Selinexor, Bortezomib and Dexamethasone After Sequential BCMA- and GPRC5D-Directed Therapy Failure in Penta-Refractory Multiple Myeloma: A Multicenter Real-World Analysis

Selinexor, Bortezomib and Dexamethasone After Sequential BCMA- and GPRC5D-Directed Therapy Failure in Penta-Refractory Multiple Myeloma: A Multicenter Real-World Analysis | 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 Selinexor, Bortezomib and Dexamethasone After Sequential BCMA- and GPRC5D-Directed Therapy Failure in Penta-Refractory Multiple Myeloma: A Multicenter Real-World Analysis Maximilian Al-Bazaz, Winfried Alsdorf, Lisa Leypoldt, Piet Sonnemann, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8124153/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 Patients with relapsed/refractory multiple myeloma (RRMM) who are penta-drug refractory, defined as resistant to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, face a dismal prognosis, particularly when progression occurs after exposure to novel T-cell redirecting therapies. Selinexor, an oral inhibitor of exportin-1, offers a distinct mechanism of action and may retain efficacy in this difficult-to-treat setting. We conducted a retrospective analysis at six German tertiary centers between 2023 and 2025 to evaluate the efficacy and safety of selinexor in combination with bortezomib and dexamethasone (SVd) in patients with penta-refractory MM who had relapsed after exposure to both BCMA- and GPRC5D-targeted therapies. 18 patients were identified, with a median of seven prior lines of therapy and a median time from diagnosis of 9.5 years. High-risk cytogenetic abnormalities were present in seven cases (including del17p in six cases). The overall response rate (ORR) was 61%, comprising one complete response, five very good partial responses (VGPR), and five partial responses (PR). The median progression-free survival (PFS) was 4.3 months (follow-up not reached). Among the nine patients (50%) with extramedullary disease (EMD), three achieved complete and one near-complete EMD resolution. Two patients who had relapsed after CAR-T cell treatment with idecabtagene vicleucel achieved PR and VGPR and were successfully transitioned to a second CAR T-cell treatment with ciltacabtagene autoleucel. Hematologic toxicities under SVd were manageable; no treatment-related deaths occurred. SVd demonstrates meaningful activity in patients with penta-refractory MM and prior failure of BCMA/GPRC5D-targeted immunotherapies. The ORR of 61% and a 78% disease control rate with median PFS of 4.3 months support evaluation of SVd in this highly refractory setting after failure of targeted immunotherapeutic approaches against both BCMA and GPRC5D. Hematology Oncology Selinexor refractory multiple myeloma immunotherapy bridging BCMA GPRC5D CAR-T bispecific antibodies resistance Figures Figure 1 Figure 2 Introduction Outcomes in multiple myeloma (MM), a malignancy of clonal plasma cells, have been substantially improved by proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 antibodies. 1 Nonetheless, most patients ultimately become refractory to these core agents. This state of triple-class refractory disease confers a dismal prognosis, particularly for those with penta-refractory MM (defined by resistance to at least two PIs, two IMiDs including pomalidomide, and an anti-CD38 antibody), where median overall survival is historically limited to 6–12 months. 2 – 5 Novel T-cell-redirecting immunotherapies, including chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers targeting B-cell maturation antigen (BCMA) or G protein–coupled receptor, class C, group 5, member D (GPRC5D), have emerged to address this unmet need, inducing deep responses in heavily pretreated patients. 6 – 12 However, therapeutic failures remain common. Relapse due to resistance mechanisms, such as antigen loss or T-cell exhaustion, underscores the persistent therapeutic gap in this vulnerable population. 13 – 18 Selinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) that targets Exportin 1 (XPO1). By blocking XPO1, selinexor compels the nuclear retention of key tumor suppressor proteins (e.g., p53, NF-κB) while preventing the export of growth-regulatory proteins, thereby inducing cell cycle arrest and apoptosis in malignant cells. 19 XPO1 is often overexpressed in MM, and high levels have been correlated with aggressive disease features and therapy resistance. 20 Moreover, XPO1 blockade also induces ribosomal stress by impeding ribosomal subunit export, targeting a critical vulnerability in MM cells reliant on high ribogenesis and potentially creating synthetic lethality. 21 The unique mechanism of selinexor provides a rationale to overcome cross-resistance from prior treatments. In a pivotal Phase II trial (STORM), selinexor combined with dexamethasone demonstrated an overall response rate (ORR) of ~ 26% in patients with triple-class refractory, penta-exposed MM with a median of seven previous treatment lines, and 53% high-risk cytogenetic abnormalities. 22 This led to its accelerated approval for heavily pretreated RRMM. Subsequently, the Phase III BOSTON trial evaluated selinexor, bortezomib, and dexamethasone (SVd) in earlier relapse (1–3 prior lines), reporting a 76.4% ORR and a median progression-free survival (PFS) of 13.9 months, supporting its approval after first relapse. 23 However, a critical knowledge gap persists regarding selinexor's efficacy in the contemporary treatment landscape. Specifically, clinical data are sparse for patients whose disease is refractory not only to the three core classes but also to novel T-cell-redirecting immunotherapies, such as BCMA-directed CAR-T cells and bispecific antibodies (targeting BCMA or GPRC5D). While isolated case reports suggest retained activity of selinexor post-CAR-T failure, systematic data are lacking. 24 Given the critical lack of data in this setting, this study was designed to quantify the clinical activity and safety of the SVd regimen in the most challenging contemporary myeloma population: patients refractory to all novel immunotherapies. We retrospectively identified a multicenter cohort of 18 penta-drug refractory MM patients, all of whom had documented disease progression following treatment with both BCMA- and GPRC5D-directed T-cell-redirecting therapies. Here, we provide the first systematic analysis of XPO1 inhibition in this emerging, highly refractory setting, offering real-world evidence for a population with an urgent unmet medical need. Methods Study Design and Ethical Oversight We conducted a retrospective, multicenter analysis of patients with RRMM treated at six German tertiary centers (University Medical Center Hamburg-Eppendorf; University Medical Center Schleswig-Holstein, Campus Lübeck; University Medical Center Göttingen; University Medical Center Cologne; Hannover Medical School; Asklepios Klinik Altona, Hamburg) between December 2023 and October 2025. This study was conducted in accordance with the Declaration of Helsinki and local legal requirements (e.g., Hamburg Hospital Act § 12). The protocol was approved by the Ethics Committee of the Medical Council of Cologne (Approval: 24-1201-retro), Göttingen (Approval: 27/3/25) and Lübeck (Approval: 2025 − 252), which waived the requirement for individual patient consent for the analysis and publication of fully anonymized, retrospective data. Patient Population The analysis cohort comprised patients who received at least one cycle of selinexor, bortezomib, and dexamethasone salvage therapy. Key eligibility criteria were: Penta-drug refractoriness: Defined as disease refractory to at least two proteasome inhibitors (e.g., bortezomib, carfilzomib), two immunomodulatory agents (lenalidomide, pomalidomide), and an anti-CD38 monoclonal antibody. Sequential immunotherapy failure: documented disease progression following exposure to both a BCMA-directed and a GPRC5D-directed T-cell-redirecting therapy. A total of 23 patients (age range, 38–78 years) meeting these criteria were identified. 18 patients subsequently received an SVd-based regimen and constituted the final analysis cohort. The remaining five patients were excluded as they received alternative salvage regimens (n = 2) or were transitioned to best supportive care due to frailty (n = 3). Treatment Regimen and Supportive Care Selinexor was administered in a triplet regimen with bortezomib and dexamethasone (SVd). The initial start dose of selinexor ranged from 60 mg to 100 mg once weekly (QW), depending on patients’ age, comorbidities, and pre-existing cytopenia, combined with dexamethasone 20–40 mg per week. Bortezomib was given at a dose of 1.3 mg/m² once weekly during the first 4 weeks of a 35-day treatment cycle. Dose modifications were implemented according to tolerability and in line with established guidelines. All patients received institutional-standard supportive care, with particular emphasis on antiemetic prophylaxis comprising olanzapine, aprepitant, and ondansetron. Data Collection and Endpoints Data were extracted from patient electronic medical records. Baseline characteristics collected included age, cytogenetic risk features (per IMWG criteria), prior lines of therapy, detailed refractoriness status, and disease status immediately preceding SVd initiation. The primary endpoints for this analysis were treatment response and PFS. Treatment response to SVd was assessed by the treating hematologist according to the International Myeloma Working Group (IMWG) criteria. 25 Adverse events (AEs) were retrospectively graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Statistical Analysis The data cut-off date for this analysis was October 31, 2025. Descriptive statistics were used to summarize all patient demographics and clinical parameters. PFS was estimated using the Kaplan-Meier method, and the duration of follow-up was calculated using the reverse Kaplan-Meier method. All statistical analyses were conducted using GraphPad Prism (Version 9 for MacOS, GraphPad Software, Boston, MA, USA). Results Patient Characteristics Eighteen patients who received SVd were included in this analysis. Baseline characteristics are detailed in Table 1 . The cohort comprised 14 males and four females with a median age of 63 years (range, 40–76) at the time of SVd initiation. This population was exceptionally heavily pretreated, with a median of 7 (range, 5–11) prior lines of therapy received over a median of 9.5 years from diagnosis. All patients (100%) had undergone prior autologous stem cell transplantation (ASCT). ECOG performance status at SVd initiation was 0 (n = 5), 1 (n = 8), 2 (n = 4) and 4 (n = 1). MM subtypes included IgG (n = 10), light chain (n = 6), and IgA (n = 2). A high prevalence of aggressive disease features was noted. Nine of 18 patients (50%) presented with active EMD at the start of SVd. Cytogenetic analysis at initial diagnosis revealed standard risk in nine patients and high risk in six (n = 3 unknown), per IMWG criteria. 26 Reflecting significant clonal evolution, three patients initially classified as standard-risk had acquired high-risk abnormalities on repeat testing at the time of SVd initiation. At this timepoint, at least six of 18 patients (33,3%) harbored del(17p), two of whom had concurrent TP53 mutations (n = 5 unknown). Prior BCMA-directed therapies, with median PFS of 8.9 months (range, 0–23.0) included idecabtagene vicleucel (n = 11), teclistamab (n = 6), elranatamab (n = 1), belantamab mafodotin (n = 2) or ciltacabtagene autoleucel (n = 2). Two patients received three anti-BCMA therapies. The median PFS following the last anti-GPRC5D therapy was 6.3 months (range, 0–16.0). Efficacy and Survival Treatment with SVd achieved an overall response rate (ORR) of 61% (n = 11) and a disease control rate (DCR) of 78% (n = 14) (Fig. 1 ). First response was achieved after a median of 0.9 months (range, 0.6–1.8). Best IMWG responses included one complete response (CR), five very good partial responses (VGPR), and five partial responses (PR). Three patients achieved stable disease (SD), while four were primary refractory (Fig. 2). Notably, SVd demonstrated significant activity against EMD. Of the nine patients with active EMD at baseline, four (44%) achieved complete or near-complete radiographic resolution (n = 4 no follow-up available) : Patient #1: A 3.9 cm axillary mass resolved after 8 months. Patient #2: A 7.5 cm thoracic-aperture lesion (concomitant with a surgically treated spinal lesion) resolved within 2 months without local therapy. Patient #4: A 3.2 cm pleura-based lesion cleared after 4 months. Patient #14: A 5 cm retroperitoneal lesion has almost completely regressed. The median PFS for the cohort was 4.3 months (Fig. 1), including durable responses lasting ≥ 6 months in five patients. Importantly, SVd served as a successful bridging strategy to a second CAR-T cell therapy in two patients: one patient with a VGPR remained in response for more than 4 months before receiving ciltacabtagene autoleucel, and another patient with a PR was likewise successfully bridged to ciltacabtagene autoleucel. Safety and Tolerability The safety profile of SVd was consistent with previous reports, and toxicities were manageable with active supportive care. Treatment-related adverse events (TRAEs) shown in Table 2 required selinexor dose modifications (reduction in n = 5; discontinuation in n = 1). The most common hematologic toxicity was thrombocytopenia, reported in 13 patients (72%; n = 2 no data available), with 10 cases (63%) reaching Grade 3 to 4. This led to bortezomib interruption or discontinuation in four patients, and one patient required weekly platelet transfusions. Grade 3 to 4 neutropenia occurred in four patients (25%; n = 2 no data available) and Grade 3 to 4 anemia in eight patients (53%; n = 3 no data available). Non-hematologic AEs were frequent but predominantly low-grade. Fatigue, limited to Grade 1 to 2 (13 patients; 72%) was the most common TRAE, with just one patient with Grade 3. Nausea (9 patients; 53%) was effectively managed with protocol-driven antiemetic prophylaxis and remained Grade 1 to 2. Cognitive slowing was reported in two patients. Notably, no Grade ≥ 3 infections were observed. One patient with a complex viral (respiratory syncytial virus, metapneumovirus) and bacterial pneumonia was successfully managed in the outpatient setting. No treatment-related deaths occurred. Discussion Prior to the advent of T-cell-redirecting therapies, patients with RRMM refractory to all major drug classes faced a dismal prognosis, with a median PFS of only 4.6 months reported in the real-world LocoMMotion trial. 27 While novel immunotherapies can induce deep responses in triple- or penta-refractory MM, therapeutic options following relapse remain severely limited. 3 , 7 , 27 , 28 This study demonstrates that SVd can elicit clinically meaningful responses even in the extremely refractory setting, specifically in penta-refractory patients relapsing after both BCMA- and GPRC5D-targeted immunotherapies. In this exceptionally challenging cohort, SVd achieved an ORR of 61% and a DCR of 78%, including one CR, five durable VGPRs and five cases or PR, with responses lasting up to ten months. For context, the median PFS following prior T-cell directed therapies in our cohort was 8.9 months (post-BCMA) and 6.3 months (post-GPRC5D). Remarkably, the median PFS of 4.3 months approximates results from the pre-immunotherapy era (e.g., the 4.6-month median PFS in the real-world LocoMMotion trial) 27 and exceeds the 3.7-month median PFS reported in the pivotal STORM trial of selinexor–dexamethasone without bortezomib in a less heavily pretreated, triple-class-refractory population lacking prior T-cell engager exposure. 22 Our data are the first systematic analysis to confirm the activity of a therapeutic agent in the post-BCMA and post-GPRC5D setting, substantially expanding case reports, such as that by Chari et al. (2020), who observed responses to selinexor-based therapy in five out of seven patients after anti-BCMA CAR-T failure, including one patient achieving stringent CR. 24 The SVd regimen was selected based on the strong synergistic antitumor effects demonstrated in the BOSTON trial, primarily mediated by interference with nuclear export and potent suppression of NF-κB signaling. Selinexor promotes nuclear accumulation of IκB-α (NF-κB inhibitor), leading to impaired NF-κB transcriptional activity. Bortezomib further amplifies this mechanism by stabilizing IκB-α and inhibiting its degradation via the proteasome, thereby enhancing the overall cytotoxic impact. 29 , 30 Activity in high-risk and extramedullary disease A striking finding of our study was the significant activity against EMD. Of the nine patients presenting with active EMD at baseline, three achieved complete and one near-complete radiographic resolution. This potent activity may be attributable to selinexor's favorable tissue penetration and its recognized efficacy against this aggressive phenotype, which is often associated with high-risk cytogenetics and resistance to novel agents, underscoring its potential utility in this challenging clinical subset. 31 – 34 Furthermore, our findings are consistent with results from Ehsan et al. (2024), who reported activity of selinexor-based regimens in 40 RRMM patients with various cytogenetic risk profiles, including a 50% objective response rate in the del(17p) subgroup and comparable efficacy across other high-risk and standard-risk groups. 35 Notably, in our cohort, four of six patients with del(17p) achieved meaningful disease control, two with VGPR up to 10 months, one with stable disease for 4 months and one stable disease for at least 1 month. This aligns with subgroup analyses from the BOSTON trial with approximately half of the patients harboring high-risk cytogenetic abnormalities, where selinexor appeared to attenuate the negative prognostic impact of high-risk cytogenetics, particularly del(17p). This effect was not seen in the control arm and supports the hypothesis that selinexor may help restore p53 function by preventing its nuclear export and degradation, allowing residual p53 to accumulate and exert tumor-suppressive effects despite genetic loss. 23 , 35 Rationale as a salvage and bridging therapy The rationale for selinexor in the late-line setting is twofold: as definitive salvage therapy and as a rational holding/bridging strategy. Its mechanism is antigen-independent and does not rely on T-cell function, making it a preferred option following the failure of T-cell-directed therapies, which are often compromised by T-cell exhaustion or antigen escape. 36 – 38 High exhaustion marker expression and prior alkylator therapy can compromise T-cell health for subsequent CAR-T manufacturing; therefore, selecting a bridging regimen that preserves immune function is essential. 39 – 41 Reassuringly, prior selinexor-based therapy has been associated with improved survival in bridging contexts and did not impair subsequent CAR-T efficacy in multivariable analyses. 42 Preclinical models show that weekly selinexor dosing preserves CD8⁺ T-cell function. 43 Wang et al. translated this into practice by using selinexor as bridging therapy and maintenance treatment after anti-BCMA CAR-T cells, achieving durable response and prolonged survival in patients with extramedullary relapse. Notably, selinexor also upregulated BCMA expression on MM cell lines, potentially improving CAR-T cell efficacy. 44 These findings support the rationale for integrating selinexor into treatment strategies as a clinically meaningful bridging option around T-cell–directed therapies in RRMM, particularly when sequential BCMA-directed approaches are planned in heavily pretreated patients. In our cohort, two patients were successfully bridged to subsequent CAR-T cell therapy following selinexor-based treatment and one patient was successfully bridged to CAR-T cell apheresis and awaits ciltacabtagene autoleucel infusion at data cut-off. Safety and Tolerability The toxicity profile of SVd in this patient population was significant but manageable. Selinexor required proactive supportive care to maintain adherence and preserve quality of life. Thrombocytopenia was the most common Grade 3 and 4 AE, necessitating bortezomib discontinuation in four patients and highlighting the hematologic toxicity in patients with poor bone marrow reserve. Non-hematologic AEs, particularly fatigue and nausea, were frequent but predominantly low-grade and manageable with stringent supportive care, including intensive antiemetic prophylaxis. These observations highlight the importance of early dose adjustments and stringent supportive measures to maintain therapeutic adherence. Limitations Key limitations include the study's retrospective nature, small sample size (n = 18), and the heterogeneity of prior treatment regimens. Furthermore, a selection bias cannot be excluded, as the 18 patients treated with SVd may represent a clinically fitter subgroup compared to those transitioned to best supportive care. Conclusion In summary, our study provides crucial real-world evidence that the SVd regimen is an effective salvage and bridging strategy for patients with highly refractory MM, even after sequential failure of both BCMA- and GPRC5D-directed immunotherapies. Selinexor, with its distinct, antigen-independent mechanism, can re-establish disease control, manage high-risk features like EMD, and facilitate transition to subsequent novel treatments. This study underscores that selinexor-based therapies can meaningfully contribute to the care of patients in this otherwise dire scenario, addressing a critical unmet need in the therapeutic landscape of late-line myeloma after the failure of modern immunotherapeutic approaches. Declarations Statement of Ethics This study was conducted in accordance with the Declaration of Helsinki and local legal requirements (e.g., Hamburg Hospital Act §12). The protocol was approved by the Ethics Committee of the Medical Council of Cologne (Approval: 24-1201-retro) and Lübeck (Approval: 2025-252), which waived the requirement for individual patient consent for the analysis and publication of fully anonymized, retrospective data. Conflict of Interest Statement Winfried Alsdorf : served as a consultant for Johnson & Johnson; received honoraria from Astellas, AstraZeneca, GlaxoSmithKline (GSK), and Johnson & Johnson; received travel support/congress funding from BioNTech, Immatics, and Johnson & Johnson; received research funding (to institution, clinical trials) from BioNTech and Affimed. Jule Artzenroth : received travel support from Sanofi and Menarini Stemline. Carsten Bokemeyer : received honoraria from AOK Germany, AstraZeneca, Bayer, Berlin-Chemie, Bristol Myers Squibb (BMS), GSO Research Organisation, Janssen, Med Update, Merck Serono, Merck Sharp & Dohme, Novartis, Roche, and Sanofi Aventis. Annamaria Brioli : received honoraria from BMS, GSK, Janssen, Pfizer, Menarini Stemline, and AstraZeneca; served on advisory boards for BMS, GSK, Janssen, Pfizer, Menarini Stemline, AstraZeneca, and Amgen; received travel support from BMS, Pfizer, AstraZeneca, and Janssen. Kerstin Brinkert : received travel support from Medac, Menarini Stemline, and Novartis. Udo Holtick : received honoraria from Amgen, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi-Aventis, Stemline Therapeutics, and Takeda; had a consulting/advisory role for BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi-Aventis, and Stemline Therapeutics. Hans Salwender : received honoraria from Janssen-Cilag, Takeda, Amgen, BMS/Celgene, Sanofi, Oncopeptides, AbbVie, GSK, Chugai, Stemline and Pfizer; received travel/accommodations/expenses from Janssen, Takeda, Amgen, BMS/Celgene, Sanofi, Stemline and GSK. Ricardo Kosch : served on an advisory board for Menarini Stemline; received congress/travel support from Amgen, BeiGene, Sanofi, and Menarini Stemline. Theo Leitner : served as a consultant for Janssen (Johnson & Johnson); received research funding from Sanofi (to institution); received travel/accommodations/expenses from Sanofi, Lilly, Janssen (Johnson & Johnson), AOP Health, BeiGene, Alexion, and Regeneron. Lisa Leypoldt : served as a consultant for GSK, Sanofi, Pfizer, and Janssen; received honoraria from Adaptive, Amgen, AbbVie, Janssen, BMS/Celgene, Pfizer, Sanofi, Takeda, AstraZeneca, and GSK; received research funding from AbbVie and GSK (to institution); received travel support from Sanofi, Johnson & Johnson, Amgen, and Oncopeptides. Markus Maulhardt : received travel/congress support from AbbVie, Kite (Gilead), Sobi, and Incyte; received honoraria from Kite (Gilead) and Lilly. Tim Richardson : served as a consultant/advisor to Janssen, BMS, Takeda, and Sanofi; received travel/accommodations/expenses from Janssen, Sanofi, Stemline Therapeutics, and Oncopeptides. Christoph Schaefers : served as a consultant for Acus Health, AstraZeneca, Janssen, Menarini Stemline, Oncopeptides, and Pfizer; received honoraria from AbbVie, AstraZeneca, Janssen-Cilag, and Sanofi; received travel expenses/congress support from Acus Health, AstraZeneca, Janssen, Menarini Stemline, Oncopeptides, and Sanofi. Jan Vorwerk : received travel/accommodations/expenses from Incyte and Johnson & Johnson. Katja Weisel : served as a consultant for AbbVie, Adaptive Biotech, Amgen, BeiGene, GSK, Johnson & Johnson, Karyopharm, Menarini, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; received honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, BMS, Celgene, GSK, Janssen, Novartis, Oncopeptides, Sanofi, Stemline, and Takeda; served on boards/advisory committees for AbbVie, Adaptive Biotech, Amgen, BeiGene, BMS, Celgene, GSK, Johnson & Johnson, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; received research funding from AbbVie, Amgen, GSK, Johnson & Johnson, Pfizer, BMS/Celgene, Novartis, Sanofi, and Takeda. The remaining authors declare no competing interests. Funding This study was not supported by any sponsor or funder. Author Contributions Maximilian Al-Bazaz, Ricardo Kosch: conceptualization; methodology; investigation (providing patient data); data curation; formal analysis; visualization; writing – original draft; writing – review & editing. Winfried Alsdorf, Lisa Leypoldt, Annamaria Brioli, Carsten Bokemeyer, Katja Weisel: supervision; investigation (providing patient data); writing – review & editing. Piet Sonnemann: investigation (providing patient data); formal analysis; visualization; writing – review & editing. Christoph Schaefers, Jule Artzenroth, Marie Harzer, Abdulaziz Kamili, Leandra Bartke, Jan Vorwerk, Theo Leitner, Markus Maulhardt, Kerstin Brinkert, Tim Richardson, Udo Holtick, Stephan Hillmann, Hans Salwender, Cyrus Khandanpour: investigation (providing patient data); writing – review & editing. All authors approved the final manuscript and agreed to be accountable for all aspects of the work. Data Availability Statement The data presented in this study are available upon reasonable request from the corresponding author. The data are not publicly available due to patients’ privacy. Involvement of third parties in the research or manuscript preparation No individuals or third-party services were involved in the research or preparation of the manuscript who are not listed as authors or already acknowledged. Therefore, no updates to the acknowledgements are necessary in this regard. References Mettias S, ElSayed A, Moore J, Berenson JR (2025) Multiple Myeloma: Improved Outcomes Resulting from a Rapidly Expanding Number of Therapeutic Options. Targ Oncol 20:247–267 Rodríguez-Otero P et al (2024) Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial. 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JCM 14, 1316 Tyler PM et al (2017) Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy. Mol Cancer Ther 16:428–439 Wang D et al (2023) A novel two-step administration of XPO-1 inhibitor may enhance the effect of anti-BCMA CAR-T in relapsed/refractory extramedullary multiple myeloma. J Transl Med 21:812 Tables Tables 1 and 2 are available in the Supplementary Files section. Additional Declarations The authors declare potential competing interests as follows: Winfried Alsdorf: consultancy for JNJ; honoraria from Astellas, AstraZeneca, GSK, and JNJ; travel support from BioNTech, Immatics, and JNJ; research funding (to institution, clinical trials) from BioNTech and Affimed. Jule Artzenroth: travel support from Sanofi, Menarini Stemline. Carsten Bokemeyer: honoraria from AOK Germany, AstraZeneca, Bayer, Berlin-Chemie, BMS, GSO Research Organisation, JNJ, Med Update, Merck Serono, MSD, Novartis, Roche, and Sanofi. Annamaria Brioli: honoraria from BMS, GSK, JNJ, Pfizer, Stemline, and AstraZeneca; advisory role for BMS, GSK, JNJ, Pfizer, Stemline, AstraZeneca, and Amgen; travel support from BMS, Pfizer, AstraZeneca, and JNJ. Kerstin Brinkert: travel support from Medac, Stemline, and Novartis. Udo Holtick: honoraria from Amgen, BMS/Celgene, GSK, JNJ, Oncopeptides, Pfizer, Sanofi, Stemline and Takeda; advisory role for BMS/Celgene, GSK, JNJ, Oncopeptides, Pfizer, Sanofi, and Stemline. Hans Salwender: honoraria from JNJ, Takeda, Amgen, BMS/Celgene, Sanofi, Oncopeptides, AbbVie, GSK, Chugai, Stemline and Pfizer; travel expenses from JNJ, Takeda, Amgen, BMS/Celgene, Sanofi, Stemline and GSK. Ricardo Kosch: advisory role for Stemline; congress support from Amgen, BeiGene, Sanofi, and Stemline. Theo Leitner: consultant for JNJ; research funding from Sanofi (to institution); travel expenses from Sanofi, Lilly, JNJ, AOP Health, BeiGene, Alexion, and Regeneron. Lisa Leypoldt: consultant for GSK, Sanofi, Pfizer, and JNJ; honoraria from Adaptive, Amgen, AbbVie, Janssen, BMS/Celgene, Pfizer, Sanofi, Takeda, AstraZeneca, and GSK; research funding from AbbVie and GSK (to institution); travel support from Sanofi, JNJ, Amgen, and Oncopeptides. Markus Maulhardt: travel support from AbbVie, Kite (Gilead), Sobi, and Incyte; honoraria from Kite (Gilead) and Lilly. Tim Richardson: consultant for JNJ, BMS, Takeda, and Sanofi; travel expenses from JNJ, Sanofi, Stemline, and Oncopeptides. Christoph Schaefers: consultant for Acus Health, AstraZeneca, JNJ, Stemline, Oncopeptides, and Pfizer; honoraria from AbbVie, AstraZeneca, JNJ, and Sanofi; travel expenses from Acus Health, AstraZeneca, JNJ, Stemline, Oncopeptides, and Sanofi. Jan Vorwerk: received travel expenses from Incyte and JNJ. Katja Weisel: consultant for AbbVie, Adaptive Biotech, Amgen, BeiGene, GSK, JNJ, Karyopharm, Stemline, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, BMS, Celgene, GSK, JNJ, Novartis, Oncopeptides, Sanofi, Stemline, and Takeda; served on boards/advisory committees for AbbVie, Adaptive Biotech, Amgen, BeiGene, BMS, Celgene, GSK, JNJ, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; received research funding from AbbVie, Amgen, GSK, JNJ, Pfizer, BMS/Celgene, Novartis, Sanofi, and Takeda. The remaining authors declare no competing interests. Supplementary Files Table1PNG.png Table 1: Characteristics of patients treated with SVd. PFS not reached in this patient yet (SVd ongoing); ** Therapy switched to ciltacabtagene autoleucel after remission induction with SVd; belamaf: belantamal mafodotin; cilta-cel: ciltacabtagene autoleucel; CR: complete response; ECOG: Eastern Cooperative Oncology Group; elra: elranatamab; EMD: extramedullary disease; HR: high-risk cytogenetics; ide-cel: idecabtagene vicleucel; IF: immunofixation; LC: light chain; MM: Multiple Myeloma; NA: not applicable; PACE: polychemotherapy with cisplatin, doxorubicin, cyclophosphamide, and etoposide; PD: progressive disease; PFS: progression-free survival; PR: partial response; SD: stable disease; SR: standard-risk cytogenetics; tec: teclistamab; VGPR: very good partial response. Table2PNG.png Table 2: Most common adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (NA = no data available). 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. 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08:58:20","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1016185,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1: Characteristics of patients treated with SVd.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e* PFS not reached in this patient yet (SVd ongoing); ** Therapy switched to ciltacabtagene autoleucel after remission induction with SVd; belamaf: belantamal mafodotin; cilta-cel: ciltacabtagene autoleucel; CR: complete response; ECOG: Eastern Cooperative Oncology Group; elra: elranatamab; EMD: extramedullary disease; HR: high-risk cytogenetics; ide-cel: idecabtagene vicleucel; IF: immunofixation; LC: light chain; MM: Multiple Myeloma; NA: not applicable; PACE: polychemotherapy with cisplatin, doxorubicin, cyclophosphamide, and etoposide; PD: progressive disease; PFS: progression-free survival; PR: partial response; SD: stable disease; SR: standard-risk cytogenetics; tec: teclistamab; VGPR: very good partial response.\u003c/p\u003e","description":"","filename":"Table1PNG.png","url":"https://assets-eu.researchsquare.com/files/rs-8124153/v1/8ab50e3e57b026c08e1ceac0.png"},{"id":96162244,"identity":"4df4f335-1acd-4394-97fc-c208af5aee36","added_by":"auto","created_at":"2025-11-18 08:58:20","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":351304,"visible":true,"origin":"","legend":"\u003cp\u003eTable 2: Most common adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (NA = no data available).\u003c/p\u003e","description":"","filename":"Table2PNG.png","url":"https://assets-eu.researchsquare.com/files/rs-8124153/v1/ff3a0e09e0b65e046f30ce72.png"}],"financialInterests":"The authors declare potential competing interests as follows: Winfried Alsdorf: consultancy for JNJ; honoraria from Astellas, AstraZeneca, GSK, and JNJ; travel support from BioNTech, Immatics, and JNJ; research funding (to institution, clinical trials) from BioNTech and Affimed. Jule Artzenroth: travel support from Sanofi, Menarini Stemline. Carsten Bokemeyer: honoraria from AOK Germany, AstraZeneca, Bayer, Berlin-Chemie, BMS, GSO Research Organisation, JNJ, Med Update, Merck Serono, MSD, Novartis, Roche, and Sanofi. Annamaria Brioli: honoraria from BMS, GSK, JNJ, Pfizer, Stemline, and AstraZeneca; advisory role for BMS, GSK, JNJ, Pfizer, Stemline, AstraZeneca, and Amgen; travel support from BMS, Pfizer, AstraZeneca, and JNJ. Kerstin Brinkert: travel support from Medac, Stemline, and Novartis. Udo Holtick: honoraria from Amgen, BMS/Celgene, GSK, JNJ, Oncopeptides, Pfizer, Sanofi, Stemline and Takeda; advisory role for BMS/Celgene, GSK, JNJ, Oncopeptides, Pfizer, Sanofi, and Stemline. Hans Salwender: honoraria from JNJ, Takeda, Amgen, BMS/Celgene, Sanofi, Oncopeptides, AbbVie, GSK, Chugai, Stemline and Pfizer; travel expenses from JNJ, Takeda, Amgen, BMS/Celgene, Sanofi, Stemline and GSK. Ricardo Kosch: advisory role for Stemline; congress support from Amgen, BeiGene, Sanofi, and Stemline. Theo Leitner: consultant for JNJ; research funding from Sanofi (to institution); travel expenses from Sanofi, Lilly, JNJ, AOP Health, BeiGene, Alexion, and Regeneron. Lisa Leypoldt: consultant for GSK, Sanofi, Pfizer, and JNJ; honoraria from Adaptive, Amgen, AbbVie, Janssen, BMS/Celgene, Pfizer, Sanofi, Takeda, AstraZeneca, and GSK; research funding from AbbVie and GSK (to institution); travel support from Sanofi, JNJ, Amgen, and Oncopeptides. Markus Maulhardt: travel support from AbbVie, Kite (Gilead), Sobi, and Incyte; honoraria from Kite (Gilead) and Lilly. Tim Richardson: consultant for JNJ, BMS, Takeda, and Sanofi; travel expenses from JNJ, Sanofi, Stemline, and Oncopeptides. Christoph Schaefers: consultant for Acus Health, AstraZeneca, JNJ, Stemline, Oncopeptides, and Pfizer; honoraria from AbbVie, AstraZeneca, JNJ, and Sanofi; travel expenses from Acus Health, AstraZeneca, JNJ, Stemline, Oncopeptides, and Sanofi. Jan Vorwerk: received travel expenses from Incyte and JNJ. Katja Weisel: consultant for AbbVie, Adaptive Biotech, Amgen, BeiGene, GSK, JNJ, Karyopharm, Stemline, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, BMS, Celgene, GSK, JNJ, Novartis, Oncopeptides, Sanofi, Stemline, and Takeda; served on boards/advisory committees for AbbVie, Adaptive Biotech, Amgen, BeiGene, BMS, Celgene, GSK, JNJ, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; received research funding from AbbVie, Amgen, GSK, JNJ, Pfizer, BMS/Celgene, Novartis, Sanofi, and Takeda. The remaining authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eSelinexor, Bortezomib and Dexamethasone After Sequential BCMA- and GPRC5D-Directed Therapy Failure in Penta-Refractory Multiple Myeloma: A Multicenter Real-World Analysis\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOutcomes in multiple myeloma (MM), a malignancy of clonal plasma cells, have been substantially improved by proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 antibodies.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Nonetheless, most patients ultimately become refractory to these core agents. This state of triple-class refractory disease confers a dismal prognosis, particularly for those with penta-refractory MM (defined by resistance to at least two PIs, two IMiDs including pomalidomide, and an anti-CD38 antibody), where median overall survival is historically limited to 6\u0026ndash;12 months.\u003csup\u003e\u003cspan additionalcitationids=\"CR3 CR4\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eNovel T-cell-redirecting immunotherapies, including chimeric antigen receptor (CAR) T-cells and bispecific T-cell engagers targeting B-cell maturation antigen (BCMA) or G protein\u0026ndash;coupled receptor, class C, group 5, member D (GPRC5D), have emerged to address this unmet need, inducing deep responses in heavily pretreated patients.\u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e However, therapeutic failures remain common. Relapse due to resistance mechanisms, such as antigen loss or T-cell exhaustion, underscores the persistent therapeutic gap in this vulnerable population.\u003csup\u003e\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eSelinexor is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) that targets Exportin 1 (XPO1). By blocking XPO1, selinexor compels the nuclear retention of key tumor suppressor proteins (e.g., p53, NF-κB) while preventing the export of growth-regulatory proteins, thereby inducing cell cycle arrest and apoptosis in malignant cells.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e XPO1 is often overexpressed in MM, and high levels have been correlated with aggressive disease features and therapy resistance.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e Moreover, XPO1 blockade also induces ribosomal stress by impeding ribosomal subunit export, targeting a critical vulnerability in MM cells reliant on high ribogenesis and potentially creating synthetic lethality.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe unique mechanism of selinexor provides a rationale to overcome cross-resistance from prior treatments. In a pivotal Phase II trial (STORM), selinexor combined with dexamethasone demonstrated an overall response rate (ORR) of ~\u0026thinsp;26% in patients with triple-class refractory, penta-exposed MM with a median of seven previous treatment lines, and 53% high-risk cytogenetic abnormalities.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e This led to its accelerated approval for heavily pretreated RRMM. Subsequently, the Phase III BOSTON trial evaluated selinexor, bortezomib, and dexamethasone (SVd) in earlier relapse (1\u0026ndash;3 prior lines), reporting a 76.4% ORR and a median progression-free survival (PFS) of 13.9 months, supporting its approval after first relapse.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eHowever, a critical knowledge gap persists regarding selinexor's efficacy in the contemporary treatment landscape. Specifically, clinical data are sparse for patients whose disease is refractory not only to the three core classes but also to novel T-cell-redirecting immunotherapies, such as BCMA-directed CAR-T cells and bispecific antibodies (targeting BCMA or GPRC5D). While isolated case reports suggest retained activity of selinexor post-CAR-T failure, systematic data are lacking.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eGiven the critical lack of data in this setting, this study was designed to quantify the clinical activity and safety of the SVd regimen in the most challenging contemporary myeloma population: patients refractory to all novel immunotherapies. We retrospectively identified a multicenter cohort of 18 penta-drug refractory MM patients, all of whom had documented disease progression following treatment with both BCMA- and GPRC5D-directed T-cell-redirecting therapies. Here, we provide the first systematic analysis of XPO1 inhibition in this emerging, highly refractory setting, offering real-world evidence for a population with an urgent unmet medical need.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design and Ethical Oversight\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective, multicenter analysis of patients with RRMM treated at six German tertiary centers (University Medical Center Hamburg-Eppendorf; University Medical Center Schleswig-Holstein, Campus L\u0026uuml;beck; University Medical Center G\u0026ouml;ttingen; University Medical Center Cologne; Hannover Medical School; Asklepios Klinik Altona, Hamburg) between December 2023 and October 2025.\u003c/p\u003e\u003cp\u003e This study was conducted in accordance with the Declaration of Helsinki and local legal requirements (e.g., Hamburg Hospital Act \u0026sect;\u0026nbsp;12). The protocol was approved by the Ethics Committee of the Medical Council of Cologne (Approval: 24-1201-retro), G\u0026ouml;ttingen (Approval: 27/3/25) and L\u0026uuml;beck (Approval: 2025\u0026thinsp;\u0026minus;\u0026thinsp;252), which waived the requirement for individual patient consent for the analysis and publication of fully anonymized, retrospective data.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003ePatient Population\u003c/h3\u003e\n\u003cp\u003eThe analysis cohort comprised patients who received at least one cycle of selinexor, bortezomib, and dexamethasone salvage therapy. Key eligibility criteria were:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003ePenta-drug refractoriness: Defined as disease refractory to at least two proteasome inhibitors (e.g., bortezomib, carfilzomib), two immunomodulatory agents (lenalidomide, pomalidomide), and an anti-CD38 monoclonal antibody.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSequential immunotherapy failure: documented disease progression following exposure to both a BCMA-directed and a GPRC5D-directed T-cell-redirecting therapy.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eA total of 23 patients (age range, 38\u0026ndash;78 years) meeting these criteria were identified. 18 patients subsequently received an SVd-based regimen and constituted the final analysis cohort. The remaining five patients were excluded as they received alternative salvage regimens (n\u0026thinsp;=\u0026thinsp;2) or were transitioned to best supportive care due to frailty (n\u0026thinsp;=\u0026thinsp;3).\u003c/p\u003e\n\u003ch3\u003eTreatment Regimen and Supportive Care\u003c/h3\u003e\n\u003cp\u003eSelinexor was administered in a triplet regimen with bortezomib and dexamethasone (SVd). The initial start dose of selinexor ranged from 60 mg to 100 mg once weekly (QW), depending on patients\u0026rsquo; age, comorbidities, and pre-existing cytopenia, combined with dexamethasone 20\u0026ndash;40 mg per week. Bortezomib was given at a dose of 1.3 mg/m\u0026sup2; once weekly during the first 4 weeks of a 35-day treatment cycle. Dose modifications were implemented according to tolerability and in line with established guidelines.\u003c/p\u003e\u003cp\u003eAll patients received institutional-standard supportive care, with particular emphasis on antiemetic prophylaxis comprising olanzapine, aprepitant, and ondansetron.\u003c/p\u003e\n\u003ch3\u003eData Collection and Endpoints\u003c/h3\u003e\n\u003cp\u003eData were extracted from patient electronic medical records. Baseline characteristics collected included age, cytogenetic risk features (per IMWG criteria), prior lines of therapy, detailed refractoriness status, and disease status immediately preceding SVd initiation.\u003c/p\u003e\u003cp\u003eThe primary endpoints for this analysis were treatment response and PFS. Treatment response to SVd was assessed by the treating hematologist according to the International Myeloma Working Group (IMWG) criteria.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e Adverse events (AEs) were retrospectively graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe data cut-off date for this analysis was October 31, 2025. Descriptive statistics were used to summarize all patient demographics and clinical parameters. PFS was estimated using the Kaplan-Meier method, and the duration of follow-up was calculated using the reverse Kaplan-Meier method. All statistical analyses were conducted using GraphPad Prism (Version 9 for MacOS, GraphPad Software, Boston, MA, USA).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003ePatient Characteristics\u003c/h2\u003e\u003cp\u003eEighteen patients who received SVd were included in this analysis. Baseline characteristics are detailed in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. The cohort comprised 14 males and four females with a median age of 63 years (range, 40\u0026ndash;76) at the time of SVd initiation.\u003c/p\u003e\u003cp\u003eThis population was exceptionally heavily pretreated, with a median of 7 (range, 5\u0026ndash;11) prior lines of therapy received over a median of 9.5 years from diagnosis. All patients (100%) had undergone prior autologous stem cell transplantation (ASCT). ECOG performance status at SVd initiation was 0 (n\u0026thinsp;=\u0026thinsp;5), 1 (n\u0026thinsp;=\u0026thinsp;8), 2 (n\u0026thinsp;=\u0026thinsp;4) and 4 (n\u0026thinsp;=\u0026thinsp;1). MM subtypes included IgG (n\u0026thinsp;=\u0026thinsp;10), light chain (n\u0026thinsp;=\u0026thinsp;6), and IgA (n\u0026thinsp;=\u0026thinsp;2).\u003c/p\u003e\u003cp\u003eA high prevalence of aggressive disease features was noted. Nine of 18 patients (50%) presented with active EMD at the start of SVd. Cytogenetic analysis at initial diagnosis revealed standard risk in nine patients and high risk in six (n\u0026thinsp;=\u0026thinsp;3 unknown), per IMWG criteria.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Reflecting significant clonal evolution, three patients initially classified as standard-risk had acquired high-risk abnormalities on repeat testing at the time of SVd initiation. At this timepoint, at least six of 18 patients (33,3%) harbored del(17p), two of whom had concurrent TP53 mutations (n\u0026thinsp;=\u0026thinsp;5 unknown).\u003c/p\u003e\u003cp\u003ePrior BCMA-directed therapies, with median PFS of 8.9 months (range, 0\u0026ndash;23.0) included idecabtagene vicleucel (n\u0026thinsp;=\u0026thinsp;11), teclistamab (n\u0026thinsp;=\u0026thinsp;6), elranatamab (n\u0026thinsp;=\u0026thinsp;1), belantamab mafodotin (n\u0026thinsp;=\u0026thinsp;2) or ciltacabtagene autoleucel (n\u0026thinsp;=\u0026thinsp;2). Two patients received three anti-BCMA therapies. The median PFS following the last anti-GPRC5D therapy was 6.3 months (range, 0\u0026ndash;16.0).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEfficacy and Survival\u003c/h3\u003e\n\u003cp\u003eTreatment with SVd achieved an overall response rate (ORR) of 61% (n\u0026thinsp;=\u0026thinsp;11) and a disease control rate (DCR) of 78% (n\u0026thinsp;=\u0026thinsp;14) (Fig.\u0026nbsp;1\u003cb\u003e).\u003c/b\u003e First response was achieved after a median of 0.9 months (range, 0.6\u0026ndash;1.8).\u003c/p\u003e\u003cp\u003eBest IMWG responses included one complete response (CR), five very good partial responses (VGPR), and five partial responses (PR). Three patients achieved stable disease (SD), while four were primary refractory (Fig.\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eNotably, SVd demonstrated significant activity against EMD. Of the nine patients with active EMD at baseline, four (44%) achieved complete or near-complete radiographic resolution (n\u0026thinsp;=\u0026thinsp;4 no follow-up available) :\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003ePatient #1: A 3.9 cm axillary mass resolved after 8 months.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePatient #2: A 7.5 cm thoracic-aperture lesion (concomitant with a surgically treated spinal lesion) resolved within 2 months without local therapy.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePatient #4: A 3.2 cm pleura-based lesion cleared after 4 months.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003ePatient #14: A 5 cm retroperitoneal lesion has almost completely regressed.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThe median PFS for the cohort was 4.3 months (Fig.\u0026nbsp;1), including durable responses lasting\u0026thinsp;\u0026ge;\u0026thinsp;6 months in five patients. Importantly, SVd served as a successful bridging strategy to a second CAR-T cell therapy in two patients: one patient with a VGPR remained in response for more than 4 months before receiving ciltacabtagene autoleucel, and another patient with a PR was likewise successfully bridged to ciltacabtagene autoleucel.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSafety and Tolerability\u003c/h2\u003e\u003cp\u003eThe safety profile of SVd was consistent with previous reports, and toxicities were manageable with active supportive care. Treatment-related adverse events (TRAEs) shown in \u003cb\u003eTable\u0026nbsp;2\u003c/b\u003e required selinexor dose modifications (reduction in n\u0026thinsp;=\u0026thinsp;5; discontinuation in n\u0026thinsp;=\u0026thinsp;1). The most common hematologic toxicity was thrombocytopenia, reported in 13 patients (72%; n\u0026thinsp;=\u0026thinsp;2 no data available), with 10 cases (63%) reaching Grade 3 to 4. This led to bortezomib interruption or discontinuation in four patients, and one patient required weekly platelet transfusions. Grade 3 to 4 neutropenia occurred in four patients (25%; n\u0026thinsp;=\u0026thinsp;2 no data available) and Grade 3 to 4 anemia in eight patients (53%; n\u0026thinsp;=\u0026thinsp;3 no data available).\u003c/p\u003e\u003cp\u003eNon-hematologic AEs were frequent but predominantly low-grade. Fatigue, limited to Grade 1 to 2 (13 patients; 72%) was the most common TRAE, with just one patient with Grade 3. Nausea (9 patients; 53%) was effectively managed with protocol-driven antiemetic prophylaxis and remained Grade 1 to 2. Cognitive slowing was reported in two patients.\u003c/p\u003e\u003cp\u003eNotably, no Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 infections were observed. One patient with a complex viral (respiratory syncytial virus, metapneumovirus) and bacterial pneumonia was successfully managed in the outpatient setting. No treatment-related deaths occurred.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003ePrior to the advent of T-cell-redirecting therapies, patients with RRMM refractory to all major drug classes faced a dismal prognosis, with a median PFS of only 4.6 months reported in the real-world LocoMMotion trial.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e While novel immunotherapies can induce deep responses in triple- or penta-refractory MM, therapeutic options following relapse remain severely limited.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e This study demonstrates that SVd can elicit clinically meaningful responses even in the extremely refractory setting, specifically in penta-refractory patients relapsing after both BCMA- and GPRC5D-targeted immunotherapies.\u003c/p\u003e\u003cp\u003eIn this exceptionally challenging cohort, SVd achieved an ORR of 61% and a DCR of 78%, including one CR, five durable VGPRs and five cases or PR, with responses lasting up to ten months. For context, the median PFS following prior T-cell directed therapies in our cohort was 8.9 months (post-BCMA) and 6.3 months (post-GPRC5D). Remarkably, the median PFS of 4.3 months approximates results from the pre-immunotherapy era (e.g., the 4.6-month median PFS in the real-world LocoMMotion trial)\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e and exceeds the 3.7-month median PFS reported in the pivotal STORM trial of selinexor\u0026ndash;dexamethasone without bortezomib in a less heavily pretreated, triple-class-refractory population lacking prior T-cell engager exposure.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Our data are the first systematic analysis to confirm the activity of a therapeutic agent in the post-BCMA and post-GPRC5D setting, substantially expanding case reports, such as that by Chari et al. (2020), who observed responses to selinexor-based therapy in five out of seven patients after anti-BCMA CAR-T failure, including one patient achieving stringent CR.\u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThe SVd regimen was selected based on the strong synergistic antitumor effects demonstrated in the BOSTON trial, primarily mediated by interference with nuclear export and potent suppression of NF-κB signaling. Selinexor promotes nuclear accumulation of IκB-α (NF-κB inhibitor), leading to impaired NF-κB transcriptional activity. Bortezomib further amplifies this mechanism by stabilizing IκB-α and inhibiting its degradation via the proteasome, thereby enhancing the overall cytotoxic impact.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eActivity in high-risk and extramedullary disease\u003c/h2\u003e\u003cp\u003eA striking finding of our study was the significant activity against EMD. Of the nine patients presenting with active EMD at baseline, three achieved complete and one near-complete radiographic resolution. This potent activity may be attributable to selinexor's favorable tissue penetration and its recognized efficacy against this aggressive phenotype, which is often associated with high-risk cytogenetics and resistance to novel agents, underscoring its potential utility in this challenging clinical subset.\u003csup\u003e\u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eFurthermore, our findings are consistent with results from Ehsan et al. (2024), who reported activity of selinexor-based regimens in 40 RRMM patients with various cytogenetic risk profiles, including a 50% objective response rate in the del(17p) subgroup and comparable efficacy across other high-risk and standard-risk groups.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Notably, in our cohort, four of six patients with del(17p) achieved meaningful disease control, two with VGPR up to 10 months, one with stable disease for 4 months and one stable disease for at least 1 month. This aligns with subgroup analyses from the BOSTON trial with approximately half of the patients harboring high-risk cytogenetic abnormalities, where selinexor appeared to attenuate the negative prognostic impact of high-risk cytogenetics, particularly del(17p). This effect was not seen in the control arm and supports the hypothesis that selinexor may help restore p53 function by preventing its nuclear export and degradation, allowing residual p53 to accumulate and exert tumor-suppressive effects despite genetic loss.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eRationale as a salvage and bridging therapy\u003c/h2\u003e\u003cp\u003eThe rationale for selinexor in the late-line setting is twofold: as definitive salvage therapy and as a rational holding/bridging strategy. Its mechanism is antigen-independent and does not rely on T-cell function, making it a preferred option following the failure of T-cell-directed therapies, which are often compromised by T-cell exhaustion or antigen escape.\u003csup\u003e\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e High exhaustion marker expression and prior alkylator therapy can compromise T-cell health for subsequent CAR-T manufacturing; therefore, selecting a bridging regimen that preserves immune function is essential.\u003csup\u003e\u003cspan additionalcitationids=\"CR40\" citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e Reassuringly, prior selinexor-based therapy has been associated with improved survival in bridging contexts and did not impair subsequent CAR-T efficacy in multivariable analyses.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e Preclinical models show that weekly selinexor dosing preserves CD8⁺ T-cell function.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e Wang et al. translated this into practice by using selinexor as bridging therapy and maintenance treatment after anti-BCMA CAR-T cells, achieving durable response and prolonged survival in patients with extramedullary relapse. Notably, selinexor also upregulated BCMA expression on MM cell lines, potentially improving CAR-T cell efficacy.\u003csup\u003e\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e These findings support the rationale for integrating selinexor into treatment strategies as a clinically meaningful bridging option around T-cell\u0026ndash;directed therapies in RRMM, particularly when sequential BCMA-directed approaches are planned in heavily pretreated patients. In our cohort, two patients were successfully bridged to subsequent CAR-T cell therapy following selinexor-based treatment and one patient was successfully bridged to CAR-T cell apheresis and awaits ciltacabtagene autoleucel infusion at data cut-off.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eSafety and Tolerability\u003c/h2\u003e\u003cp\u003eThe toxicity profile of SVd in this patient population was significant but manageable. Selinexor required proactive supportive care to maintain adherence and preserve quality of life. Thrombocytopenia was the most common Grade 3 and 4 AE, necessitating bortezomib discontinuation in four patients and highlighting the hematologic toxicity in patients with poor bone marrow reserve. Non-hematologic AEs, particularly fatigue and nausea, were frequent but predominantly low-grade and manageable with stringent supportive care, including intensive antiemetic prophylaxis. These observations highlight the importance of early dose adjustments and stringent supportive measures to maintain therapeutic adherence.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eKey limitations include the study's retrospective nature, small sample size (n\u0026thinsp;=\u0026thinsp;18), and the heterogeneity of prior treatment regimens. Furthermore, a selection bias cannot be excluded, as the 18 patients treated with SVd may represent a clinically fitter subgroup compared to those transitioned to best supportive care.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our study provides crucial real-world evidence that the SVd regimen is an effective salvage and bridging strategy for patients with highly refractory MM, even after sequential failure of both BCMA- and GPRC5D-directed immunotherapies. Selinexor, with its distinct, antigen-independent mechanism, can re-establish disease control, manage high-risk features like EMD, and facilitate transition to subsequent novel treatments. This study underscores that selinexor-based therapies can meaningfully contribute to the care of patients in this otherwise dire scenario, addressing a critical unmet need in the therapeutic landscape of late-line myeloma after the failure of modern immunotherapeutic approaches.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and local legal requirements (e.g., Hamburg Hospital Act §12). The protocol was approved by the Ethics Committee of the Medical Council of Cologne (Approval: 24-1201-retro) and Lübeck (Approval: 2025-252), which waived the requirement for individual patient consent for the analysis and publication of fully anonymized, retrospective data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWinfried Alsdorf\u003c/strong\u003e: served as a consultant for Johnson \u0026amp; Johnson; received honoraria from Astellas, AstraZeneca, GlaxoSmithKline (GSK), and Johnson \u0026amp; Johnson; received travel support/congress funding from BioNTech, Immatics, and Johnson \u0026amp; Johnson; received research funding (to institution, clinical trials) from BioNTech and Affimed. \u003cstrong\u003eJule Artzenroth\u003c/strong\u003e: received travel support from Sanofi and Menarini Stemline. \u003cstrong\u003eCarsten Bokemeyer\u003c/strong\u003e: received honoraria from AOK Germany, AstraZeneca, Bayer, Berlin-Chemie, Bristol Myers Squibb (BMS), GSO Research Organisation, Janssen, Med Update, Merck Serono, Merck Sharp \u0026amp; Dohme, Novartis, Roche, and Sanofi Aventis. \u003cstrong\u003eAnnamaria Brioli\u003c/strong\u003e: received honoraria from BMS, GSK, Janssen, Pfizer, Menarini Stemline, and AstraZeneca; served on advisory boards for BMS, GSK, Janssen, Pfizer, Menarini Stemline, AstraZeneca, and Amgen; received travel support from BMS, Pfizer, AstraZeneca, and Janssen. \u003cstrong\u003eKerstin Brinkert\u003c/strong\u003e: received travel support from Medac, Menarini Stemline, and Novartis. \u003cstrong\u003eUdo Holtick\u003c/strong\u003e: received honoraria from Amgen, BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi-Aventis, Stemline Therapeutics, and Takeda; had a consulting/advisory role for BMS/Celgene, GSK, Janssen, Oncopeptides, Pfizer, Sanofi-Aventis, and Stemline Therapeutics. \u003cstrong\u003eHans Salwender\u003c/strong\u003e: received honoraria from Janssen-Cilag, Takeda, Amgen, BMS/Celgene, Sanofi, Oncopeptides, AbbVie, GSK, Chugai, Stemline and Pfizer; received travel/accommodations/expenses from Janssen, Takeda, Amgen, BMS/Celgene, Sanofi, Stemline and GSK. \u003cstrong\u003eRicardo Kosch\u003c/strong\u003e: served on an advisory board for Menarini Stemline; received congress/travel support from Amgen, BeiGene, Sanofi, and Menarini Stemline. \u003cstrong\u003eTheo Leitner\u003c/strong\u003e: served as a consultant for Janssen (Johnson \u0026amp; Johnson); received research funding from Sanofi (to institution); received travel/accommodations/expenses from Sanofi, Lilly, Janssen (Johnson \u0026amp; Johnson), AOP Health, BeiGene, Alexion, and Regeneron. \u003cstrong\u003eLisa Leypoldt\u003c/strong\u003e: served as a consultant for GSK, Sanofi, Pfizer, and Janssen; received honoraria from Adaptive, Amgen, AbbVie, Janssen, BMS/Celgene, Pfizer, Sanofi, Takeda, AstraZeneca, and GSK; received research funding from AbbVie and GSK (to institution); received travel support from Sanofi, Johnson \u0026amp; Johnson, Amgen, and Oncopeptides. \u003cstrong\u003eMarkus Maulhardt\u003c/strong\u003e: received travel/congress support from AbbVie, Kite (Gilead), Sobi, and Incyte; received honoraria from Kite (Gilead) and Lilly. \u003cstrong\u003eTim Richardson\u003c/strong\u003e: served as a consultant/advisor to Janssen, BMS, Takeda, and Sanofi; received travel/accommodations/expenses from Janssen, Sanofi, Stemline Therapeutics, and Oncopeptides. \u003cstrong\u003eChristoph Schaefers\u003c/strong\u003e: served as a consultant for Acus Health, AstraZeneca, Janssen, Menarini Stemline, Oncopeptides, and Pfizer; received honoraria from AbbVie, AstraZeneca, Janssen-Cilag, and Sanofi; received travel expenses/congress support from Acus Health, AstraZeneca, Janssen, Menarini Stemline, Oncopeptides, and Sanofi. \u003cstrong\u003eJan Vorwerk\u003c/strong\u003e: received travel/accommodations/expenses from Incyte and Johnson \u0026amp; Johnson. \u003cstrong\u003eKatja Weisel\u003c/strong\u003e: served as a consultant for AbbVie, Adaptive Biotech, Amgen, BeiGene, GSK, Johnson \u0026amp; Johnson, Karyopharm, Menarini, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; received honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, BMS, Celgene, GSK, Janssen, Novartis, Oncopeptides, Sanofi, Stemline, and Takeda; served on boards/advisory committees for AbbVie, Adaptive Biotech, Amgen, BeiGene, BMS, Celgene, GSK, Johnson \u0026amp; Johnson, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Regeneron, Roche, Sanofi, and Takeda; received research funding from AbbVie, Amgen, GSK, Johnson \u0026amp; Johnson, Pfizer, BMS/Celgene, Novartis, Sanofi, and Takeda. \u003cstrong\u003eThe remaining authors declare no competing interests.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was not supported by any sponsor or funder.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMaximilian Al-Bazaz, Ricardo Kosch: conceptualization; methodology; investigation (providing patient data); data curation; formal analysis; visualization; writing – original draft; writing – review \u0026amp; editing. Winfried Alsdorf, Lisa Leypoldt, Annamaria Brioli, Carsten Bokemeyer, Katja Weisel: supervision; investigation (providing patient data); writing – review \u0026amp; editing. Piet Sonnemann: investigation (providing patient data); formal analysis; visualization; writing – review \u0026amp; editing. Christoph Schaefers, Jule Artzenroth, Marie Harzer, Abdulaziz Kamili, Leandra Bartke, Jan Vorwerk, Theo Leitner, Markus Maulhardt, Kerstin Brinkert, Tim Richardson, Udo Holtick, Stephan Hillmann, Hans Salwender, Cyrus Khandanpour: investigation (providing patient data); writing – review \u0026amp; editing. All authors approved the final manuscript and agreed to be accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data presented in this study are available upon reasonable request from the corresponding author. The data are not publicly available due to patients’ privacy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInvolvement of third parties in the research or manuscript preparation\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo individuals or third-party services were involved in the research or preparation of the manuscript who are not listed as authors or already acknowledged. Therefore, no updates to the acknowledgements are necessary in this regard.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMettias S, ElSayed A, Moore J, Berenson JR (2025) Multiple Myeloma: Improved Outcomes Resulting from a Rapidly Expanding Number of Therapeutic Options. 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Nat Med 24:563\u0026ndash;571\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarc\u0026iacute;a-Calder\u0026oacute;n CB et al (2023) Monitoring of kinetics and exhaustion markers of circulating CAR-T cells as early predictive factors in patients with B-cell malignancies. Front Immunol 14:1152498\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRytlewski J et al (2020) Effects of Prior Alkylating Therapies on Preinfusion Patient Characteristics and Starting Material for CAR T Cell Product Manufacturing in Late-Line Multiple Myeloma. Blood 136:7\u0026ndash;8\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCosta BA et al (2025) Impact of Prior Selinexor Exposure on Outcomes of Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma: An Exploratory Analysis. \u003cem\u003eJCM\u003c/em\u003e 14, 1316\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTyler PM et al (2017) Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy. Mol Cancer Ther 16:428\u0026ndash;439\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang D et al (2023) A novel two-step administration of XPO-1 inhibitor may enhance the effect of anti-BCMA CAR-T in relapsed/refractory extramedullary multiple myeloma. J Transl Med 21:812\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\n\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"University Medical Center Hamburg-Eppendorf","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":"Selinexor, refractory multiple myeloma, immunotherapy, bridging, BCMA, GPRC5D, CAR-T, bispecific antibodies, resistance","lastPublishedDoi":"10.21203/rs.3.rs-8124153/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8124153/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients with relapsed/refractory multiple myeloma (RRMM) who are penta-drug refractory, defined as resistant to two proteasome inhibitors, two immunomodulatory agents, and an anti-CD38 monoclonal antibody, face a dismal prognosis, particularly when progression occurs after exposure to novel T-cell redirecting therapies. Selinexor, an oral inhibitor of exportin-1, offers a distinct mechanism of action and may retain efficacy in this difficult-to-treat setting. We conducted a retrospective analysis at six German tertiary centers between 2023 and 2025 to evaluate the efficacy and safety of selinexor in combination with bortezomib and dexamethasone (SVd) in patients with penta-refractory MM who had relapsed after exposure to both BCMA- and GPRC5D-targeted therapies. 18 patients were identified, with a median of seven prior lines of therapy and a median time from diagnosis of 9.5 years. High-risk cytogenetic abnormalities were present in seven cases (including del17p in six cases). The overall response rate (ORR) was 61%, comprising one complete response, five very good partial responses (VGPR), and five partial responses (PR). The median progression-free survival (PFS) was 4.3 months (follow-up not reached). Among the nine patients (50%) with extramedullary disease (EMD), three achieved complete and one near-complete EMD resolution. Two patients who had relapsed after CAR-T cell treatment with idecabtagene vicleucel achieved PR and VGPR and were successfully transitioned to a second CAR T-cell treatment with ciltacabtagene autoleucel. Hematologic toxicities under SVd were manageable; no treatment-related deaths occurred. SVd demonstrates meaningful activity in patients with penta-refractory MM and prior failure of BCMA/GPRC5D-targeted immunotherapies. The ORR of 61% and a 78% disease control rate with median PFS of 4.3 months support evaluation of SVd in this highly refractory setting after failure of targeted immunotherapeutic approaches against both BCMA and GPRC5D.\u003c/p\u003e","manuscriptTitle":"Selinexor, Bortezomib and Dexamethasone After Sequential BCMA- and GPRC5D-Directed Therapy Failure in Penta-Refractory Multiple Myeloma: A Multicenter Real-World Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-18 08:58:15","doi":"10.21203/rs.3.rs-8124153/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":"ed33d20c-6f2c-4ccf-9b16-7a8fbee93a66","owner":[],"postedDate":"November 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58051916,"name":"Hematology"},{"id":58051917,"name":"Oncology"}],"tags":[],"updatedAt":"2025-11-18T08:58:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-18 08:58:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8124153","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8124153","identity":"rs-8124153","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}