Debulking strategy prior to anti-BCMA/CD3 bispecific antibodies in extramedullary and/or high tumor burden RRMM: a retrospective cohort study

Debulking strategy prior to anti-BCMA/CD3 bispecific antibodies in extramedullary and/or high tumor burden RRMM: a retrospective cohort study | 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 Article Debulking strategy prior to anti-BCMA/CD3 bispecific antibodies in extramedullary and/or high tumor burden RRMM: a retrospective cohort study Thomas Chalopin, Elise Cellerin, Hélène Demarquette, andrea pieragostini, and 15 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6841736/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 21 Oct, 2025 Read the published version in Blood Cancer Journal → Version 1 posted 5 You are reading this latest preprint version Abstract T-cell redirecting immunotherapies have improved outcomes in relapsed/refractory multiple myeloma (RRMM), yet patients with extramedullary disease (EMD) and/or high tumor burden continue to fare poorly. We evaluated chemotherapy-based tumor debulking prior to anti-BCMA/CD3 bispecific antibody (BsAb) therapy in this high-risk population. In this multicenter retrospective study (15 IFM centers), RRMM patients receiving BsAb therapy after chemotherapy within the prior month were analyzed. High tumor burden included medullary/para-medullary disease or elevated monoclonal protein. High-risk cytogenetics comprised del(17p), 1q21 gain/amplification, t(4;14), or t(14;16). Forty-four patients (median age 67) were included: 93% were triple-class refractory, 50% had EMD, and 50% had high-risk cytogenetics. Chemotherapy regimens included alkylators (89%), anthracyclines (34%), and etoposide (50%). Teclistamab (70%) or elranatamab (30%) was initiated after a median of 28 days post-chemotherapy. At 12 months median follow-up, ORR post-chemotherapy was 32%. ORR with BsAb reached 64% after cycle 1, 73% after cycle 3, and 87% after cycle 6. Median progression-free survival was 10.2 months; median overall survival, 20.1 months. Chemotherapy-based debulking prior to anti-BCMA/CD3 BsAb is feasible and safe, achieving high response rates and durable outcomes in high-risk RRMM. Health sciences/Diseases/Haematological diseases/Haematological cancer/Myeloma Health sciences/Risk factors multiple myeloma immunotherapy chemotherapy extramedullary Figures Figure 1 Figure 2 Figure 3 Introduction Despite promising response rates and survival outcomes with anti-BCMA bispecific antibodies (BsAbs), certain patient subgroups present unique challenges [ 1 ]. These include patients with extramedullary disease (EMD), high-risk cytogenetic abnormalities (HRCA), or a combination of an International Staging System (ISS) stage III score with other high-tumor burden criteria such as medullary plasma cell infiltration or elevated beta-2-microglobulin levels [ 1 – 3 ]. The patients with EMD, high tumour burdens or HRCA frequently exhibit lower overall response rate (ORR) and poorer survival outcomes with anti-BCMA agents [ 4 – 8 ]. A sub-analysis of the MagnetisMM-3 trial reported an ORR of 0% in patients with ISS stage III disease and HRCA or EMD, compared to ORRs of 47.4% and 71.4% in patients with ISS stages I and II with EMD or HRCA, respectively [ 9 ]. Teclistamab achieved an ORR of 63% and a median progression-free survival (PFS) of 11.3 months in MajesTec-1 trial [ 5 ]. In real-life setting, PFS for patients with EMD was 3.7 months vs 11.3 months for patients without EMD and ORR decreased at 37.2% [ 10 , 11 ]. Before the advent of novel T-cell-targeting immunotherapies, conventional chemotherapy was the primary treatment for EMD in heavily pretreated patients. Regimens such as PAd (bortezomib, doxorubicin, dexamethasone), DT-PACE (thalidomide, cyclophosphamide, etoposide, dexamethasone, cisplatin, and doxorubicin) and VDT-PACE (adding bortezomib) were frequently used [ 12 – 14 ]. Additional strategies incorporating pomalidomide or carfilzomib have also been reported [ 15 , 16 ]. In registrational trials of anti-BCMA CAR-T cells, approximately 40–50% of patients required bridging therapy, often including alkylating agents [ 17 – 18 ]. Cyclophosphamide, a commonly used alkylator, offers tumor debulking and lymphodepletion while mitigating T-cell exhaustion, modulating the tumor microenvironment, and inducing durable anti-MM immunity [ 19 ]. A bridging therapy type regimen may be crucial for patients treated with BsAbs BCMA/CD3 with aggressive disease, with or without HRCA or EMD. This retrospective study aims to evaluate the efficacy and tolerability of conventional chemotherapy as a debulking strategy prior to BCMA/CD3 BsAb therapy in patients with RRMM characterized with high-risk cytogenetic, EMD and/or high tumor burden. Materials and Methods Patients from Intergroupe Francophone du Myélome (IFM) centers in France were included if they had received at least one full treatment dose of BsAbs and a cycle of conventional chemotherapy within the preceding month. Patients with plasma cell leukemia, amyloidosis, or those enrolled in clinical trials were excluded. Extramedullary disease was defined as a lesion confined to soft tissue without contact with bony structures. The presence of EMD was evaluated through computed tomography (CT) scans, magnetic resonance imaging (MRI), or positron emission tomography (PET) scans conducted before the initiation of therapy. High tumor burden was determined based on medullary plasma cell infiltration (> 60%), para-medullary disease, and/or elevated levels of monoclonal protein (peak > 30 g/dl and/or abnormal light chain > 5000mg/L). High-risk cytogenetic abnormalities (HRCAs) were defined by the presence of del(17p), t(4;14), or t(14;16). Outcomes were assessed according to the International Myeloma Working Group (IMWG) response criteria, with additional imaging-based assessments for patients with EMD [ 20 ]. Adverse events, including cytokine release syndrome (CRS), immune-effector cell-associated syndrome (ICANS), hematologic toxicity and infections, were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Time-to-event analyses were performed using the Kaplan-Meier method. Survival comparisons between subgroups were conducted using the log-rank test, and Cox regression was employed for univariate analyses. Differences in overall response rates (ORR) between groups were analyzed using chi-square tests. All statistical analyses were performed using [version R 4.3.2]. Patient records were retrospectively reviewed from medical databases. Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools. REDCap is a secure, web-based software platform designed to support data capture for research studies. This study was approved by the local Ethics Committees, in compliance with applicable ethical standards (n° 2024 053 and CNIL n° 18355189). Results Patient’s characteristics We included 44 patients in 14 centers in France between March 2022 and July 2024. Median age was 67 years old (min-max: 45–82) with 50% female (n = 22). Triple-class refractory MM represented 93% (n = 41), and median of prior lines was 4 (min-max: 2–9) ( Table 1 ) . We found an ISS score at 3 in 48% (n = 20), elevated LDH and B2M level in 31% (n = 13) and 35% (n = 15) respectively. Median of bone marrow plasma cell infiltration was 66% in 12 patients evaluated (min-max: 0–93). Monoclonal component had a median level at 13 g/l (min-max: 0–72) for Ig and 2042 mg/L (min-max: 0-11435) for light-chain. Acute kidney failure was present in 14 patients (32%) and hypercalcemia in 10 patients (23%). 18FDG PET-scan was realized before chemotherapy in 28 patients and was abnormal in 59% (n = 26). EMD was found in 22 patients (50%) and PMD in 15 patients (34%). Twenty-two patients (50%) had an HRCA with 17p deletion in 41% (n = 9), 1q21 gain in 23% (n = 5), t(4;14) in 14% (n = 3) and t(14;16) in 9.1% (n = 2) Debulking regimen-based treatment and BCMA/CD3 BsAb Details on treatment is report on Table 2 . Number of cycles of chemotherapy was one in 68% (n = 30), two and ≥ 3 cycles in 16% (n = 7) both. The most frequent class used was alkylating agent in 89% (n = 39), followed by anthracycline in 34% (n = 15), etoposide in 50% (n = 22), cisplatin in 16% (n = 7) and vincristine in 9.1% (n = 4). The most used agents were cyclophosphamide in 84% (n = 37), etoposide in 50% (n = 22) and Adriamycin in 34% (n = 15). Combination of anthracycline and alkylating agent was used in 27% of cases (n = 12). The time between chemotherapy and anti-BCMA BsAbs was 28 days (min-max: 4-197). teclistamab was used in 70% (n = 31) and elranatamab in 30% (n = 13). No patients received radiotherapy. BsAbs safety profile Cytokine release syndrome (CRS) rate was 64% (n=28), with a majority of grade 1 (75%, n=21), 21% of grade 2 (n=6) and 3.6% of grade 3 (n=1). The immune effector cell-associated syndrome (ICANS) rate was 7% (n=3) with two grade 1 and one grade 4. CRS and/or ICANS were managed with tocilizumab in 23% of cases (n=10%), dexamethasone in 9.1% (n=4) and anakinra in 2.3% (n=1). Grade ≥3 infections were reported in 35% (n=15) documented in 73% of cases. Use of immunoglobulin replacement was done in 80% (n=35), antibioprophylaxis in 55% (n=44), antipneumocystis agent in 89% (n=39) and antiviral in 98% (n=43). Hematological toxicity with grade ≥3 cytopenia was reported in 33% (n=14) indicating use of G-CSF in 7 patients (Table 2) . Response rate After the debulking chemotherapy-based regimen, ORR was 32% (n = 37) with 16% of ≥ VGPR. ORR after cycle 1 of BsAb was 64% (n = 39) with 33% of CR and 46% VGPR or better. After cycle 3 (n = 34), the ORR was 73% and 87% at cycle 6 (n = 21). At one year, in the 10 patients evaluated, ORR was 80% with 30% of CR. Only few patients did have a PET-CT after C1 (n = 4), C3 (n = 7) and C6 (n = 7) (Fig. 1A) . Best response rate after debulking treatment and best response to BsAb for all patient was presented in Fig. 1B. Among patients in CR or VGPR after debulking (n = 3, both), 100% responded to BsAb (≥ PR or better). For patients with disease progression after chemotherapy (n = 8), 50% had a response to BsAB (Fig. 2A). Conversion of response rate was reported on Fig. 2B. Among patients with EMD, ORR after C1 and C3 was 53% (n = 9/17 and n = 8/15), at C6 ORR was 77.8% (n = 7/9) and 50% at C12 (2/4). Concerning patient with HRCA, ORR after C1 was 64% (n = 12/19), 73% after C3 (n = 12/15), 82% (n = 9/11) and 83% (n = 5/6) after C6 and C12 respectively. Survival The median follow-up of the study was 12 months (range: 1–31). In the overall population, median PFS was 10.2 months (95%CI: 6.87–18.6) (Fig. 3A). Regarding EMD, patients without EMD had a median PFS at 14.1 months (95%CI: 6.47-NR) vs 9.3 months (95%CI: 3.7-NR) for patients with EMD (p = 0.05) (Fig. 3B). Patients with HRCA had a median PFS at 10.2 months (95%CI: 5.02-NR) versus 7.6 (95%CI: 5.0-NR) for patients without HRCA (p = 0.9). Median OS was 20.1 months (95%CI: 13.8-NR) for all patients (Fig. 3C) . For patients with EMD, median OS was 13.7 months (95%CI: 6.5-NR), not reached for patients without EMD (95%CI: 13.8-NR) (p = 0.1) (Fig. 3D). In patients with HRCA, median OS was 19.3 (95%CI: 13.8-NR) vs 13.8 (95%CI: 7.45-NR) for patient without HRCA (p = 0.8). Death occurred in 19 patients (43%), 14 due to disease progression, 3 to infection and 2 others causes. Discussion This multicenter retrospective study is among the first to evaluate the efficacy and tolerability of conventional debulking chemotherapy prior to initiating anti-BCMA bispecific antibody therapy in patients with RRMM and either EMD or high tumor burden. Our findings suggest that this sequential approach is both effective and tolerable, even in a high-risk, heavily pretreated patient population. Our cohort had a median of four prior treatment lines, and 93% of patients were triple-class refractory. Half had EMD and 50% had high-risk cytogenetics—both markers of poor prognosis. Despite these adverse features, the ORR after the first BsAb cycle was 64%, comparable to results from pivotal trials such as MajesTEC-1 and MagnetisMM-3, which reported ORRs of 63% and 61%, respectively [ 5 – 9 ]. Among patients with EMD, the ORR was 53% after both cycle one and three, increasing to 77.8% at six cycles. These results are particularly notable given prior data showing limited efficacy of BsAbs in EMD, such as the 0% ORR reported in a subgroup analysis of MagnetisMM-3 in patients with ISS stage III and EMD or high-risk cytogenetics [ 9 ]. Herein, the choice of chemotherapy was largely based on alkylating agents, especially cyclophosphamide (84%). Cyclophosphamide not only induces cytotoxicity but also modulates the immune microenvironment, reduces T-cell exhaustion, and enhances T-cell activation—all potentially boosting BsAb efficacy [ 19 ]. These immunomodulatory effects, combined with tumor debulking, may help improve the effector-to-target cell ratio, which plays a key role in the success of BsAb therapies. There is also a theoretical rationale that chemotherapy-induced cell death may promote neoantigen release and immune priming, further amplifying BsAb effectiveness [ 20 , 21 ]. In 27% of patients, alkylating agents were combined with anthracyclines, and 50% received etoposide. These regimens resemble intensive protocols such as DT-PACE, previously used in EMD before the advent of immunotherapy. However, 68% of patients received only a single cycle of chemotherapy, which likely reduced cumulative toxicity while achieving rapid cytoreduction [ 12 , 13 ]. At a median follow-up of 12 months in our study, median progression-free survival (PFS) was 10.2 months. Patients without EMD had a significantly longer PFS (16.1 vs . 11.9 months; p = 0.05). These outcomes align with prior BsAb trial data, such as teclistamab (11.3 months) and elranatamab (17.6 months) [ 5 – 9 ]. In the IFM 2024-09 real-world study, the median PFS for patients with EMD was 3.7 months vs 11.3 months for patients without EMD treated by Teclistamab [ 10 ]. A real-world analysis of teclistamab use in Germany show an ORR of 37.2% and a median PFS of 2.07 months for patients with EMD [ 11 ]. In contrast, our results suggest improved disease control in this subgroup, although long-term benefit remains limited. This highlights the need for continued efforts to optimize treatment for patients with EMD. The safety profile of this approach was acceptable given the heavily pretreated patient population [ 24 – 26 ]. Despite prior chemotherapy, the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remained low—7% for ICANS and no apparent increase in CRS severity [ 24 – 27 ]. Hematological toxicity ≥ grade 3 occurred in 33% of patients, and infections ≥ grade 3 were reported in 35%. This observation suggests that prior chemotherapy does not significantly increase the risk or severity of CRS associated with bispecific antibodies, countering some theoretical concerns. Preventive strategies, including immunoglobulin supplementation, antibiotic and antiviral prophylaxis, and pneumocystis prevention, were widely used and likely contributed to infection management. Importantly, toxicity rates were similar between patients with and without EMD, suggesting that worse disease biology does not necessarily imply greater treatment-related toxicity. The retrospective nature and modest size of our study introduce limitations. The heterogeneity of chemotherapy regimens and the lack of a comparator group make it difficult to draw definitive conclusions about the superiority of the sequential approach over BsAb monotherapy. Infrequent PET-CT assessments also limited our ability to fully evaluate depth of response, especially in patients with EMD. Prospective trials are needed to refine these aspects and to validate our findings. Additionally, translational studies evaluating immune markers, T-cell subsets, and changes in the tumor microenvironment before and after chemotherapy could help elucidate mechanisms of synergy and resistance. Anti-BCMA CAR-T cell therapies have shown high response rates (> 70%) and median PFS of 8.8 to 12.9 months, but their use often necessitates bridging therapy during manufacturing, in 40–50% of cases [ 18 , 19 , 28 ]. In this context, chemotherapy-based debulking may represent a practical option for disease control while awaiting CAR-T infusion. Moreover, emerging combinations of BsAbs with IMiDs, proteasome inhibitors, or even other BsAbs have been explored in clinical trials with promising results [ 29 , 30 ]. Whether debulking chemotherapy can be integrated into such regimens to improve outcomes in patients with high tumor burden or EMD remains an open question. Conclusion Our study suggests that chemotherapy-based tumor debulking before anti-BCMA BsAb therapy is a feasible and promising strategy for patients with RRMM and high tumor burden or EMD. It appears to enhance early responses while maintaining a manageable safety profile. These preliminary findings warrant confirmation in larger, prospective trials, along with deeper investigation into the biological underpinnings of this potentially synergistic treatment sequence. Table 1 Patient’s characteristics Characteristics, n(%) N = 44 patients Median Age, years-old 66 (min-max : 45–82) Female, n(%) 22 (50) Median of Prior lines 4 (min-max : 2–9) Triple class refractory, n(%) 41 (93) ISS score III, n(%) 20 (48) Cytogenetic abnormalities, n(%) 22 (50) 17p deletion 9 (20) 1q21 gain 5 (11) t(4 ;14) 3 (7) t(14 ;16) 2 (4) Del1p32 2 (4) 1q21 amplification 1 (2) Extramedullary disease, n(%) 22 (50) Number of involved sites, n(%) 1 4 (9) 2 5 (11) ≥3 10 (23) Type of localization, n(%) Cerebral 2 (4) Lung 4 (9) Liver 3 (7) Kidney 3 (7) Digestive 7 (16) Cutaneous 8 (18) Muscle 5 (11) ORL 1 (2) High Plasma cell infiltration, n(%) 12 (28) Acute kidney failure, n(%) 14 (32) Hypercalcemia, n(%) 10 (23) Table 2 Details on chemotherapy and bispecific treatments. N = 44 patients Chemotherapy Number of cycles, n(%) 1 30 (68) 2 7 (16) ≥3 7 (16) Alkylating agent, n(%) 39 (89) Cyclosphosphamide 37 (84) Bendamustine 5 (11) Belustine 1 (2.3) Anthracycline agent, n(%) 15 (34) Etoposide 22 (50) Vincristine 4 (9.1) Cisplatin 7 (16) Other 9 (20) Anti-BCMA bispecific, n(%) Teclistamab 31 (70) Elranatamab 13 (30) Delay between chemotherapy and bispecific, median days (min-max) 28 (4-197) CRS rate, n(%) 28 (64) Grade 1 21 (75) Grade 2 6 (21) Grade 3 1 (3.6) ICANS rate, n(%) 3 (7) Grade 1 2 (67) Grade 2–3 0 Grade 4 1 (33) Tocilizumab use, n(%) 10 (23) Dexamethasone use, n(%) 4 (9.1) Infection, n(%) Grade 3 infection 12 (80) Ig supplementation therapy 35 (80) Antipneumocystisis agent 38 (89) Antibioprophylaxis 24 (55) Antiviral agent 43 (98) Grade 3 cytopenias, n(%) 14 (33) Declarations AUTHOR CONTRIBUTIONS TC, HD, AP, CS, CJ, ZDW, AR, MR, GL, VM, LV, VS, TC and AB followed study patients. TC, EC, XL and SM interpreted the results; EC performed statistical analysis; TC wrote the manuscript; XL and SM supervised the project; XL, EC and SM revised the manuscript. All authors approved the manuscript. COMPETING INTERESTS TC: Consultant/Advisory Boards: BMS, Takeda, Janssen, GSK, Griffols, Amgen, Sanofi, Pfizer, Stemline. X.L. has received consultancy, honoraria and travel fees from Sanofi, Janssen-Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GSK and Bristol Myers Squibb. A.B. received consultancy and honoraria from Sanofi, Janssen-Cilag. The other authors declare no competing interests. References Mateos MV, Weisel K, De Stefano V, et al. LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma. Leukemia. 2022;36(5):1371-1376. Bladé J, Beksac M, Caers J, et al. Extramedullary disease in multiple myeloma: a systematic literature review. 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Chimeric antigen receptor T-Cell and bispecific antibody therapy in multiple myeloma: moving Into the future. J Clin Oncol. 2023;41(27):4416-4429. Cohen YC, Magen H, Gatt M, et al. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2025;392(2):138-149. Holstein SA, Grant SJ, Wildes TM. Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future. J Clin Oncol. 2023;41(27):4416-4429. Additional Declarations There is NO conflict of interest to disclose. Cite Share Download PDF Status: Published Journal Publication published 21 Oct, 2025 Read the published version in Blood Cancer Journal → Version 1 posted Editorial decision: revise 18 Jun, 2025 Editor assigned by journal 11 Jun, 2025 Submission checks completed at journal 11 Jun, 2025 First submitted to journal 11 Jun, 2025 Unknown event 09 Jun, 2025 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-6841736","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":473159425,"identity":"adf40598-125c-40be-9747-bcc4b815eba3","order_by":0,"name":"Thomas Chalopin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYHACNgaGAhDJfIAZIWiDWz0PWIsBiGRLAGmRgIinEaEFyDQgTos9A/OzBz8MbPL4pHs+fi5sY6jjl8h9/IEh4R4eW9jMDXsM0orZZM5ulp7ZxiAhOSPdTIIhoRiPFh42CR6Dw4ltErnbmHnb/ksY3EhjY2D8kYBXi+QfsJacZ0AtDCAtzECH4dciDbElhw2mBRgG+LQcZjOTlgH5RSLNWJrnHIPkzJ5nbBIJeLSwtzc/k3xTYZMnPyP54WeeMgZ+fnagwz7g0cIAjXE0FXg0kKRmFIyCUTAKRioAAF2OP2LLzwaZAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-9833-3115","institution":"University Hospital, Tours","correspondingAuthor":true,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Chalopin","suffix":""},{"id":473159426,"identity":"d6c044df-2711-45fe-b75d-dfac92962a79","order_by":1,"name":"Elise Cellerin","email":"","orcid":"","institution":"University Hospital of Tours","correspondingAuthor":false,"prefix":"","firstName":"Elise","middleName":"","lastName":"Cellerin","suffix":""},{"id":473159427,"identity":"1a7cf081-28ed-4587-8733-180e382c6241","order_by":2,"name":"Hélène Demarquette","email":"","orcid":"","institution":"Centre Hospitaliser de Dunkerque","correspondingAuthor":false,"prefix":"","firstName":"Hélène","middleName":"","lastName":"Demarquette","suffix":""},{"id":473159428,"identity":"34d8d4d0-35be-460e-8486-0c6a19c0d894","order_by":3,"name":"andrea pieragostini","email":"","orcid":"","institution":"University Hospital of Dijon","correspondingAuthor":false,"prefix":"","firstName":"andrea","middleName":"","lastName":"pieragostini","suffix":""},{"id":473159429,"identity":"d2b4f736-dfcb-4208-93c6-42c079844ceb","order_by":4,"name":"Cecile Sonntag","email":"","orcid":"","institution":"University Hospital, Hôpital Hautepierre","correspondingAuthor":false,"prefix":"","firstName":"Cecile","middleName":"","lastName":"Sonntag","suffix":""},{"id":473159430,"identity":"76f01140-e4ec-426f-89d6-e942d20aa18f","order_by":5,"name":"Caroline Jacquet","email":"","orcid":"","institution":"University Hospital, Nancy","correspondingAuthor":false,"prefix":"","firstName":"Caroline","middleName":"","lastName":"Jacquet","suffix":""},{"id":473159431,"identity":"41cadcea-e9c5-49ae-a504-3331ee8900d9","order_by":6,"name":"Zoe van de Wyngaert","email":"","orcid":"https://orcid.org/0000-0001-9463-2823","institution":"Hôpital Saint-Antoine, AP-HP","correspondingAuthor":false,"prefix":"","firstName":"Zoe","middleName":"van","lastName":"de Wyngaert","suffix":""},{"id":473159432,"identity":"8d079e53-1040-4426-9d79-befe9c32050c","order_by":7,"name":"Anne Rumpler","email":"","orcid":"","institution":"University Hospital of Besançon","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"","lastName":"Rumpler","suffix":""},{"id":473159433,"identity":"e3c00dd3-0d7f-4db0-8fcd-09f9c5877d36","order_by":8,"name":"murielle Roussel","email":"","orcid":"","institution":"CHU Limoges","correspondingAuthor":false,"prefix":"","firstName":"murielle","middleName":"","lastName":"Roussel","suffix":""},{"id":473159434,"identity":"04a678ca-b7d0-49ce-ba61-c9873994be37","order_by":9,"name":"Gaelle Labouré","email":"","orcid":"","institution":"Centre Hospitalier de Libourne","correspondingAuthor":false,"prefix":"","firstName":"Gaelle","middleName":"","lastName":"Labouré","suffix":""},{"id":473159435,"identity":"e8fc0fa2-99e8-4211-8b1e-43a5bd43e498","order_by":10,"name":"veronique morel","email":"","orcid":"","institution":"Pitié-Salpêtrière (AP-HP)","correspondingAuthor":false,"prefix":"","firstName":"veronique","middleName":"","lastName":"morel","suffix":""},{"id":473159436,"identity":"42a66dd9-4e96-4fc5-8173-f24204bf3a40","order_by":11,"name":"Laure Vincent","email":"","orcid":"https://orcid.org/0000-0001-5904-1286","institution":"Montpellier University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Laure","middleName":"","lastName":"Vincent","suffix":""},{"id":473159437,"identity":"08ff24a2-5bf2-4eec-b825-c7f0ef713519","order_by":12,"name":"Valery Salle","email":"","orcid":"","institution":"University Hospital of Amiens","correspondingAuthor":false,"prefix":"","firstName":"Valery","middleName":"","lastName":"Salle","suffix":""},{"id":473159438,"identity":"3f2cd000-c640-4e6d-9106-741299259ecb","order_by":13,"name":"Titouan Cazaubiel","email":"","orcid":"","institution":"University Hospital, Bordeaux","correspondingAuthor":false,"prefix":"","firstName":"Titouan","middleName":"","lastName":"Cazaubiel","suffix":""},{"id":473159439,"identity":"09876fad-ac42-4ded-bf2d-9702b6ba8af2","order_by":14,"name":"Arthur Bobin","email":"","orcid":"","institution":"CHU de Poitiers","correspondingAuthor":false,"prefix":"","firstName":"Arthur","middleName":"","lastName":"Bobin","suffix":""},{"id":473159440,"identity":"ddbe0d39-ea38-4d30-8a65-e7ac32b5cbfd","order_by":15,"name":"Anaïs Schavgoulidze","email":"","orcid":"https://orcid.org/0000-0002-5526-4279","institution":"Institut Universitaire du Cancer-Oncopole and Centre de Recherche en Cancérologie de Toulouse INSERM U1037","correspondingAuthor":false,"prefix":"","firstName":"Anaïs","middleName":"","lastName":"Schavgoulidze","suffix":""},{"id":473159441,"identity":"02290e8e-6609-48f0-b20e-7012eb3a5259","order_by":16,"name":"Jill Corre","email":"","orcid":"https://orcid.org/0000-0003-1580-6106","institution":"Institut Universitaire du Cancer-Oncopole and Centre de Recherche en Cancérologie de Toulouse INSERM U1037","correspondingAuthor":false,"prefix":"","firstName":"Jill","middleName":"","lastName":"Corre","suffix":""},{"id":473159442,"identity":"1eda75a0-914b-4282-8573-1a382bbd7039","order_by":17,"name":"Xavier Leleu","email":"","orcid":"https://orcid.org/0000-0002-9822-4170","institution":"Universite and Inserm U 1313, 1402, CHU","correspondingAuthor":false,"prefix":"","firstName":"Xavier","middleName":"","lastName":"Leleu","suffix":""},{"id":473159443,"identity":"1f7dccab-d70a-48e7-959f-6734cd88c651","order_by":18,"name":"Salomon Manier","email":"","orcid":"","institution":"University of Lille","correspondingAuthor":false,"prefix":"","firstName":"Salomon","middleName":"","lastName":"Manier","suffix":""}],"badges":[],"createdAt":"2025-06-07 08:55:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6841736/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6841736/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41408-025-01365-y","type":"published","date":"2025-10-21T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":86420835,"identity":"908bcebb-21e9-42b6-b3da-2390ea0206a5","added_by":"auto","created_at":"2025-07-10 12:48:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":69639,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6841736/v1/ecb275f5221f73bac9b54ab0.png"},{"id":86422107,"identity":"86e3f27a-7008-42cb-ba66-0a9f205dfa8a","added_by":"auto","created_at":"2025-07-10 12:56:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":92171,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6841736/v1/23a9851977662b97ce35b863.png"},{"id":86420841,"identity":"d3faa76a-c5d0-46af-a240-7316a8ecfb63","added_by":"auto","created_at":"2025-07-10 12:48:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":251808,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6841736/v1/e15a3710e3e1c6e598efee4b.png"},{"id":94062664,"identity":"f2814b95-682a-4302-adf9-16bbb78d5f6b","added_by":"auto","created_at":"2025-10-22 07:14:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1213753,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6841736/v1/1d5f7f60-17f2-47ea-bc61-53c0cd224d39.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"\u003cp\u003eDebulking strategy prior to anti-BCMA/CD3 bispecific antibodies in extramedullary and/or high tumor burden RRMM: a retrospective cohort study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDespite promising response rates and survival outcomes with anti-BCMA bispecific antibodies (BsAbs), certain patient subgroups present unique challenges [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. These include patients with extramedullary disease (EMD), high-risk cytogenetic abnormalities (HRCA), or a combination of an International Staging System (ISS) stage III score with other high-tumor burden criteria such as medullary plasma cell infiltration or elevated beta-2-microglobulin levels [\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The patients with EMD, high tumour burdens or HRCA frequently exhibit lower overall response rate (ORR) and poorer survival outcomes with anti-BCMA agents [\u003cspan additionalcitationids=\"CR5 CR6 CR7\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. A sub-analysis of the MagnetisMM-3 trial reported an ORR of 0% in patients with ISS stage III disease and HRCA or EMD, compared to ORRs of 47.4% and 71.4% in patients with ISS stages I and II with EMD or HRCA, respectively [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Teclistamab achieved an ORR of 63% and a median progression-free survival (PFS) of 11.3 months in MajesTec-1 trial [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In real-life setting, PFS for patients with EMD was 3.7 months vs 11.3 months for patients without EMD and ORR decreased at 37.2% [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBefore the advent of novel T-cell-targeting immunotherapies, conventional chemotherapy was the primary treatment for EMD in heavily pretreated patients. Regimens such as PAd (bortezomib, doxorubicin, dexamethasone), DT-PACE (thalidomide, cyclophosphamide, etoposide, dexamethasone, cisplatin, and doxorubicin) and VDT-PACE (adding bortezomib) were frequently used [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Additional strategies incorporating pomalidomide or carfilzomib have also been reported [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn registrational trials of anti-BCMA CAR-T cells, approximately 40\u0026ndash;50% of patients required bridging therapy, often including alkylating agents [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Cyclophosphamide, a commonly used alkylator, offers tumor debulking and lymphodepletion while mitigating T-cell exhaustion, modulating the tumor microenvironment, and inducing durable anti-MM immunity [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A bridging therapy type regimen may be crucial for patients treated with BsAbs BCMA/CD3 with aggressive disease, with or without HRCA or EMD.\u003c/p\u003e \u003cp\u003eThis retrospective study aims to evaluate the efficacy and tolerability of conventional chemotherapy as a debulking strategy prior to BCMA/CD3 BsAb therapy in patients with RRMM characterized with high-risk cytogenetic, EMD and/or high tumor burden.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003ePatients from Intergroupe Francophone du My\u0026eacute;lome (IFM) centers in France were included if they had received at least one full treatment dose of BsAbs and a cycle of conventional chemotherapy within the preceding month. Patients with plasma cell leukemia, amyloidosis, or those enrolled in clinical trials were excluded.\u003c/p\u003e \u003cp\u003eExtramedullary disease was defined as a lesion confined to soft tissue without contact with bony structures. The presence of EMD was evaluated through computed tomography (CT) scans, magnetic resonance imaging (MRI), or positron emission tomography (PET) scans conducted before the initiation of therapy. High tumor burden was determined based on medullary plasma cell infiltration (\u0026gt;\u0026thinsp;60%), para-medullary disease, and/or elevated levels of monoclonal protein (peak\u0026thinsp;\u0026gt;\u0026thinsp;30 g/dl and/or abnormal light chain\u0026thinsp;\u0026gt;\u0026thinsp;5000mg/L). High-risk cytogenetic abnormalities (HRCAs) were defined by the presence of del(17p), t(4;14), or t(14;16).\u003c/p\u003e \u003cp\u003eOutcomes were assessed according to the International Myeloma Working Group (IMWG) response criteria, with additional imaging-based assessments for patients with EMD [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Adverse events, including cytokine release syndrome (CRS), immune-effector cell-associated syndrome (ICANS), hematologic toxicity and infections, were graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.\u003c/p\u003e \u003cp\u003eTime-to-event analyses were performed using the Kaplan-Meier method. Survival comparisons between subgroups were conducted using the log-rank test, and Cox regression was employed for univariate analyses. Differences in overall response rates (ORR) between groups were analyzed using chi-square tests. All statistical analyses were performed using [version R 4.3.2]. Patient records were retrospectively reviewed from medical databases. Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools. REDCap is a secure, web-based software platform designed to support data capture for research studies. This study was approved by the local Ethics Committees, in compliance with applicable ethical standards (n\u0026deg; 2024 053 and CNIL n\u0026deg; 18355189).\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003ePatient\u0026rsquo;s characteristics\u003c/h2\u003e \u003cp\u003eWe included 44 patients in 14 centers in France between March 2022 and July 2024. Median age was 67 years old (min-max: 45\u0026ndash;82) with 50% female (n\u0026thinsp;=\u0026thinsp;22). Triple-class refractory MM represented 93% (n\u0026thinsp;=\u0026thinsp;41), and median of prior lines was 4 (min-max: 2\u0026ndash;9) \u003cb\u003e(\u003c/b\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eWe found an ISS score at 3 in 48% (n\u0026thinsp;=\u0026thinsp;20), elevated LDH and B2M level in 31% (n\u0026thinsp;=\u0026thinsp;13) and 35% (n\u0026thinsp;=\u0026thinsp;15) respectively. Median of bone marrow plasma cell infiltration was 66% in 12 patients evaluated (min-max: 0\u0026ndash;93). Monoclonal component had a median level at 13 g/l (min-max: 0\u0026ndash;72) for Ig and 2042 mg/L (min-max: 0-11435) for light-chain. Acute kidney failure was present in 14 patients (32%) and hypercalcemia in 10 patients (23%).\u003c/p\u003e \u003cp\u003e18FDG PET-scan was realized before chemotherapy in 28 patients and was abnormal in 59% (n\u0026thinsp;=\u0026thinsp;26). EMD was found in 22 patients (50%) and PMD in 15 patients (34%). Twenty-two patients (50%) had an HRCA with 17p deletion in 41% (n\u0026thinsp;=\u0026thinsp;9), 1q21 gain in 23% (n\u0026thinsp;=\u0026thinsp;5), t(4;14) in 14% (n\u0026thinsp;=\u0026thinsp;3) and t(14;16) in 9.1% (n\u0026thinsp;=\u0026thinsp;2)\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDebulking regimen-based treatment and BCMA/CD3 BsAb\u003c/h3\u003e\n\u003cp\u003eDetails on treatment is report on Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Number of cycles of chemotherapy was one in 68% (n\u0026thinsp;=\u0026thinsp;30), two and \u0026ge;\u0026thinsp;3 cycles in 16% (n\u0026thinsp;=\u0026thinsp;7) both. The most frequent class used was alkylating agent in 89% (n\u0026thinsp;=\u0026thinsp;39), followed by anthracycline in 34% (n\u0026thinsp;=\u0026thinsp;15), etoposide in 50% (n\u0026thinsp;=\u0026thinsp;22), cisplatin in 16% (n\u0026thinsp;=\u0026thinsp;7) and vincristine in 9.1% (n\u0026thinsp;=\u0026thinsp;4). The most used agents were cyclophosphamide in 84% (n\u0026thinsp;=\u0026thinsp;37), etoposide in 50% (n\u0026thinsp;=\u0026thinsp;22) and Adriamycin in 34% (n\u0026thinsp;=\u0026thinsp;15). Combination of anthracycline and alkylating agent was used in 27% of cases (n\u0026thinsp;=\u0026thinsp;12).\u003c/p\u003e \u003cp\u003eThe time between chemotherapy and anti-BCMA BsAbs was 28 days (min-max: 4-197). teclistamab was used in 70% (n\u0026thinsp;=\u0026thinsp;31) and elranatamab in 30% (n\u0026thinsp;=\u0026thinsp;13). No patients received radiotherapy.\u003c/p\u003e\u003cp\u003e\u003cem\u003eBsAbs safety profile \u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCytokine release syndrome (CRS) rate was 64% (n=28), with a majority of grade 1 (75%, n=21), 21% of grade 2 (n=6) and 3.6% of grade 3 (n=1). The immune effector cell-associated syndrome (ICANS) rate was 7% (n=3) with two grade 1 and one grade 4. CRS and/or ICANS were managed with tocilizumab in 23% of cases (n=10%), dexamethasone in 9.1% (n=4) and anakinra in 2.3% (n=1). Grade \u0026ge;3 infections were reported in 35% (n=15) documented in 73% of cases. Use of immunoglobulin replacement was done in 80% (n=35), antibioprophylaxis in 55% (n=44), antipneumocystis agent in 89% (n=39) and antiviral in 98% (n=43).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHematological toxicity with grade \u0026ge;3 cytopenia was reported in 33% (n=14) indicating use of G-CSF in 7 patients \u003cstrong\u003e(Table 2)\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003eResponse rate\u003c/h3\u003e\n\u003cp\u003eAfter the debulking chemotherapy-based regimen, ORR was 32% (n\u0026thinsp;=\u0026thinsp;37) with 16% of \u0026ge;\u0026thinsp;VGPR.\u003c/p\u003e \u003cp\u003eORR after cycle 1 of BsAb was 64% (n\u0026thinsp;=\u0026thinsp;39) with 33% of CR and 46% VGPR or better. After cycle 3 (n\u0026thinsp;=\u0026thinsp;34), the ORR was 73% and 87% at cycle 6 (n\u0026thinsp;=\u0026thinsp;21). At one year, in the 10 patients evaluated, ORR was 80% with 30% of CR. Only few patients did have a PET-CT after C1 (n\u0026thinsp;=\u0026thinsp;4), C3 (n\u0026thinsp;=\u0026thinsp;7) and C6 (n\u0026thinsp;=\u0026thinsp;7) \u003cb\u003e(Fig.\u0026nbsp;1A)\u003c/b\u003e. Best response rate after debulking treatment and best response to BsAb for all patient was presented in \u003cb\u003eFig.\u0026nbsp;1B.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAmong patients in CR or VGPR after debulking (n\u0026thinsp;=\u0026thinsp;3, both), 100% responded to BsAb (\u0026ge;\u0026thinsp;PR or better). For patients with disease progression after chemotherapy (n\u0026thinsp;=\u0026thinsp;8), 50% had a response to BsAB \u003cb\u003e(Fig.\u0026nbsp;2A).\u003c/b\u003e Conversion of response rate was reported on \u003cb\u003eFig.\u0026nbsp;2B.\u003c/b\u003e\u003c/p\u003e \u003cp\u003eAmong patients with EMD, ORR after C1 and C3 was 53% (n\u0026thinsp;=\u0026thinsp;9/17 and n\u0026thinsp;=\u0026thinsp;8/15), at C6 ORR was 77.8% (n\u0026thinsp;=\u0026thinsp;7/9) and 50% at C12 (2/4). Concerning patient with HRCA, ORR after C1 was 64% (n\u0026thinsp;=\u0026thinsp;12/19), 73% after C3 (n\u0026thinsp;=\u0026thinsp;12/15), 82% (n\u0026thinsp;=\u0026thinsp;9/11) and 83% (n\u0026thinsp;=\u0026thinsp;5/6) after C6 and C12 respectively.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSurvival\u003c/h2\u003e \u003cp\u003eThe median follow-up of the study was 12 months (range: 1\u0026ndash;31). In the overall population, median PFS was 10.2 months (95%CI: 6.87\u0026ndash;18.6) \u003cb\u003e(Fig.\u0026nbsp;3A).\u003c/b\u003e Regarding EMD, patients without EMD had a median PFS at 14.1 months (95%CI: 6.47-NR) vs 9.3 months (95%CI: 3.7-NR) for patients with EMD (p\u0026thinsp;=\u0026thinsp;0.05) \u003cb\u003e(Fig.\u0026nbsp;3B).\u003c/b\u003e Patients with HRCA had a median PFS at 10.2 months (95%CI: 5.02-NR) versus 7.6 (95%CI: 5.0-NR) for patients without HRCA (p\u0026thinsp;=\u0026thinsp;0.9).\u003c/p\u003e \u003cp\u003eMedian OS was 20.1 months (95%CI: 13.8-NR) for all patients \u003cb\u003e(Fig.\u0026nbsp;3C)\u003c/b\u003e. For patients with EMD, median OS was 13.7 months (95%CI: 6.5-NR), not reached for patients without EMD (95%CI: 13.8-NR) (p\u0026thinsp;=\u0026thinsp;0.1) \u003cb\u003e(Fig.\u0026nbsp;3D).\u003c/b\u003e In patients with HRCA, median OS was 19.3 (95%CI: 13.8-NR) vs 13.8 (95%CI: 7.45-NR) for patient without HRCA (p\u0026thinsp;=\u0026thinsp;0.8). Death occurred in 19 patients (43%), 14 due to disease progression, 3 to infection and 2 others causes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis multicenter retrospective study is among the first to evaluate the efficacy and tolerability of conventional debulking chemotherapy prior to initiating anti-BCMA bispecific antibody therapy in patients with RRMM and either EMD or high tumor burden. Our findings suggest that this sequential approach is both effective and tolerable, even in a high-risk, heavily pretreated patient population.\u003c/p\u003e \u003cp\u003eOur cohort had a median of four prior treatment lines, and 93% of patients were triple-class refractory. Half had EMD and 50% had high-risk cytogenetics\u0026mdash;both markers of poor prognosis. Despite these adverse features, the ORR after the first BsAb cycle was 64%, comparable to results from pivotal trials such as MajesTEC-1 and MagnetisMM-3, which reported ORRs of 63% and 61%, respectively [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Among patients with EMD, the ORR was 53% after both cycle one and three, increasing to 77.8% at six cycles. These results are particularly notable given prior data showing limited efficacy of BsAbs in EMD, such as the 0% ORR reported in a subgroup analysis of MagnetisMM-3 in patients with ISS stage III and EMD or high-risk cytogenetics [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHerein, the choice of chemotherapy was largely based on alkylating agents, especially cyclophosphamide (84%). Cyclophosphamide not only induces cytotoxicity but also modulates the immune microenvironment, reduces T-cell exhaustion, and enhances T-cell activation\u0026mdash;all potentially boosting BsAb efficacy [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. These immunomodulatory effects, combined with tumor debulking, may help improve the effector-to-target cell ratio, which plays a key role in the success of BsAb therapies. There is also a theoretical rationale that chemotherapy-induced cell death may promote neoantigen release and immune priming, further amplifying BsAb effectiveness [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn 27% of patients, alkylating agents were combined with anthracyclines, and 50% received etoposide. These regimens resemble intensive protocols such as DT-PACE, previously used in EMD before the advent of immunotherapy. However, 68% of patients received only a single cycle of chemotherapy, which likely reduced cumulative toxicity while achieving rapid cytoreduction [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAt a median follow-up of 12 months in our study, median progression-free survival (PFS) was 10.2 months. Patients without EMD had a significantly longer PFS (16.1 \u003cem\u003evs\u003c/em\u003e. 11.9 months; p\u0026thinsp;=\u0026thinsp;0.05). These outcomes align with prior BsAb trial data, such as teclistamab (11.3 months) and elranatamab (17.6 months) [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In the IFM 2024-09 real-world study, the median PFS for patients with EMD was 3.7 months \u003cem\u003evs\u003c/em\u003e 11.3 months for patients without EMD treated by Teclistamab [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A real-world analysis of teclistamab use in Germany show an ORR of 37.2% and a median PFS of 2.07 months for patients with EMD [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In contrast, our results suggest improved disease control in this subgroup, although long-term benefit remains limited. This highlights the need for continued efforts to optimize treatment for patients with EMD.\u003c/p\u003e \u003cp\u003eThe safety profile of this approach was acceptable given the heavily pretreated patient population [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Despite prior chemotherapy, the incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) remained low\u0026mdash;7% for ICANS and no apparent increase in CRS severity [\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Hematological toxicity\u0026thinsp;\u0026ge;\u0026thinsp;grade 3 occurred in 33% of patients, and infections\u0026thinsp;\u0026ge;\u0026thinsp;grade 3 were reported in 35%. This observation suggests that prior chemotherapy does not significantly increase the risk or severity of CRS associated with bispecific antibodies, countering some theoretical concerns. Preventive strategies, including immunoglobulin supplementation, antibiotic and antiviral prophylaxis, and pneumocystis prevention, were widely used and likely contributed to infection management. Importantly, toxicity rates were similar between patients with and without EMD, suggesting that worse disease biology does not necessarily imply greater treatment-related toxicity.\u003c/p\u003e \u003cp\u003eThe retrospective nature and modest size of our study introduce limitations. The heterogeneity of chemotherapy regimens and the lack of a comparator group make it difficult to draw definitive conclusions about the superiority of the sequential approach over BsAb monotherapy. Infrequent PET-CT assessments also limited our ability to fully evaluate depth of response, especially in patients with EMD.\u003c/p\u003e \u003cp\u003eProspective trials are needed to refine these aspects and to validate our findings. Additionally, translational studies evaluating immune markers, T-cell subsets, and changes in the tumor microenvironment before and after chemotherapy could help elucidate mechanisms of synergy and resistance.\u003c/p\u003e \u003cp\u003eAnti-BCMA CAR-T cell therapies have shown high response rates (\u0026gt;\u0026thinsp;70%) and median PFS of 8.8 to 12.9 months, but their use often necessitates bridging therapy during manufacturing, in 40\u0026ndash;50% of cases [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In this context, chemotherapy-based debulking may represent a practical option for disease control while awaiting CAR-T infusion. Moreover, emerging combinations of BsAbs with IMiDs, proteasome inhibitors, or even other BsAbs have been explored in clinical trials with promising results [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Whether debulking chemotherapy can be integrated into such regimens to improve outcomes in patients with high tumor burden or EMD remains an open question.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur study suggests that chemotherapy-based tumor debulking before anti-BCMA BsAb therapy is a feasible and promising strategy for patients with RRMM and high tumor burden or EMD. It appears to enhance early responses while maintaining a manageable safety profile. These preliminary findings warrant confirmation in larger, prospective trials, along with deeper investigation into the biological underpinnings of this potentially synergistic treatment sequence.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient\u0026rsquo;s characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003e Characteristics, n(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;44 patients\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian Age, years-old\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e66 (min-max\u0026nbsp;: 45\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMedian of Prior lines\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (min-max\u0026nbsp;: 2\u0026ndash;9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTriple class refractory, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eISS score III, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (48)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCytogenetic abnormalities, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e22 (50)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17p deletion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1q21 gain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003et(4\u0026nbsp;;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003et(14\u0026nbsp;;16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDel1p32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1q21 amplification\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eExtramedullary disease, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e22 (50)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eNumber of involved sites, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eType of localization, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCerebral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDigestive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCutaneous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMuscle\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHigh Plasma cell infiltration, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAcute kidney failure, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eHypercalcemia, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetails on chemotherapy and bispecific treatments.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;44 patients\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eChemotherapy\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of cycles, n(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (68)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAlkylating agent, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39 (89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCyclosphosphamide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBendamustine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBelustine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnthracycline agent, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEtoposide\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVincristine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCisplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAnti-BCMA bispecific, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTeclistamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eElranatamab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (30)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelay between chemotherapy and bispecific, median days (min-max)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (4-197)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCRS rate, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (64)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eICANS rate, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 2\u0026ndash;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTocilizumab use, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDexamethasone use, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (9.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eInfection, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGrade 3 infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIg supplementation therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35 (80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntipneumocystisis agent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibioprophylaxis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntiviral agent\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (98)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eGrade 3 cytopenias, n(%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTC, HD, AP, CS, CJ, ZDW, AR, MR, GL, VM, LV, VS, TC and AB followed study patients. \u0026nbsp;TC, EC, XL and SM interpreted the results; EC performed statistical analysis; TC wrote the manuscript;\u003c/p\u003e\n\u003cp\u003eXL and SM supervised the project; XL, EC and SM revised the manuscript. All authors approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003eCOMPETING INTERESTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTC: Consultant/Advisory Boards: BMS, Takeda, Janssen, GSK, Griffols, Amgen, Sanofi, Pfizer, Stemline. X.L. has received consultancy, honoraria and travel fees from Sanofi, Janssen-Cilag, Kite/Gilead, Amgen, Novartis, Takeda, Pfizer, Oncopeptide, AbbVie, GSK and Bristol Myers Squibb. A.B. received consultancy and honoraria from Sanofi, Janssen-Cilag. The other authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMateos MV, Weisel K, De Stefano V, et al. LocoMMotion: a prospective, non-interventional, multinational study of real-life current standards of care in patients with relapsed and/or refractory multiple myeloma. Leukemia. 2022;36(5):1371-1376. \u003c/li\u003e\n\u003cli\u003eBlad\u0026eacute; J, Beksac M, Caers J, et al. Extramedullary disease in multiple myeloma: a systematic literature review. Blood Cancer J. 2022;12(3):45. \u003c/li\u003e\n\u003cli\u003eHanamura I. Multiple myeloma with high-risk cytogenetics and its treatment approach. Int J Hematol. 2022;115(6):762-777. \u003c/li\u003e\n\u003cli\u003eSanchez L, Richard S. Extramedullary myeloma in the era of CAR T-cell and bispecific antibody therapies. Semin Hematol. 2025;62(1):31-37.\u003c/li\u003e\n\u003cli\u003eMoreau P, Garfall AL, van de Donk N, et al. Teclistamab in relapsed or refractory multiple Myeloma. N Engl J Med. 2022;387(6):495-505.\u003c/li\u003e\n\u003cli\u003eGarfall A, Nooka AK, van de Donk NWCJ, et al. Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(16_Suppl):7540.\u003c/li\u003e\n\u003cli\u003eLesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. \u003c/li\u003e\n\u003cli\u003eLesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267.\u003c/li\u003e\n\u003cli\u003eTomasson MH, Iida S, Niesvizky R, et al. Long-term survival and safety of elranatamab in patients with relapsed or refractory multiple myeloma: Update from the MagnetisMM-3 study. Hemasphere. 2024;8(7):e136. \u003c/li\u003e\n\u003cli\u003ePerrot A, Hulin C, Boumendil A, et al. Teclistamab in relapsed refractory multiple myeloma: a multi-institutional real-world study from the French early access program. Haematologica. \u003c/li\u003e\n\u003cli\u003eRiedhammer C, Bassermann F, Besemer B, et al. Real-world analysis of teclistamab in 123 RRMM patients from Germany. Leukemia. 2024;38(2):365-371.\u003c/li\u003e\n\u003cli\u003ePalumbo A, Gay F, Bringhen S, et al. Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol. 2008;19(6):1160-1165. \u003c/li\u003e\n\u003cli\u003eLee C-K, Barlogie B, Munshi N, et al. DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma. J Clin Oncol. 2003;21(14):2732-2739.\u003c/li\u003e\n\u003cli\u003eMoehler TM, Neben K, Benner A, et al. Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy. Blood. 2001;98(13):3846-3848.\u003c/li\u003e\n\u003cli\u003eGezer D, Nogueira MS, Kirschner M, et al. Retrospective study on pomalidomide-PACE as a salvage regimen in aggressive relapsed and refractory multiple myeloma. Eur J Haematol. 2024;113(4):465‐471.\u003c/li\u003e\n\u003cli\u003eAlsouqi A, Khan M, Dhakal B, et al. KD-PACE salvage therapy for aggressive relapsed refractory multiple myeloma, plasma cell leukemia and extramedullary myeloma. Clin Lymphoma Myeloma Leuk. 2021;21(8):526-535\u003c/li\u003e\n\u003cli\u003eZafar A, Huang CY, Lo M, et al. Intensity of Cyclophosphamide-Based Bridging Therapy Before Chimeric Antigen Receptor T Cell Therapy in Myeloma. Transplant Cell Ther. 2023;29(8):504.e1-504.e7. \u003c/li\u003e\n\u003cli\u003eMunshi NC, Anderson Jr LD, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384:705\u0026ndash;716.\u003c/li\u003e\n\u003cli\u003eBerdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398:314\u0026ndash;324.\u003c/li\u003e\n\u003cli\u003eNikonova A, Caplan SN, Shamy A, Gyger M. High-dose cyclophosphamide in highly refractory multiple myeloma patients as a bridge to further novel therapies. Blood. 2016;128. 5676-5676.\u003c/li\u003e\n\u003cli\u003eKumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346. \u003c/li\u003e\n\u003cli\u003eLouvet C, Nadeem O, Smith EL. Finding the optimal partner to pair with bispecific antibody therapy for multiple myeloma. Blood Cancer Discov. 2021;2(4):297-299.\u003c/li\u003e\n\u003cli\u003eFoureau DM, Bhutani M, Robinson M, et al. Ex vivo efficacy of BCMA-bispecific antibody TNB-383B in relapsed/refractory multiple myeloma. EJHaem. 2020;1(1):113-121.\u003c/li\u003e\n\u003cli\u003eRaje N, Anderson K, Einsele H, et al. Monitoring, prophylaxis, and treatment of infections in patients with MM receiving bispecific antibody therapy: consensus recommendations from an expert panel. Blood Cancer J. 2023;13(1):116.\u003c/li\u003e\n\u003cli\u003eLudwig H, Munshi NC, Terpos E, et al. Proposal for harmonizing the reporting of infections during treatment with bispecific antibodies in multiple myeloma. Blood Adv. 2024;8(18):4979-4982.\u003c/li\u003e\n\u003cli\u003eRodriguez-Otero P, Usmani S, Cohen AD, et al. International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell- engaging bispecific antibodies in multiple myeloma. Lancet Oncol. 2024;25(5):e205-e216\u003c/li\u003e\n\u003cli\u003eJourdes A, Cellerin E, Touzeau C, et al. Characteristics and incidence of infections in patients with multiple myeloma treated by bispecific antibodies: a national retrospective study. Clin Microbiol Infect. 2024;30(6):764-771.\u003c/li\u003e\n\u003cli\u003eHolstein SA, Grant SJ, Wildes TM. Chimeric antigen receptor T-Cell and bispecific antibody therapy in multiple myeloma: moving Into the future. J Clin Oncol. 2023;41(27):4416-4429.\u003c/li\u003e\n\u003cli\u003eCohen YC, Magen H, Gatt M, et al. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2025;392(2):138-149. \u003c/li\u003e\n\u003cli\u003eHolstein SA, Grant SJ, Wildes TM. Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future. J Clin Oncol. 2023;41(27):4416-4429.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"blood-cancer-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bcj","sideBox":"Learn more about [Blood Cancer Journal](http://www.nature.com/bcj/)","snPcode":"41408","submissionUrl":"https://mts-bcj.nature.com/cgi-bin/main.plex","title":"Blood Cancer Journal","twitterHandle":"@bloodcancerjnl","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"multiple myeloma, immunotherapy, chemotherapy, extramedullary ","lastPublishedDoi":"10.21203/rs.3.rs-6841736/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6841736/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eT-cell redirecting immunotherapies have improved outcomes in relapsed/refractory multiple myeloma (RRMM), yet patients with extramedullary disease (EMD) and/or high tumor burden continue to fare poorly. We evaluated chemotherapy-based tumor debulking prior to anti-BCMA/CD3 bispecific antibody (BsAb) therapy in this high-risk population. In this multicenter retrospective study (15 IFM centers), RRMM patients receiving BsAb therapy after chemotherapy within the prior month were analyzed. High tumor burden included medullary/para-medullary disease or elevated monoclonal protein. High-risk cytogenetics comprised del(17p), 1q21 gain/amplification, t(4;14), or t(14;16). Forty-four patients (median age 67) were included: 93% were triple-class refractory, 50% had EMD, and 50% had high-risk cytogenetics. Chemotherapy regimens included alkylators (89%), anthracyclines (34%), and etoposide (50%). Teclistamab (70%) or elranatamab (30%) was initiated after a median of 28 days post-chemotherapy. At 12 months median follow-up, ORR post-chemotherapy was 32%. ORR with BsAb reached 64% after cycle 1, 73% after cycle 3, and 87% after cycle 6. Median progression-free survival was 10.2 months; median overall survival, 20.1 months. Chemotherapy-based debulking prior to anti-BCMA/CD3 BsAb is feasible and safe, achieving high response rates and durable outcomes in high-risk RRMM.\u003c/p\u003e","manuscriptTitle":"Debulking strategy prior to anti-BCMA/CD3 bispecific antibodies in extramedullary and/or high tumor burden RRMM: a retrospective cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-10 12:47:58","doi":"10.21203/rs.3.rs-6841736/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"revise","date":"2025-06-18T14:39:48+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-12T00:52:08+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-11T11:12:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"Blood Cancer Journal","date":"2025-06-11T07:40:42+00:00","index":"","fulltext":""},{"type":"checksFailed","content":"","date":"2025-06-09T11:42:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"blood-cancer-journal","isNatureJournal":false,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"bcj","sideBox":"Learn more about [Blood Cancer Journal](http://www.nature.com/bcj/)","snPcode":"41408","submissionUrl":"https://mts-bcj.nature.com/cgi-bin/main.plex","title":"Blood Cancer Journal","twitterHandle":"@bloodcancerjnl","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ca25c876-7d23-4151-afd2-df7f712e954b","owner":[],"postedDate":"July 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":51295607,"name":"Health sciences/Diseases/Haematological diseases/Haematological cancer/Myeloma"},{"id":51295608,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2025-10-22T07:14:52+00:00","versionOfRecord":{"articleIdentity":"rs-6841736","link":"https://doi.org/10.1038/s41408-025-01365-y","journal":{"identity":"blood-cancer-journal","isVorOnly":false,"title":"Blood Cancer Journal"},"publishedOn":"2025-10-21 04:00:00","publishedOnDateReadable":"October 21st, 2025"},"versionCreatedAt":"2025-07-10 12:47:58","video":"","vorDoi":"10.1038/s41408-025-01365-y","vorDoiUrl":"https://doi.org/10.1038/s41408-025-01365-y","workflowStages":[]},"version":"v1","identity":"rs-6841736","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6841736","identity":"rs-6841736","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}