Multiple myeloma is the second most common blood cancer diagnosis, after non-Hodgkin lymphoma, in the US. Myeloma incidence is strongly related to age, with the highest incidence rates being in older people and most frequently diagnosed among people aged 65 and above.

Multiple myeloma treatment strategies have also evolved with the emergence of new therapies with novel mechanisms of action and also with more complex combination regimens being used, such as quadruplets, triplets, and doublets. TECVAYLI (teclistamab), TALVEY (talquetamab), and ELREXFIO (elranatamab), the three currently approved bispecifics, have better activity in terms of both progression-free survival and duration of response when compared to existing standards of treatment. 

Johnson & Johnson is evaluating the combination of TALVEY with cetrelimab (a PD-1 inhibitor) for Relapsed/Refractory Multiple Myeloma (RRMM). Findings of the Phase I TRIMM-3 study showed that, at a medium follow-up of 11.5 months, the Objective Response Rate (ORR) with the combination in the overall population was 70.5%, with a Very Good Partial Response (VGPR) or higher rate of in 65.9%; the Complete Response (CR) rate was 6.8%, the VGPR rate was 25%, and the Partial Response (PR) rate was 4.5%. The median time to first response was 1.9 months, the median time to best response was 4 months, and the median Duration of Response (DOR) was 16.8 months. The 9-month Duration of Response (DOR) and 6-month Progression-free Survival (PFS) rates were 72.6% and 69.9%, respectively.

Adverse events (AEs) related to GPRC5D were common and included taste changes in 82% of patients (39% Grade 1, 43% Grade 2), nail-related issues in 75% (all Grade 1/2), skin-related effects in 73% (all Grade 1/2), and rash in 39% (mostly Grade 1/2). PD-1-related AEs occurred in 7 patients (16%), including skin-related events in 7%, hematologic in 5%, and gastrointestinal in 5%. Grade 3/4 AEs occurred in 82% of patients, with neutropenia (41%) and anemia (39%) being the most common. Cytokine release syndrome (CRS) was reported in 61% of patients (all Grade 1/2). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in one patient (2%; Grade 1). Infections were reported in 80% of patients, with 27% experiencing Grade 3/4 severity. Hypogammaglobulinemia occurred in 57% of patients. Around 11% experienced AEs that led to treatment discontinuation—one due to Talquetamab/Cetuximab-related effects and four due to Cetuximab alone (with Talquetamab continued). One death occurred due to pneumonia.

KOL insights

“These data support talquetamab as a versatile combination partner and suggest potential activity of PD-1 inhibitors in relapsed/refractory multiple myeloma.” – Expert Opinion

Conclusion

Similar to TECVAYLI and ELREXFIO, TALVEY (talquetamab) is a bispecific antibody that targets CD3 and GPRC. It has similarly been granted accelerated approval by the FDA. When GPRC directed bispecific antibodies are used instead of BCMA-targeted bispecifics, the number of deaths, infections, and cases of neutropenia typically decreases. When choosing which bispecific antibody to give a patient, doctors must consider the safety profile of TALVEY, which is different from that of the BCMA-directed bispecifics. TALVEY has led to an increased risk of taste, skin, and nail adverse events. It is highlighted that since GPRC-directed treatments don't overlap with existing medications, combination regimens using them may be simpler to construct. Nonetheless, adverse events linked to GPRC5D targeting remain a concern, prompting the need for optimized dosing strategies, such as reduced frequency or fixed-duration treatment, along with other mitigation tactics to minimize toxicity while preserving therapeutic benefit.

GPRC5D has gained attention as a promising target for the treatment of multiple myeloma. Clinical trials are currently evaluating the safety and efficacy of combining GPRC5D-directed T-cell–engaging therapies with other anti-myeloma agents in patients with relapsed or refractory disease. These combinations include TALVEY (talquetamab) with agents like TECVAYLI (teclistamab), DARZALEX (daratumumab), POMALYST (pomalidomide), anti-PD-1 therapies, carfilzomib, cetrelimab, and lenalidomide, highlighting the potential of GPRC5D bispecific antibodies as flexible partners in multi-agent regimens.  Other emerging therapies that target GPRC5D are BMS-986393 (BMS), Forimtamig (Roche), CAR-GPRC5D (Nanjing IASO Biotechnology), and others.