Background Bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA) and G-protein receptor class C, group 5, member D (GPRC5D) have transformed the therapeutic landscape of relapsed/refractory multiple myeloma (RRMM). With multiple BsAbs approved, patients (pts) can receive sequential BsAbs after progression, although the efficacy and safety of this strategy is not defined. We retrospectively analyzed the outcomes and toxicities associated with BsAb sequencing in heavily pretreated RRMM.

Methods We identified 31 pts with RRMM who received two sequential BsAbs (1st BsAb= BsAb#1, 2nd BsAb=BsAb#2), including teclistamab (Tec), talquetamab (Tal) or elranatamab (Elran) in any order. Patient demographics, treatment history and BsAb details including sequence, response, outcomes, and toxicities were collected. Kaplan-Meier methods were used to estimate progression-free survival (PFS) and overall survival (OS) after individual BsAb treatments. Baseline characteristics and toxicity were analyzed using Fisher's exact or chi-square tests.

Results Median age at initiation of BsAb#1 was 64 (range: 39-82) yrs; 52% pts. were female, and 74% were White. 55% pts had extramedullary disease, 1 pt had CNS involvement, and 1 pt had concomitant AL amyloidosis. Pts were heavily pre-treated with a median of 7 (range: 3-12) prior lines of therapy before BsAb#1, and 58% pts received prior CAR T. The median time from last BCMA CAR T exposure to BsAb#1 was 9.7 (range: 4.7-16) months.

Most common BsAb#1 agent was Tec (74%), followed by Tal (23%). Median time on BsAb#1 was 119 (IQR 42–283) days (d). Best responses to BsAb#1 included CR (16%), VGPR (35%), PR (16%), and SD (10%), yielding an overall response rate (ORR) of 68% and ≥ VGPR rate of 51%. Median PFS (mPFS) from BsAb#1 was 162 d (95% CI: 64–258), and median OS was 608 d (95% CI: 411–NR). Outcomes did not significantly differ based on prior CAR T exposed vs non-exposed (mPFS 128 vs. 168 d, p=1.0; mOS 637 vs. 452 d, p=1.0). There was no difference based on the sequencing of BCMA →GPRC5D vs GPRC5D → BCMA (mPFS 165 vs. 114 d, p= 0.3; mOS 452 d vs. NR, p= 0.9).

All pts received a BsAb#2 following progression. The most common BsAb#2 was Tal (74%), followed by Tec (19%). Most common sequences of use were Tec→Tal (71%), followed by Tal→Tec (16%), followed by Tal→Elran (6.5%). Median interval between last exposure to BsAb#1 and initiation of #2 was 22 d (IQR 12–99), and median time on BsAb#2 was 93d (range: 2-419). ORR for BsAb#2 was 55% [CR (16%), VGPR (13%), and PR (26%)]. A third of the pts. (33%) had r/r disease (PD/SD) in response to BsAb#2. mPFS2 from BsAb#2 was 111 d (95% CI: 77–247), and mOS2 was 241 d (95% CI: 160–not reached). Neither PFS2 nor OS2 differed significantly by BsAb sequence or initial BsAb class. mPFS2 for BCMA→GPRC5D BsAb vs. vice-versa sequencing was 106 d vs. NR (p=0.4) and mOS2 was 268 vs. 147 d (p=0.9).

Cytokine release syndrome (CRS) occurred in 58% and 52% (grade≥2: 28% and 31%) in pts. on BsAb#1 and BsAb#2, respectively. Most CRS was managed with tocilizumab (BsAb#1: 78%; BsAb#2: 83%); dexamethasone was added in 17% of cases each. Development of CRS on BsAb#1 was associated with increased risk of CRS on BsAb#2 (72% of pts with CRS with BsAb#1 had recurrence with BsAb#2; p=0.007). ICANS occurred in 16% of pts. with each course of BsAb. Prior ICANS did not predict recurrence (p>0.9).

Neutropenia of any grade occurred in 81% (BsAb#1) and 65% (BsAb#2) pts; median ANC nadirs were 0.86 and 0.81 ×10⁹/L, respectively. Time to resolution of neutropenia was 27d and 35d with BsAb#1 and BsAb#2, respectively. Only 1 pt in each cohort experienced ANC <500 for >7 d. Hypogammaglobulinemia occurred in 52% (BsAb#1) and 44% (BsAb#2), with 65–74% receiving IVIG. Infections within 90 d occurred in 55% (BsAb#1) and 48% (BsAb#2). 2 pts (6%) died due to treatment-related toxicity following BsAb#2.

Conclusions Sequential BsAb therapy yields meaningful responses in heavily pretreated RRMM, with ORRs exceeding 50% with both BsAb#1 & 2. mPFS and OS were modestly but not significantly influenced by the sequence of BsAb class. CRS, ICANS, and cytopenias remain common and often recur upon re-exposure. A prior episode of CRS may predict future events, highlighting the need for toxicity risk stratification. These findings support the feasibility of sequential BsAb use and underscore the need for prospective studies to guide optimal sequencing and supportive care strategies.

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2025
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