Due to the increased use of quadruplet induction regimens and maintenance therapies, multiple myeloma (MM) often becomes refractory early, creating a need for innovative treatments. TALVEY (talquetamab-tgvs) is the first drug class to be approved that targets GPRC5D in myeloma, confirming GPRC5D as an active immunotherapeutic target in multiple myeloma. This has led to the development of GPRC5D-targeted CAR T-cell therapy in multiple myeloma (BMS-986393).

BMS-986393, a potential first-in-class autologous CAR T cell therapy targeting G protein-coupled receptor class C group 5 member D (GPRC5D), has received FDA Regenerative Medicine Advanced Therapy designation for relapsed/refractory multiple myeloma (RRMM). Earlier findings from the same trial indicate that BMS-986393 is safe and effective in heavily pretreated patients with RRMM (median of 5 prior regimens), regardless of prior B-cell maturation antigen (BCMA)-targeted therapy. At a dose of 150 × 10^6 CAR T cells, the overall response rate (ORR) was 91%, and the complete response rate was 48%. 

In the CC-95266-MM-001 study (NCT04674813), as of March 18, 2024, 31 patients with 1-3 prior regimens had received BMS-986393. BMS-986393 manufacturing was successful for 100% of patients (31/31). 16 (52%) patients had prior stem cell transplantation and 71% had prior anti-CD38 therapy.

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A total of 24 patients were evaluable for efficacy, with a median follow-up of 5.3 months (ranging from 2.0 to 9.3 months). Of these, 23 patients achieved a response, resulting in an overall response rate (ORR) of 96% and 46% complete response. The median time to response was 1.0 months (ranging from 0.9 to 2.9 months), and the median duration of response was not reached. Pharmacokinetic analyses showed rapid and robust cellular expansion, peaking at transgene levels 14 days after the BMS-986393 infusion. This peak transgene level was comparable to that observed in patients with heavily pretreated RRMM. Exploratory analysis revealed that longitudinal assessment of SBCMA levels indicated deep tumor clearance due to BMS-986393, with the nadir occurring within 2-3 months post-infusion.

Treatment-emergent adverse events (TEAEs) occurred in 30 (97%) of 31 treated patients. 25 patients (81%) experienced a grade 3/4 TEAE. Cytokine release syndrome occurred in 25 patients (81%); all were grade 1/2 and resolved. The median onset was 3 days (1-4) after infusion of BMS-986393, and median duration was 3.5 days (1-7). No patients had macrophage activation syndrome or hemophagocytic lymphohistiocytosis while Infections were reported in 10 patients (32%).

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KOL insights

“We see cytokine release syndrome, some neurotoxicity and low blood counts with CAR T cells. When you compare this with other CAR-T, I think it performs favorably.” – MD, United States.

“GPRC5D overall is an important target in myeloma. There remain several questions about the adequate sequencing of this approach in the current landscape of all of the development that we are lucky enough to have in myeloma.”– MD, United States.

Conclusion 

The competition in multiple myeloma space is intensifying. Currently, the GPRC5D segment is less saturated than that of BCMA targeting medicines. At present, only one GPRC5D targeting therapy is approved (TALVEY). In addition to CC-95266-MM-001 study, BMS-986393 is being studied in ongoing studies as a combination treatment for RRMM (Phase I; NCT06121843) and as a monotherapy for quadruple-class exposed RRMM (Phase II; NCT06297226; QUINTESSENTIAL study). In addition to BMS, few other companies are also developing their own GPRC5D-directed treatments, including antibody-drug conjugates, CAR-T cell therapies, and bispecific antibodies (for example, CT071; CARsgen Therapeutics, OriCAR-017; Oricell, AZD0305; AstraZeneca, Forimtamig; Roche). Roche, known for its expertise in bispecific therapies for blood cancers, is developing forimtamig, a GPRC5D x CD3 bispecific that directly competes with J&J's TALVEY.

GPRC5D-targeted CAR T cells in multiple myeloma could address an unmet need if approved. The effectiveness of this therapy in relapsed myeloma, even after prior BCMA-directed treatments, including BCMA-CAR-T, is particularly promising. However, CAR T-cell therapies in myeloma come with several practical challenges. The complex and technically demanding nature of CAR T-cell therapies has limited their availability to major academic centers. This means that community oncology practices, which treat the majority of myeloma patients in the United States, cannot widely use CAR T-cell therapy. Additionally, post-CAR T-cell therapy care requires careful management of hypogammaglobinemia with IV immune globulin and infection prophylaxis with appropriate antimicrobial agents due to a high risk of infections. While BiTE therapies have the potential for broader use in community practices, the risks of infections, onset and management of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) continue to be significant concerns for hematologists and oncologists, limiting widespread adoption.