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Although B-cell maturation antigen (BCMA)-directed immunotherapies have induced deep responses and prolonged survival in patients with multiple myeloma (MM), the majority will still experience disease progression.1 Therefore there is a need for more potent and differentiated therapeutic options for these patients.1
The Multiple Myeloma Hub has previously highlighted the rationale of targeting G protein-coupled receptor family C group 5 member D (GPRC5D) in MM, including its higher and differentiated expression in MM cells compared with healthy tissue and its expression independent of BCMA expression.1,2
In this article, we summarize the latest data regarding specific GPRC5D-targeted CAR T-cell therapy and bispecific antibodies for patients with relapsed/refractory (R/R) MM, including recent data presented during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition.
Talquetamab is an anti-GPRC5D bispecific antibody that has received breakthrough therapy designation from the U.S. Food and Drug Administration (FDA) for patients with R/R MM based on the latest data from the MonumenTAL-1 trial (NCT03399799) reported here.
Forimtamig is another novel bispecific GPRC5D T-cell-engaging bispecific antibody. Its dual binding 2:1 mode of action and biomarker analysis from the first-in-human clinical trial were previously reported on the Multiple Myeloma Hub. Here, we report on the following:
At data cut-off (October 21, 2022), the overall response rate for evaluable patients across all tested doses in the IV and SC arms were 71.4% and 63.6%, respectively (Figure 1). Of note, 10 out of 14 patients across both arms achieved a minimal residual disease (MRD)-negative complete response (CR) at 10−5 in a next-generation sequencing-based analysis. The median duration of response was 10.8 months and 12.5 months for the IV and SC arms, respectively.
Figure 1. Response rates for IV (dose, 18–10,000 µg) and SC (dose, 30–72,000 µg) arms*
CR, complete response; IV, intravenous; ORR, overall response rate; PR, partial response; SC, subcutaneous; sCR, stringent CR; VGPR, very good partial response.
*Adapted from Carlo-Stella.2
Grade 3–4 adverse events (AEs) occurred in 68% and 74% of the IV and SC arms, respectively.
Results from the biomarker analysis of forimtamig by administration route are as follows:
In an MM xenograft mouse model, forimtamig demonstrated higher efficacy across all tested doses when compared with talquetamab and alnuctamab despite higher BCMA expression at baseline.
In the ex vivo analysis of autologous bone marrow aspirates from newly diagnosed MM, forimtamig monotherapy showed high potency by inducing increased tumor-infiltrating lymphocyte activation (increased CD25 expression on CD4+ and CD8+ T cells). It also demonstrated high efficacy indicated by the rapid killing of tumor cells at very low doses. Combined with standard-of-care therapies, forimtamig induced higher T-cell activation and resulted in tumor cell killing in combination.
To further establish the biomarker analysis, a longitudinal analysis using an orthotopic in vivo model of MM in mice was performed.
The Multiple Myeloma Hub previously reported key findings from two GPRC5D-directed CAR T-cell therapies; OriCAR-017 (a second-generation, autologous, GPRC5D-directed CAR T-cell therapy investigated in the phase I POLARIS study [NCT05016778] recently published in The Lancet Haematology)5 and MCARH109 (NCT04555551), which have demonstrated safety and efficacy in heavily pretreated patients with R/R MM. The first results on another GPRC5D-targeted CAR T-cell, CC-95266 (NCT04674813), were presented by Berdeja6 at ASH 2022. We report the key findings below.
Figure 2. Response rates*
BCMA, B-cell maturation antigen; CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent CR; VGPR, very good partial response.
*Data from Berdeja.6
The most common non-hematologic toxicity was CRS (any grade, 64%; Grade 3–4, 6%), followed by pyrexia, hypokalemia, and headache (all reported in 30% of patients). The incidence of CRS was reported across all dose levels, with no dose effect observed. The median time to CRS onset and median duration of CRS was 3 days and 4 days, respectively. The occurrence of low-grade ICANS was seen in two patients and was reversed with steroid treatment. The on-target AEs reported were all Grade 1 (skin, 30%; taste disorder, 15%; nail dysmorphia, 9%, and dysphagia, 3%) with most cases not requiring intervention.
Pharmacodynamic analysis of CC-95266 showed reduced soluble BCMA levels indicating reduced tumor burden across all dose levels. Pharmacokinetic profiling revealed consistent fast expansion and multiphasic decline after infusion, dose-dependent cellular expansion on increased dose up to 150 × 106, and pharmacokinetic variability at higher dose levels.
GPRC5D-directed bispecific antibodies have demonstrated promising results in R/R MM. The updated analysis of forimtamig demonstrated high clinical activity with high response rates, early durability, and ongoing responses observed across both SC and IV arms. The safety profile was consistent with the known forimtamig mode of action and GDRC5D target expression, with step-up dosing mitigating the risk of severe CRS.
In the biomarker analysis, forimtamig displayed T-cell engagement and rapidly effective T-cell mediated antitumor activity across both routes of administration, with SC administration resulting in a delayed cytokine release that could offer a safety benefit in patients with R/R MM.
These data confirm the preclinical findings, which showed the high potency and efficacy of forimtamig as both a monotherapy and in combination with standard-of-care therapies, and the importance of step-up dosing for managing CRS. Investigations to optimize SC and IV dosing of forimtamig are ongoing.
Similarly, GPRC5D-targeted CAR T-cell therapies have revealed encouraging results. Preliminary data on the directed CAR T-therapy CC-95266 showed a favorable safety profile, with no high-grade CRS or ICANS neurotoxicity reported. Efficacious responses were also observed in patients treated with prior BCMA-directed treatments, with MRD-negative CRs achieved in some patients.
Based on these data, GPRC5D-directed CAR T-cells and bispecific antibodies remain promising regimens for the treatment of patients with R/R MM.
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