GPRC5D as a Myeloma Target: Why It Matters Beyond BCMA

GPRC5D is a G-protein-coupled receptor selectively expressed on malignant plasma cells in multiple myeloma, making it a high-value surface antigen for immune-engaging therapies that operate independently of the BCMA pathway. Its restricted expression pattern — concentrated on myeloma plasma cells with limited presence on normal tissues except keratinocytes — provides both the therapeutic opportunity and the characteristic toxicity profile that distinguishes GPRC5D-directed agents from BCMA-targeted treatments.

The significance of GPRC5D as a target lies in its orthogonality to BCMA. As patients are increasingly exposed to anti-BCMA therapies — including teclistamab, elranatamab, idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) — BCMA antigen loss and downregulation emerge as resistance mechanisms. GPRC5D-directed therapy with talquetamab sidesteps this resistance pathway entirely, offering meaningful clinical activity in patients who have progressed on prior BCMA-directed treatment, according to data published in The New England Journal of Medicine.

The keratinocyte expression of GPRC5D accounts for talquetamab’s class-specific adverse events — skin rash, nail changes, and dysgeusia — which are on-target, off-tumour effects not observed with BCMA-directed agents. Understanding this mechanistic distinction is essential for sequencing decisions, combination design, and patient selection in the relapsed/refractory myeloma setting.

Talquetamab’s Clinical Profile and the MonumenTAL Programme

Talquetamab (Talvey) is a subcutaneously administered bispecific T-cell engaging antibody that simultaneously binds GPRC5D on myeloma plasma cells and CD3 on T cells, physically bridging the two cell types to trigger cytotoxic T-cell killing of tumour cells. Johnson & Johnson’s MonumenTAL clinical programme encompasses the pivotal trials that established talquetamab’s regulatory approval and the ongoing Phase III studies evaluating combination regimens.

The MonumenTAL-1 study established the pivotal single-agent data supporting talquetamab’s accelerated approval by the FDA in August 2023 for adults with relapsed/refractory multiple myeloma who had received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. Two dosing schedules were evaluated: 0.4 mg/kg weekly and 0.8 mg/kg biweekly, both administered subcutaneously.

The characteristic toxicity profile of talquetamab — driven by GPRC5D expression on keratinocytes — includes skin-related adverse events (rash, dry skin), nail changes (onycholysis, nail dystrophy), and dysgeusia (altered taste sensation). These effects are on-target but off-tumour, and their management has become a key focus of supportive care guidelines accompanying the MonumenTAL programme. Cytokine release syndrome (CRS), consistent with the bispecific antibody class broadly, is also observed, predominantly at lower grades.

Phase III Combination Strategies: Daratumumab, Teclistamab, and Beyond

The MonumenTAL Phase III programme is advancing talquetamab beyond monotherapy by pairing it with established myeloma agents and, notably, with other bispecific antibodies to create dual-target immune engagement strategies. The two most clinically advanced combination approaches are talquetamab plus daratumumab (anti-CD38 monoclonal antibody) and talquetamab plus teclistamab (a BCMA × CD3 bispecific antibody), the latter representing a novel dual-bispecific strategy.

The rationale for combining talquetamab with daratumumab is mechanistically compelling: daratumumab depletes CD38-expressing immunosuppressive cells in the bone marrow microenvironment, potentially enhancing T-cell function and thereby augmenting talquetamab’s T-cell redirecting activity. This combination also addresses the clinical reality that most heavily pre-treated myeloma patients will have received prior daratumumab, making the combination relevant in both daratumumab-naïve and daratumumab-exposed settings.

“Combining talquetamab with teclistamab creates a dual-bispecific strategy targeting both GPRC5D and BCMA simultaneously — a novel approach to prevent antigen escape and deepen responses in relapsed/refractory multiple myeloma.”

The dual-bispecific combination of talquetamab plus teclistamab — evaluated in the RedirecTT-1 study — is particularly novel because it simultaneously engages two distinct myeloma antigens (GPRC5D and BCMA) through separate bispecific antibodies, both redirecting T cells. The theoretical advantage is prevention of single-antigen escape: if a myeloma cell loses BCMA expression, GPRC5D-directed killing via talquetamab continues, and vice versa. This strategy is being advanced to Phase III based on early-phase signals of deep responses. According to data reviewed by ASCO, dual-bispecific combinations in myeloma have demonstrated encouraging response rates in heavily pre-treated populations.

The BCMA-Targeted Landscape: Teclistamab, Elranatamab, and CAR-T Long-Term Data

BCMA-targeted therapies dominate the current bispecific antibody and CAR-T landscape in multiple myeloma, with teclistamab (Tecvayli, Johnson & Johnson) and elranatamab (Elrexfio, Pfizer) both approved as BCMA × CD3 bispecific antibodies for heavily pre-treated patients. Long-term follow-up data from these agents, alongside maturing survival data from BCMA-directed CAR-T therapies, are increasingly informing sequencing strategies and the competitive context for talquetamab.

Long-term follow-up data from the MajesTEC-1 study of teclistamab, presented at major hematology congresses, demonstrate durable responses in a subset of patients with heavily pre-treated myeloma, including those with prior anti-CD38 exposure. The maturing dataset from MajesTEC-1 provides the clinical benchmark against which talquetamab’s MonumenTAL data are contextualised, even in the absence of a head-to-head comparison. According to analyses published by Blood, response durability and minimal residual disease (MRD) negativity rates are emerging as key endpoints in long-term myeloma bispecific data.

BCMA-directed CAR-T therapies — idecabtagene vicleucel (ide-cel, Bristol-Myers Squibb/2seventy bio) and ciltacabtagene autoleucel (cilta-cel, Johnson & Johnson/Legend Biotech) — represent the most potent single-agent anti-myeloma interventions currently available, with cilta-cel demonstrating significant progression-free survival benefit over standard of care in earlier relapse settings in the CARTITUDE-4 trial. However, the manufacturing lead time, single-use nature, and BCMA antigen loss after treatment create a defined clinical niche for off-the-shelf GPRC5D-directed bispecifics such as talquetamab in the post-CAR-T setting.

Competitive Positioning: GPRC5D vs. BCMA in the Sequencing Era

The competitive positioning of talquetamab against BCMA-targeted therapies is fundamentally a sequencing and combination question rather than a head-to-head efficacy contest. As the myeloma treatment paradigm shifts toward earlier use of highly effective agents — including BCMA CAR-T in earlier relapse lines — the post-BCMA treatment landscape grows in clinical importance, and GPRC5D-directed therapy occupies a structurally advantaged position within it.

Johnson & Johnson’s ownership of both talquetamab (GPRC5D × CD3) and teclistamab (BCMA × CD3) creates a unique portfolio dynamic: the company can pursue combination strategies pairing its own bispecific antibodies, optimise sequencing protocols across both agents, and generate data that positions both products as complementary rather than competitive. This dual-asset strategy is difficult for single-agent BCMA-directed competitors such as Pfizer (elranatamab) or Regeneron (linvoseltamab) to replicate.

The patent and intellectual property dimension of the GPRC5D bispecific antibody space is an important competitive moat. According to WIPO patent database records, filings covering GPRC5D-targeting antibody formats, combination therapies, and manufacturing processes have increased substantially since talquetamab’s clinical advancement, reflecting both J&J’s own IP strategy and competitor efforts to develop alternative GPRC5D-directed modalities. Analysing this patent landscape with tools such as PatSnap’s life sciences intelligence platform provides R&D teams with visibility into freedom-to-operate risks and white-space opportunities in GPRC5D-directed therapy.

• Post-BCMA CAR-T sequencing: Talquetamab’s GPRC5D targeting retains activity after BCMA antigen loss, positioning it as the leading off-the-shelf option for patients who have progressed on ide-cel or cilta-cel.
• Combination depth: The dual-bispecific combination with teclistamab (RedirecTT-1) provides J&J with a differentiated Phase III asset that no competitor can replicate with a single BCMA-directed agent.
• Toxicity differentiation: GPRC5D-specific adverse events (skin, nail, taste) are distinct from BCMA-directed toxicities and from CAR-T-associated toxicities, enabling combination regimens with manageable, non-overlapping safety profiles.
• Manufacturing advantage: As an off-the-shelf subcutaneous bispecific antibody, talquetamab avoids the manufacturing lead time and logistical constraints of autologous CAR-T therapies, enabling rapid treatment initiation in the relapsed/refractory setting.

The long-term competitive outlook for talquetamab depends substantially on Phase III data maturation. If the MonumenTAL Phase III combination studies demonstrate superior progression-free survival versus standard-of-care comparators, talquetamab combinations could move into earlier lines of therapy — a market expansion that would substantially increase the addressable patient population and competitive pressure on BCMA-directed agents. Industry analysts tracking the myeloma pipeline through platforms such as PatSnap are monitoring patent expiry timelines, biosimilar entry risks for daratumumab (a key combination partner), and emerging GPRC5D competitors as key variables in the long-term competitive model.