Talquetamab in B Cell Maturation Antigen (BCMA) Exposed Relapsed-Refractory Multiple Myeloma Patients

Background: Talquetamab is a G protein-coupled receptor class C group 5 member D (GPRC5D) targeting bispecific T-cell engager (TCE) approved in August 2023 for patients with relapsed-refractory multiple myeloma (RRMM) who have received at least 4 prior lines of therapy (LOT) including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. In this multicenter retrospective study, we evaluated the real-world safety and efficacy of talquetamab in patients exposed to B cell maturation antigen (BCMA) directing therapy.

Methods: Retrospectively, we reviewed electronic medical records of RRMM who received talquetamab monotherapy in five U.S. academic medical centers before 6/1/24. All patients included in the analysis had received at least one full dose of talquetamab. Responses to therapy were evaluated using the International Myeloma Working Group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. Kaplan-Meier methods were used for progression-free (PFS), duration of response (DOR), and overall survival (OS) calculations. Chi-square tests were used to compare responders and non-responders.

Results: Of the total 63 patients (pts) included in this study, 52/63 (83%) were refractory to BCMA directed therapy (BDT). BDT included: CAR-T in 43, TCE in 49, antibody drug conjugate (ADC) in six pts. About half of the patients (31/61) received ≥2 BDT, 29 of these receiving both CAR-T and TCE. BDT was an immediate prior therapy for a significant number of pts (41%, 25/61) and 59% received BDT within 6 months of starting talquetamab.

The cohort received a median of 7 (4–17) prior LOT, most were triple class (87%), penta-drug (68%) refractory, and 46% had extramedullary disease (EMD). Estimated 6-month OS was 75% (95% CI 59-85%) and PFS was 42% (95% CI 27-56%).

Best ORR was the lowest in patients treated previously with ADC (50%) or TCE (59%), when compared to those who had prior CAR-T (72%) or the overall BDT population (68%). In all BDT pts, very good partial response or better (≥VGPR) was observed in 48% while 22% had complete response or better (>CR). There was no statistically significant difference in ORR by CAR-T or ADC exposure, while ORR was lower in pts with prior TCE exposure compared to those without (59% vs 100%, respectively, p<0.01).

BDT as an immediate line was significantly associated with lower ORR (48% vs 81%, p=<0.01) and shorter PFS (HR 2.1, p=0.04). Similarly, BDT within 6 months of talquetamab negatively affected ORR (57% vs 85%, p=0.02), PFS (HR 2.3, p=0.03) and OS (HR 4.8, p=0.04).

Cytokine release syndrome (CRS) was observed in 63% (34/54), with 1 grade III/IV event. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 13% (7/56), with 1 grade III/IV event. The most common grade III/IV hematological toxicities were thrombocytopenia (24%, 10/42) and anemia (18%, 8/45). Dysgeusia (72%, 39/54), dry mouth (42%, 22/53), weight loss ≥10% (25%, 13/53), nail changes (41%, 21/54), and skin-related events (48%, 25/52) were also noted. Infections occurred in 37% (20/54) of patients, most (70%) involving the respiratory tract.

Conclusion: With the availability of multiple treatment options for RRMM, optimal sequencing of therapies is a challenging question. Our data shows that talquetamab conferred high responses in patients previously treated with BDT. However, in this cohort of pts, the immediate prior use of BDT, particularly within 6 months of talquetamab was associated with inferior outcomes.