that DCs can be loaded with Id-proteins, pulsed with MM-AA mRNA (MAGE3, BCMA, and Survivin), or fused with whole tumor MM cells as MM-specific TAA to evoke particular immune responses. We compare the efficient immunization of these three TAA, as previously discussed. Clinical trials show poor immunization of DC-based vaccines without boosters, which could not excite crucial responses\u0026nbsp;(20, 22, 24, 48, 49). However, in the advanced stage of MM, DC-based therapy followed by three boosters has shown encouraging outcomes, such as adequate humoral and cellular responses and declined MM cell permeation. The disease stage may also account for the weak immunity\u0026nbsp;(22).\u003c/p\u003e\n\u003cp\u003eMoreover, studies found that subcutaneous and intranodal administration of mature DCs and TAA mRNA-loaded DC vaccinations resulted in specific responses in MM patients\u0026nbsp;(23, 27). Despite the low level of induced immunity by Id-proteins, the TAA mRNA-loaded DC immunization induced a TAA-specific CTL response in MM patients and was well tolerated. Importantly, it has been demonstrated that loading DC with the entire MM-antigen is a method that allows for a polyvalent immune response and the chance to target unique neoantigens, thereby circumventing the drawbacks of employing a single TAA. Researchers also noted that DC vaccination efficacy in MM patients may be significantly increased by combination therapy with immunomodulatory drugs and checkpoint inhibitors that target the immunosuppressive milieu\u0026nbsp;(50, 51, 52, 53, 54, 55)\u0026nbsp;(Figure 2).\u003c/p\u003e\n\u003cp\u003eInvestigations clarified that although the DC-based strategies provide anti-tumor immunity, long-term clinical responses are limited. Notably, the included studies differ widely based on study design, patient age, illness stage, combination therapy, the significance of DC dosage for immune responses, and DC vaccine manufacturing and delivery procedures. These factors impacted the various post-DC vaccination complications. Consequently, the findings of the included trials must be clarified in light of their unique design, and further research must be conducted to determine the best DC vaccination plan for individuals with MM.\u003c/p\u003e\n\u003cp\u003eFinally, this systematic review demonstrated that DC-based immunotherapy is affordable and effective for individuals with MM. Results support the safety with consistent responses and remission. However, more research in a broad population and with other combination therapies should be considered due to the necessity for long-term and protected immunity by this therapeutic method. With fewer side effects and more advanced perspectives, DC immunotherapy may become a vital treatment for many cancer types, such as MM.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eBehzad Baradaran and Jamal Motallebzadeh Khanmiri: Study conception and design, acquisition of data, analysis, and interpretation of data, writing the manuscript, and critical revision. Mohammad Khani-Eshratabadi, Mahdis Helmi Oskouei, Narjes Seddighi, Maryam Haddadi, Sina Esmaeili: Acquisition of data, analysis, and interpretation of data, writing the manuscript, and critical revision. Alireza Khanahmad, Mohsen Alizadeh, Amir Baghbanzadeh, Nazila Alizadeh: Writing the manuscript, review, and critical revision.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. American journal of hematology. 2020;95(5):548\u0026ndash;67.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahindra A, Laubach J, Raje N, Munshi N, Richardson PG, Anderson K. Latest advances and current challenges in the treatment of multiple myeloma. Nature reviews Clinical oncology. 2012;9(3):135\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBanchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature. 1998;392(6673):245\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalucka K, Banchereau J. Cancer immunotherapy via dendritic cells. 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Blood, The Journal of the American Society of Hematology. 2001;97(5):1508\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Multiple Myeloma, Dendritic Cells, Immunotherapy, Vaccination, Neoplasm Vaccines","lastPublishedDoi":"10.21203/rs.3.rs-5347479/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5347479/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eMultiple myeloma (MM) presents significant challenges in treatment, necessitating the exploration of innovative therapeutic strategies. Standard treatments, such as chemotherapy and stem cell transplantation, have limitations, particularly regarding adverse effects and relapse rates. This systematic review aims to evaluate the potential of dendritic cell (DC) vaccination therapy as a promising approach in MM management, contributing to the expanding range of therapeutic options for this complex hematologic malignancy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA systematic search was conducted across PubMed, Scopus, ProQuest, and Web of Science databases to identify relevant studies. Strict inclusion criteria were applied to select studies within the review\u0026rsquo;s scope, and a rigorous quality assessment was performed using Cochrane risk-of-bias tools. Evaluation parameters included remission rates, survival outcomes, and immunological impacts.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFrom an initial pool of 2,923 studies, 15 were deemed eligible for inclusion. The analysis revealed that DC vaccination therapy demonstrated efficacy in inducing both complete and partial remissions and showed potential in enhancing immune responses. Significant improvements were observed in various immune cell populations and cytokine levels, indicating a multifaceted therapeutic mechanism.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis review highlights the potential of DC vaccination therapy as a viable treatment option for MM. While the observed outcomes are promising, further research is necessary to refine administration protocols, optimize treatment efficacy, and ensure long-term safety and sustainability. Advancing our understanding and application of DC vaccination therapy could significantly impact MM management and improve patient outcomes by offering more effective and personalized treatment strategies.\u003c/p\u003e","manuscriptTitle":"Evaluating Dendritic Cell Vaccination Therapy for Multiple Myeloma: A Systematic Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 15:00:11","doi":"10.21203/rs.3.rs-5347479/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"09b3e55a-e706-4ab2-b42f-e8a448419880","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-11-20T15:00:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-20 15:00:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5347479","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5347479","identity":"rs-5347479","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}