GPRC5D: The Next Frontier for Immunotherapy in Multiple Myeloma

In the first-in-human dose-escalation study MCARH109, a GPRC5D-targeted CAR-T therapy, was administered at four dose levels to 17 patients with heavily pretreated relapsed/refractory MM (RRMM).⁶  Even in the early dose escalation setting, impressive responses were observed. A response of 71 percent in the entire cohort and in 58 percent of those who received doses of 25×10⁶ to 150×10⁶ cells was reported, with very good partial response (VGPR; or better) of 59 percent. Importantly, responses were seen in seven of 10 patients who had received prior BCMA-targeted therapy. Cytokine release syndrome (CRS) was seen in 15 patients (88%) and was of grade 1 or 2 in all patients except for one patient treated at the highest dose level (450×10⁶ cells) who had a grade 4 event associated with immune effector cell–associated neurotoxicity syndrome (ICANS) and macrophage activation syndrome. Two other patients who received highest dose levels developed grade 3 cerebellar disorder, which is not a well-described adverse event in published research on ICANS and needs further studies. On-target, off-tumor adverse effects included transient rash (18%), dysgeusia (12%), and nail changes (65%), all of which were limited to grade 1 or 2 events.

Other companies are also developing GPRC5D-targeted CAR-T therapy. At the 2022 ASH Annual Meeting, interim results from an ongoing phase I study evaluating BMS-986393 (CC 95266), another GPRC5D-targeted autologous CAR-T therapy, were presented, showing favorable safety profile and promising efficacy in a heavily treated RRMM population, many of whom had received prior anti-BCMA therapy. Across all doses, 17 of 19 response evaluable patients went into remission, comprising a 100 percent overall response rate in the 10 who had not had prior anti-BCMA therapy, and 78 percent in the nine who had progressed on prior anti-BCMA therapy.⁷  Safety profile was similar to MCARH109.

There are currently several GPRC5D-targeted bispecific antibodies (BsAb) in clinical development that utilize dual binding GPRC5D×CD3 mechanism to induce activation of T cells and killing of malignant plasma cells. Talquetamab is further along the clinical development, being evaluated in the phase I/II MonumenTAL-1 clinical study (NCT03399799), and in combination studies RedirecTT-1 (NCT04586426), TRIMM-2 (NCT04108195), TRIMM-3 (NCT05338775), MonumenTAL-2 (NCT05050097), and MonumenTAL-3 (NCT05455320). In MonumenTAL-1, talquetamab was administered intravenously (IV) or subcutaneously (SC) to patients who had heavily pretreated (a median of 6 previous lines of therapy) RRMM.⁸  Step-up dosing regimen was used to mitigate severe CRS. At the two recommended phase II doses of talquetamab — 405 μg/kg SC QW (n=30) and 800 μg/kg SC Q2W (n=44) — response-evaluable patients had overall response rates of 70 percent (21/30 patients), and 64 percent (28/44 patients), including the VGPR or better rate of 57 percent and 52 percent, respectively. Common adverse events in the two dose-cohorts were CRS (in 77% and 80% of the patients, respectively), typically grade 1 or 2 and primarily occurring after step-up doses and the first full dose; skin-related events (in 67% and 70%); and dysgeusia (in 63% and 57%). Infections, mostly grade 1 or 2, were reported in 47 percent of the patients at 405 μg dose level and in 34 percent of those at the 800 μg dose level.

Forimtamig (previously coded as RG6234) is another GPRC5D engaging BsAb with a novel 2:1 configuration to extend half-life and reduce toxicity. An ongoing phase I study (NCT04557150) is investigating the IV and SC administration of RG6234 in patients with RRMM, in a step-up dosing regimen, up to a target optimal dose, followed by RG6234 every two weeks for one year.⁹  At data cutoff, 51 patients were enrolled into the IV cohort and 54 into the SC cohorts. Response rates were at 71.4 percent in the IV cohort and 63.6 percent in the SC cohort. Responses were observed in 10 (55.6%) or 18 patients who had received prior anti-BCMA therapies. Across all tested doses, CRS was the most common adverse event (IV, 82.4%; SC, 77.8%). Grade ≥3 CRS was uncommon, and most events were confined to cycle 1. As the study continues, clarification on the optimum dose and additional safety data will be obtained.

The GPRC5D target offers an additional avenue for immunotherapy in MM. The studies presented here provide the proof of principle that GPRC5D T cell engaging therapies (CAR T-cells and BsAb) are quite efficacious at doses where these are well-tolerated. The responses described in these studies are encouraging in heavily pre-treated patients, with including triple- and penta-class refractory cases. It is evident that patients who relapse post-BCMA therapies may still respond to GPRC5D-targeted therapies. On-target, off-tumor adverse effects included transient rash, dysgeusia and nail changes, all of which were mild and reversible. As with other T-cell engaging therapies, CRS and neurotoxicity are common adverse effects, mostly grade 1 to 2 and primarily limited to the first few doses of GPRC5D BsAb, but afterward, this type of therapy can potentially be administered outpatient. Infectious complications are common; however, the rate of grade 3 or higher infections and serious/unusual infections seems to be relatively lower with anti-GPRC5D therapy than anti-BCMA therapy. Treatment-related hypogammaglobulinemia has also been noted but has not been well characterized. The prevention of infectious complications remains an important challenge and will require careful monitoring and early interventions. Choosing GPRC5D BsAb over CAR-T therapy over will ultimately be dictated by patient choice and the accessibility of these therapies to the treating physicians especially in communities that are far away from transplant and cellular therapy centers.

The ongoing combination studies will help us learn how to optimally sequence different targets. For example, should we treat a patient post-BCMA targeted therapy with another BCMA targeted modality, or should we use GPRC5D-targeted modality and then return to BCMA therapies later. Whether a dual targeted approach of GPRC5D with BCMA (NCT05431608) will potentially eliminate tumor cells with very-low antigen-density, enhance T-cell cytotoxicity and improve sustained deep remissions. Nevertheless, GPRC5D targeted therapies will increasingly become part of treatment plans for our patients. We still face several challenges how to better manage and even prevent adverse effects, and how to improve and optimize convenience of drug administration to patients. Additional studies identifying the optimal dosing schedule and duration of therapy, CAR-T manufacturing process, and biomarkers of unique toxicity profile will be key to optimize efficacy and mitigate toxicities. Furthermore, drug resistance and immune escape are particularly challenging as with other immunotherapies in RRMM, thus calling for mechanistic studies, and clinical trials to enrich patient populations stratified by meaningful biomarkers. Given the breadth and pace of development of GPRC5D and other immunotherapeutics, the future of the field holds promise in moving the needle ever closer to cure in MM. An important consideration for all of us is to ensure timely and cost-effective access to these promising therapies globally.

Dr. Bhutani and Dr. Usmani indicated no relevant conflicts of interest.