GPRC5D bispecific antibodies are a class of immunotherapy drugs engineered to treat multiple myeloma, a blood cancer that forms in plasma cells in the bone marrow. They work by physically linking a myeloma cell to a T cell from the patient’s own immune system, triggering the T cell to kill the cancer. The name refers to their target: GPRC5D, a protein found on the surface of myeloma cells that serves as a homing signal for the drug. Talquetamab is currently the only approved GPRC5D bispecific antibody, but several others are in clinical testing, and the approach has become one of the more consequential developments in myeloma treatment in recent years.
What GPRC5D Actually Is
GPRC5D stands for G protein-coupled receptor, class C group 5 member D. It is what scientists call an “orphan receptor,” meaning no one has identified the natural molecule that activates it or fully pinned down what it does in healthy tissue. What researchers do know is where it shows up. In normal tissue, GPRC5D protein is found in hair follicles, in keratinized structures on the tongue, and in scattered plasma cells throughout the body.
The protein’s relevance to cancer came from the discovery that myeloma cells express GPRC5D at high levels on their surface. Using a technique called quantitative immunofluorescence, researchers confirmed that GPRC5D protein sits on CD138-positive myeloma cells from patient bone marrow samples, at levels similar to BCMA, the other major immunotherapy target in myeloma, but independently of it.
How These Antibodies Kill Myeloma Cells
A bispecific antibody is an engineered protein with two different binding arms. One arm grabs onto a specific target on the cancer cell; the other arm grabs CD3, a protein on T cells. By bridging the two cells together, the antibody activates the T cell and directs it to destroy the cancer cell. The patient’s own immune system does the killing; the drug just points it at the right target.
Preclinical work shows this process is tightly specific. In laboratory experiments, a GPRC5D-targeting bispecific antibody triggered T cell activation, cytokine release, and cancer cell death when co-cultured with myeloma cells that express GPRC5D. When the same antibody was tested against myeloma cells that lack GPRC5D, none of those effects occurred.
Structural studies have revealed how the drug physically latches onto its target. GPRC5D naturally forms a paired structure (a homodimer) on the cell surface, and a single binding arm of talquetamab interacts with both halves of that pair at once, contacting multiple loops of the receptor that protrude from the cell membrane.
Why Target GPRC5D Instead of BCMA
For years, BCMA was the dominant immunotherapy target in myeloma. CAR-T therapies and bispecific antibodies aimed at BCMA have produced strong results, but a practical problem emerged: patients who relapse after BCMA-directed treatment need something different to target. GPRC5D fills that role because its expression on myeloma cells is independent of BCMA. A cell can lose or reduce its BCMA and still display GPRC5D, making it reachable by a GPRC5D-directed drug.
Clinical reviews have confirmed an “undeniable benefit” from using GPRC5D-directed agents in patients who relapse after BCMA-targeted therapies. A real-world comparison found no significant difference in mortality, toxicities, or infectious outcomes between talquetamab and BCMA-directed bispecific therapy in patients who had already received prior BCMA treatment, suggesting that GPRC5D-targeting drugs hold their own even in heavily pretreated patients.
GPRC5D also has a structural advantage. Because it is a transmembrane receptor with a very short portion sticking out of the cell, it is unlikely to break off and float freely in the blood. This matters because some targets, including BCMA, can shed soluble fragments into the bloodstream, and those floating fragments can soak up the drug before it reaches the cancer cell. GPRC5D’s architecture makes that scenario less likely.
That said, there is no biological rule that BCMA therapies must be exhausted before trying a GPRC5D drug. Researchers have noted that using GPRC5D-directed treatment earlier in the disease course, rather than only as a last resort after BCMA failure, could be a more effective strategy. Clinical trials are now testing exactly that.
How Well Talquetamab Works
Talquetamab was evaluated in the MonumenTAL-1 trial, a large phase 1/2 study in patients with relapsed or refractory myeloma. The results showed strong response rates across dosing schedules. In the weekly dosing group, about three quarters of patients responded. In the every-two-weeks group, roughly seven in ten responded. Among patients who had previously received a different T-cell-redirecting therapy, the response rate was around two thirds.
Duration of response varied by dosing. In the weekly group, the median duration of response was about nine and a half months. In the every-two-weeks group, responses lasted considerably longer, with a median around 17 months. The 12-month duration of response rate in the prior T-cell-redirecting therapy group was 56%.
These numbers are striking for a population of patients who had already failed multiple lines of treatment. In myeloma, each relapse tends to become harder to treat, and response rates drop with each successive therapy. Achieving responses in two thirds or more of heavily pretreated patients is a meaningful result, particularly because many of these patients had limited remaining options.
The Distinctive Side Effect Profile
Every cancer drug has side effects, but GPRC5D bispecific antibodies produce an unusual constellation that directly reflects where the target protein lives in normal tissue. Because GPRC5D is expressed in hair follicles, skin, and keratinized structures on the tongue, patients commonly experience skin problems, nail changes, and taste disturbances. This pattern is sometimes described as “on-target, off-tumor” toxicity: the drug is doing exactly what it was designed to do, but the target also exists in places you would rather leave alone.
A systematic review and meta-analysis of talquetamab studies quantified these effects. Taste disturbances (dysgeusia) were the most common, affecting roughly seven in ten patients. Nail toxicities occurred in about half of patients, and skin toxicities in nearly half as well. Of the skin events, rashes were the most frequent type. The reassuring finding was that the vast majority of these reactions were mild to moderate; only about 3% of patients across studies experienced severe skin toxicity.
Still, even mild taste changes can significantly affect daily life when they persist for months. Patients describe food tasting metallic, bland, or simply wrong. Research into supportive care strategies has identified coping approaches that patients find helpful, including using mild herbs and aromatic cues when cooking, adding umami-rich ingredients, modifying food textures with sauces or soups, adjusting serving temperatures, and taking measures to counter dry mouth. These strategies are not cures for dysgeusia, but they can make eating more tolerable during treatment.
Cytokine Release Syndrome and Other Immune Reactions
Like other T-cell-engaging therapies, GPRC5D bispecific antibodies can trigger cytokine release syndrome, an inflammatory reaction that occurs when large numbers of T cells activate simultaneously. Symptoms range from mild fever and chills to, in rare cases, low blood pressure and difficulty breathing. With talquetamab, most cytokine release events occurred during the initial step-up dosing period and were grade 1 or 2 in severity. Grade 3 events were rare. About a third of patients experienced more than one episode.
The standard treatment for cytokine release syndrome is tocilizumab, an anti-inflammatory drug. In the MonumenTAL-1 data, patients who received tocilizumab for their first episode were less likely to have subsequent episodes, and importantly, using tocilizumab did not appear to reduce the cancer-fighting effectiveness of the treatment. Response rates were similar regardless of whether a patient needed tocilizumab.
Immune effector cell-associated neurotoxicity syndrome (ICANS), a neurological side effect seen with some T-cell-redirecting therapies, was also observed but managed consistently with approaches used for other drugs in this class. The overall toxicity profile has led researchers to explore whether the fourth dose of talquetamab, after the initial step-up sequence, could be safely administered in outpatient settings, which would reduce hospitalization time and associated costs.
Infection Risk During Treatment
T-cell-engaging therapies suppress parts of the immune system even as they activate others. Patients on bispecific antibody therapy are at increased risk of infections, and this risk appears to be linked to low immunoglobulin levels. In one study, the majority of infections during bispecific antibody therapy occurred in patients whose immunoglobulin levels had dropped below a clinical threshold, and about a fifth of those patients were already receiving immunoglobulin replacement. Patients on GPRC5D bispecific monotherapy required less immunoglobulin supplementation than those receiving combinations of GPRC5D and BCMA bispecific antibodies together.
Infection management is a core part of the treatment plan for any patient on these drugs. Monitoring immunoglobulin levels, administering prophylactic antimicrobials, and providing immunoglobulin replacement when needed are standard supportive measures. This is not unique to GPRC5D antibodies; it applies broadly across the bispecific antibody category.
Combination Therapies Are Changing the Landscape
Some of the most compelling recent data involve talquetamab combined with other myeloma drugs, particularly daratumumab, an anti-CD38 antibody that is already a backbone of myeloma treatment. A randomized phase 3 trial compared two talquetamab-daratumumab combinations against a standard daratumumab-based regimen in patients with relapsed or refractory myeloma.
The results were dramatic. At a median follow-up of roughly two years, progression-free survival at 24 months was about 81% and 78% in the two talquetamab-daratumumab arms, compared with 51% in the standard arm. Overall response rates were higher with the combinations (around 88% versus 78%), and the rates of deep responses, including complete responses and measurable residual disease negativity, were markedly better. Overall survival at 24 months favored the talquetamab combinations as well, with death rates roughly halved compared to the standard regimen.
These combination results represent a step change. Bispecific antibodies started as a salvage option for patients who had exhausted other therapies. Combination data of this quality raise the question of whether GPRC5D-targeting drugs should move earlier in the treatment sequence. Serious adverse events were somewhat more frequent in the more intensive combination arm, which is expected when layering therapies together, but fatal adverse events were actually lower in the talquetamab groups than in the standard arm.
What Happens to Quality of Life
A treatment that shrinks cancer but makes a patient miserable is a qualified victory at best. Quality-of-life data from MonumenTAL-1 paint a nuanced picture. Patients reported worsening in most quality-of-life measures during the first treatment cycle, which is expected given the initial immune activation, step-up dosing, and side effects. But with continued treatment, the trajectory reversed. By about nine months, a large proportion of patients reported meaningful improvements in global health, pain, fatigue, and physical and role functioning.
By cycle 21, patients on average reported improvements of about 5 points in global health status and 12.5 points in emotional functioning, along with reductions in pain and fatigue. These are not just statistically measurable shifts; they cross the threshold for what patients actually notice and care about. At cycle 9 in the weekly dosing group, 86% of patients reported meaningful improvement in pain, and 78% in fatigue. The pattern suggests that once the tumor burden is reduced and the body adjusts to the treatment’s side effects, patients feel meaningfully better than they did before starting therapy.
What These Drugs Cost
GPRC5D bispecific antibodies are expensive. Over a six-month period, the total cost of care for talquetamab was approximately $296,000 to $315,000 depending on the dosing schedule, compared with about $180,000 for usual care alternatives. However, because talquetamab produced higher response rates, the cost per patient who actually responded to treatment was lower: roughly $405,000 to $443,000 for talquetamab versus about $576,000 for usual care. That represents a 23 to 30% reduction in cost per responder, which is the more meaningful economic metric when comparing treatments of different effectiveness.
This is a common pattern in oncology: newer drugs cost more per course but may deliver better value when effectiveness is factored in. For individual patients, access still depends on insurance coverage, prior authorization requirements, and in some countries, health technology assessments. The cost picture will likely shift as competition increases and as treatment moves from monotherapy toward combinations that may change dosing schedules.
Agents Beyond Talquetamab
Talquetamab is the first but not the only GPRC5D bispecific antibody in development. Multiple other agents targeting the same receptor are in clinical trials, and the field is expanding beyond simple bispecifics into trispecific antibodies, which engage three targets simultaneously rather than two. The idea behind trispecifics is to add a co-stimulatory signal or engage a second tumor antigen alongside CD3 and GPRC5D, potentially increasing potency or reducing the chance that cancer cells escape by losing a single target.
GPRC5D-targeted CAR-T cells are also under investigation. These are a different modality, using genetically engineered patient T cells rather than an off-the-shelf antibody, but they share the same tumor target. Early data show promise, though the logistics of CAR-T therapy (cell collection, manufacturing, and bridging therapy during the wait) differ substantially from bispecific antibodies, which can be given as a subcutaneous injection with no manufacturing delay.
The broader trend is toward treating GPRC5D not as a backup target for BCMA failures but as a primary immunotherapy target in its own right. As combination data mature and newer agents reach later-stage trials, the treatment landscape for myeloma is likely to involve sequencing or combining BCMA and GPRC5D-directed therapies in ways that would have been difficult to imagine even five years ago.