Outcomes of Relapsed/Refractory Multiple Myeloma Patients Receiving Sequential Therapies after Exposure to T-Cell Redirected or BCMA-Targeted Novel Immunotherapies

Background: Promising results have been seen in heavily pretreated myeloma patients (pts) after the use of novel T-cell redirected bispecifics targeting BCMA, GPRC5d or FcRH5 or anti-BCMA targeted immunotherapies (bispecifics, ADC or CAR T-cell products). There is paucity of data on outcomes of these pts after they relapse and require subsequent therapy. We aimed to analyse the clinical outcomes of relapsed refractory multiple myeloma (RRMM) pts who received sequential salvage therapy (T2) after exposure to initial T-cell redirected or BCMA-targeted novel immunotherapy (T1). Methods: Using the Princess Margaret Cancer Center REB-approved myeloma database, we identified RRMM patients who received salvage therapy (novel immunotherapy or conventional myeloma therapy) after initial exposure to investigational or commercial T-cell redirected or anti-BCMA targeted immunotherapy (T1). Patients who received subsequent novel immunotherapies were classified as double-exposed (DE) and those who received other treatments were classified as single exposed (SE). Overall survival (OS) and progression free survival (PFS) for T1 (PFS1, estimated from start to progression of T1) and T2 (PFS2, estimated from start of T1 to progression of T2) were estimated using Kaplan-Meier curves. Results: We identified 66 pts who were treated with T1 from April 2015 to April 2023 followed by sequential therapies. Median age at the time of T1 was 58 (range 41-78) years. Median number of prior lines of therapy before T1 was 4 (2-10). Forty-eight (72%) pts were triple-class refractory and 32% penta-refractory. Prior to starting T1, 47% (n=31/65) had high-risk cytogenetics, sixteen (24%) pts had extramedullary disease (EMD) while 18 (27%) had EMD prior to T2. Although DE patients were older (median age 60 vs 58 years), had more prior lines (6 vs 5) and had more EMD (36% vs 16%); differences were not statistically significant. Forty (60%) pts received anti-BCMA directed therapies as T1 [33 (50%) ADC, 5 (7.6%) bispecific antibodies and 2 (3%) CAR T cell therapy]. Amongst non-BCMA redirected T-cell therapies, FcRH5 targeting bispecific constituted the majority [24 (36%)] of pts and 2 (3%) pts had received an anti-GPRC5D bispecific. Overall response rate (ORR) to T1 was 51% (34/66). (35% >VGPR, 17% PR). Median time from T1-T2 was 8.7 (range 1.2- 63) months. The most common subsequent line of therapy was another novel immunotherapy. Thirty-six (54%) pts were DE with subsequent exposure to bispecific antibodies in 25 (38%) (12 anti-FcRH5, 7 anti-GPRC5D, 5 anti-BCMA; 1 anti-BCMA plus anti-GPRC5D), 8 BCMA targeting ADC and 3 anti-BCMA CAR T cell product. Amongst the SE pts (n=30), various doublet and triplet combinations were used. Most common drug combinations were with selinexor (16%), carfilzomib or bortezomib (14%), celmod (5%), chemotherapy (DPACE) in 5% including 1 pt who received stem cell support after melphalan. Pts who were DE had a trend towards significant better response rates after T2 compared to pts who received conventional non-immune myeloma treatments (>PR 69% vs 50%; p=0.082). On stratifying based on T1 response, DE pts treated with consecutive bispecifics (n=13), demonstrated an ORR to T2 of 84%. At a median follow-up of 22 months since T1 exposure, 37 (56%) had died with progression being the most common cause in 30 (81%) patients. PFS2 of the entire cohort was 18 months and superior in DE (24 months; 95% CI 17-42) compared to SE (11 months; 95%CI 7-15) pts. (p=0.024). For pts treated with anti-BCMA ADCs (n=33) or with anti-FcRH5 bispecific (n=24) at T1 the median PFS2 was 17 months (95%CI, 10-23) and 24 months (95%CI, 14-not reached), respectively. Median OS of the whole cohort was 27 months (95% CI, 20-78) with 1-year and 2-year OS of 83% and 57%. We analysed the factors predictive of OS after T1; pts with penta-refractory disease [median OS 21 months vs 35 months (non-penta-refractory); p=0.033] and high-risk cytogenetics [median OS 21 months vs 78 months (standard risk); p= 0.068] had significantly poor survival outcomes. Conclusions: Sequential use of T-cell redirected therapy or BCMA-targeted immunotherapies translated to improved OS and PFS2 rates in heavily pretreated RRMM. Penta-refractory disease and high-risk cytogenetics continue to portend poor outcomes. Use of novel T-cell directed therapies or anti-BCMA targeted agents should be encouraged where feasible instead of conventional doublet/ triplet therapies.

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