Debulking Conventional Chemotherapy before Treatment By Anti-BCMA Bispecific Antibody in Extramedullary and/or High Tumor Burden Relapsed/Refractory Multiple Myeloma

Background. New immunotherapies have improved response rates and survival in relapse/refractory multiple myeloma (RRMM) setting. However, patients with extramedullary disease (EMD) and/or high tumor burden continue to have poor response rates and inferior survival, representing an unmet medical need. Currently, there are no recommended strategies to enhance the efficacy anti-BCMA bispecific antibodies (BsAb) for these patients. In this study, we aim to evaluate the efficacy and tolerability of conventional chemotherapy as a debulking strategy prior to the administration of anti-BCMA BsAb in patients with EMD and/or high tumor burden with RRMM.

Methods. We conducted a retrospective study across 15 IFM centers, including patients with RRMM treated with anti-BCMA BsAb between March 2022 and May 2023. Patients received chemotherapy in the month prior BsAbs administration. EMD was defined as a lesion restricted to soft tissue without contact with bony structures. High tumor-burden was based on medullary plasma cell infiltration, para-medullary disease and/or high levels of monoclonal component. High-risk cytogenetic status was defined by presence of 17p deletion, t(4;14) and t(14;16). Patients with plasma-cell leukemia were excluded.

Results. In total, 36 patients were included with median age of 68 years (range: 52-84), and 49% were female. Among them, 97% (n=35) were triple-class refractory, 53% (n=19) had EMD, 33% (n=12) had high-risk cytogenetic abnormalities with 42% of 17p deletion (n=8). Eighteen (50%) had an ISS score of 3, 38% (n=11) and 40% (n=14) had elevated levels of LDH and B2m, respectively.

Regarding debulking chemotherapy, 92% (n=33) received alkylating agents, including cyclophosphamide (89%, n=32) and belustine (14%, n=5), 42% (n=15) received anthracyclines, 56% (n=20) received etoposide, 11% (n=4) received vincristine, and 14% (n=5) received cisplatin. Twenty-five patients (69%) received one cycle. Teclistamab was used in 29 patients (81%) and elranatamab in 7 patients (19%) with a median interval between chemotherapy and BsAb administration of 36 days (range: 4-197). CRS rate was 67% with one grade 3 (4.2%) and ICANS rate was 8.3% with one grade 4. Tocilizumab was used in 7 patients (19%) and dexamethasone in 4 patients (11%). Cytopenia grade≥3 occurred in 31% (n=11) and infections in 40% (n=14).

With a median follow-up of 11 months (range: 1-28), the overall response rate (ORR) after cycle 1 of BsAb was 63% with 37% of complete response (CR) and 49% of very good partial response (VGRP) or better. After cycle 3, the ORR was 74%, 88% at cycle 6 and 75% at one year. Median progression-free survival (PFS) was 9.4 months (95%CI: 4.11-18.1). Death occurred in 15 patients (42%), ten due to disease progression, 3 to infection and 2 others causes.

Conclusion. This study confirms the feasibility of debulking chemotherapy before use of an anti-BCMA BsAb in a high-risk population. We reported a high response rate and a PFS comparable to the overall population receiving BsAb. This strategy can be used in a challenging population to improve response to novel immunotherapy.