BCMA+ extracellular vesicles predict response and toxicity in patients with multiple myeloma treated with anti-BCMA bispecific antibodies Free

Anti-BCMA bispecific antibodies (BiAbs) improved outcomes of patients (pts) with relapsed/refractory multiple myeloma (RRMM). In this setting, predicting response and toxicities such as cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) is still a challenge. Extracellular vesicles (EVs) are membrane-bound particles with emerging role in intercellular communication and modulation of biological functions. EVs have also been explored as markers of minimal residual disease and predictor of ICANS following CAR T cell therapy.

We prospectively assessed BCMA+ EVs released from plasma cell and CD3+, CD4+, and CD8+ EVs released from lymphocytes in peripheral blood (PB) of RRMM treated with anti-BCMA BiAbs. Pts received either teclistamab (tec) or elranatamab (elra) as per clinical practice. PB samples were collected at different timepoints: baseline (T0), +24h after 1^st step up dose (T1), +24h after 2^nd step up dose (T2), +24h after 1^stfull-dose (T3), then at D1C4 (T4), D1C7 (T5) and D1C13 (T6).

We report preliminary results of 13 RRMM pts treated at our Institution between October 1^st, 2024, and June 30^th, 2025. At baseline median age was 65 years (range 50 – 77), 8 pts (61%) were male, 1 pts (8%) had ISS 3, 4 pts (31%) had R-ISS 3, 9 pts (69%) had high-risk FISH abnormalities, and 4 pts (31%) had extramedullary disease. Median number of prior lines of therapy was 3 (range 3 – 5), 13 pts (100%) and 11 pts (85%) were triple-class exposed and refractory, respectively. 7 pts (54%) received tec and 6 pts (46%) received elra. Median follow up was 6 months (range 1 – 9). Median number of BiAbs cycles was 4 (range 0 – 10). At 1-month, overall response rates (ORR) and ≥very good partial response (VGPR) were 77% and 38%, respectively. After a median of 2.4 months (range 0.5 – 7.5), best ORR and ≥VGPR were 77% and 54%, respectively. Median PFS and OS were both not reached. CRS occurred in 7 pts (54%), all grade 1, tocilizumab was given in 3/7 pts. ICANS occurred in 2 pts (15%), 1 grade 2 and 1 grade 3, both resolved with dexamethasone. Infections occurred in 8 pts (61%), 6 events (46%) were grade 3/4, 12 pts (92%) regularly supplemented IVIG. At data cut-off, 4 pts discontinued BiAbs (3 disease progression, 1 toxicity).

At T0, median number (N) of total EVs/μL was 10857 (range 1820 – 30816.8), median N of BCMA+ EVs/μL was 473.2 (range 2.8 – 2088.8), median N of CD4+ EVs/μL was 383.6 (range 0 – 10123.4), median N of CD8+ EVs/μL was 217 (range 0 – 1064.2). At T1, median N of total EVs/μL was 13119.4 (range 153.72 – 49400.4), median N of BCMA+ EVs/μL was 115.2 (range 25.2 – 1495.2), median N of CD4+ EVs/μL was 333.2 (range 0 – 21585.2), median N of CD8+ EVs/μL was 67.2 (range 2.8 – 5870.2). At T2, median N of total EVs/μL was 16144.8 (range 2067.8 – 57673), median N of BCMA+ EVs/μL was 210.7 (range 26.6 – 1145.2), median N of CD4+ EVs/μL was 727.3 (range 37.8 – 22786.4), median N of CD8+ EVs/μL was 200.2 (range 0 – 1586.2). At T3, median N of total EVs/μL was 5644.8 (range 1915.2 – 44252.6), median N of BCMA+ EVs/μL was 93.8 (range 0 – 3694.6), median N of CD4+ EVs/μL was 576.8 (range 0 – 47069.4), median N of CD8+ EVs/μL was 148.4 (range 0 – 2125.2).

Pts experiencing any grade CRS had significantly lower BCMA+ EVs/μL at T2 compared to those without CRS (72.8 vs 429.8, respectively; Mann-Whitney test p=0.048). Lower BCMA+ EVs/μL at T2 also predicted ORR at C1 and best ORR compared to those pts not responding to BiAbs (189 vs 817.4, respectively; point biserial correlation p=0.02). Similarly, lower CD4+ EVs/μL at T2 and T3 predicted achievement of ≥VGPR at C1 compared to pts not obtaining at least VGPR (T2: 144.9 vs 1978.2, respectively; Mann-Whitney test p=0.01) (T3: 147 vs 2248.4, respectively; Mann-Whitney test p=0.02). A trend for higher risk of ICANS was observed among pts with lower %CD4+ EVs at T1 compared to pts without ICANS (0.04 vs 14.25, respectively; Mann-Whitney test p=0.07).

Preliminary results from our prospective cohort showed that EVs appear as novel promising markers of response and toxicity in RRMM treated with anti-BCMA BiAbs. BMCA+ EVs assessed at T2 predicted CRS and disease response. Those pts obtaining rapid and deep response had lower CD4+ EVs both at T2 and T3. A trend for higher risk of ICANS was observed among pts with lower %CD4+ EVs at T1. Longer follow up and greater population might further confirm these initial findings.