The Growing Rationale for Earlier Targeting of GPRC5D in Multiple Myeloma

In an interview, Peter Voorhees, MD, of Atrium Health Levine Cancer Institute, evaluates the optimal sequencing and patient selection for talquetamab (Talvey), a GPRC5D-directed bispecific antibody. The MonumenTAL-1 study (NCT03399799) initially established talquetamab monotherapy as an effective treatment option for heavily pretreated multiple myeloma populations. A critical finding from the study was the performance of a sub-cohort consisting of individuals who had progressed on prior T-cell redirecting therapies, including anti-BCMA chimeric antigen receptor (CAR) T-cell therapy. Within this group, talquetamab elicited a median progression-free survival (PFS) of 13 months. This survival milestone mirrors the median PFS observed across the entire trial population of T-cell redirection-naive patients, proving that switching the therapeutic target to GPRC5D delivers strong efficacy even after a patient relapses on a BCMA-targeted agent. Furthermore, this 13-month PFS significantly outperforms historical clinical expectations for patients who are sequentially treated with a BCMA-directed bispecific antibody immediately following a BCMA-directed treatment failure.

Although these late-relapse findings validate the biological benefit of altering target antigens, investigators are working to definitively replicate these sequencing advantages earlier in the disease course, such as in the phase 3 MonumenTAL-3 trial (NCT05455320) presented by Voorhees at the European Hematology Association Annual Congress. Based on the current risk-benefit profiles of available T-cell redirecting agents, the consensus among oncologists favors an initial BCMA-targeted approach, seamlessly followed by a GPRC5D-targeted strategy like talquetamab at the next relapse.

However, Voorhees highlights specific clinical scenarios where this standard sequence could be reversed, favoring upfront talquetamab over a BCMA-directed agent. Patients with a clinical history of severe, repeating infections are poorly suited for BCMA therapies, which severely deplete normal plasma cells and compound immunodeficiency. He suggests that if a patient faces insurance denials or resides in a region lacking stable access to intravenous immunoglobulin support to manage hypogammaglobulinemia, an upfront non-BCMA approach might be preferred. He also included individuals with advanced underlying lung disease who cannot tolerate the added burden of severe respiratory tract infections, which are less prevalent under a GPRC5D-directed safety profile.

For patients who do eventually experience disease relapse after completing a baseline BCMA-targeted CAR T-cell therapy, Voorhees underscores that a combination of daratumumab (Darzalex) and talquetamab investigated in MonumenTAL-3 could serve as a highly effective option to regain disease control.