Maximizing Myeloma Outcomes With GPRC5D-Directed Therapy:
Practical Expert Case Studies and Best Practices
T-Cell-Redirecting Therapies in RRMM
Despite the availability of many active treatments that induce deep and durable responses, nearly all patients with multiple myeloma (MM) eventually relapse, and the modern-day disease course generally consists of multiple remissions and relapses.1,2 Patients who have received multiple lines of therapy and have disease that is refractory to proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies have historically poor outcomes.3 Over the last 5 years, however, a number of new T-cell-redirecting therapies, including chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies, have demonstrated deep and durable responses, even in patients with heavily pretreated and highly refractory disease.4-12
T-cell-redirecting therapies currently approved by the United States Food and Drug Administration (FDA) for relapsed or refractory multiple myeloma (RRMM) include the CAR T-cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel as well as the bispecific antibodies elranatamab, teclistamab, and talquetamab.13 All but talquetamab target the B-cell maturation antigen (BCMA); talquetamab targets G protein-coupled receptor class C group 5 member D (GPRC5D).11
GPRC5D protein is highly expressed on MM cells compared with nonmalignant plasma cells. In healthy tissue, GPRC5D is expressed in the immune cell compartment with predominance in plasma cells and minimal expression in B-cells, T-cells, natural killer cells, monocytes, granulocytes, and bone marrow progenitors. GPRC5D is also found in keratinized structures in the epithelial compartments, including hair follicles, eccrine glands, skin, and at the base of filiform papillae on the tongue.14 These expression patterns differ from BCMA, and although patients with MM who are undergoing treatment with GPRC5D-directed treatments experience class-related adverse events (AEs), they also experience unique on-target, off-tumor AEs including skin, nail, and oral toxicities.14-16
GPRC5D-Targeted Treatments in RRMM
The CD3 and GPRC5D-targeted bispecific antibody talquetamab is currently the only GPRC5D-directed therapy approved for the treatment of RRMM. The approval was based on findings from the pivotal phase 1/2 MonumenTAL-1 clinical trial which showed an overall response rate of 64% to 70% depending on the dose.11 Other GPRC5D-targeted agents are in development but are not currently approved by the FDA (Table 1).14
Table 1: Select GPRC5D-Targeted Therapies for the Treatment of RRMM.
Agent | Class | US Clinical Development Status |
Talquetamab | Bispecific antibody (CD3 and GPRC5D) | FDA-approved as monotherapy |
AZD0305 | Antibody-drug conjugate | Phase 1/2 |
MCARH109 | CAR T-cell therapy | Phase 1 |
OriCAR-017 | CAR T-cell therapy | Phase 1/2 |
BMS-986393 (CC-95266) | CAR T-cell therapy | Phase 2 |
Class Side Effects of T-Cell-Redirecting Therapies
Case: 57-year-old woman with RRMM |
- Diagnosed 6 years ago with IgG lambda MM
- 4 prior lines of therapy
- Documented symptomatic relapse
- IgG: 3360 mg/dL
- Lambda free light chains: 1072.4 mg/L
- M protein spike: 3.3
- Bone marrow biopsy: 70% to 80% involvement of lambda light chain-restricted plasma cells
- Undergoing treatment on clinical study evaluating talquetamab in combination with pomalidomide
- 1st step-up dose of talquetamab: 10 ng/kg (day 0)
- Developed a temperature of 40.1°C without hypotension or hypoxia (grade 1 CRS)
- Received a single dose of tocilizumab
- 2nd step-up dose: 60 ng/kg (day 3)
- First full dose on day 6
- Pomalidomide 2 mg days 1-21/28 days added at cycle 2 (per protocol)
- No further CRS events noted
|
Cytokine release syndrome (CRS), cytopenias, infections, and neurotoxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS), are associated with both CAR T-cell therapies and bispecific antibodies. However, the incidence and severity differ depending on the agent’s mechanism of action.17 CRS and ICANS are generally acute and occur within days of treatment (Figure 1).
“I think that the CRS, when I talk to my community colleagues, is the one thing that gives them pause, right? The management of CRS makes a lot of physicians in the community hesitant to adopt bispecific therapy.”
-Jeffrey Matous, MD
Infections are still a risk with GPRC5D-directed treatment. While the incidence and severity of infections is lower with GPRC5D-directed bispecific antibodies compared with BCMA-directed agents, any-grade infections were reported in 59% to 66% of patients in the MonumenTAL-1 study, depending on the dose and schedule, and 15% to 19% of patients had grade 3/4 infections. Notably, these infections generally occurred within the first 100 days.11,14,18 Patients should still receive appropriate prophylaxis for infections, careful monitoring, and appropriate workup with symptoms.19
Figure 1 Timing of Toxicities Associated With Bispecific Antibodies and CAR T-Cell Therapies for the Treatment of RRMM.

CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; IEC-HS, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome.
Patients treated with bispecific antibodies tend to have lower-grade CRS and fewer cases of any-grade neurotoxicity compared with CAR T-cell therapies.17 In clinical trials with GPRC5D-directed bispecific antibodies, the incidence of CRS was approximately 70% and 80%, with grade 3 or higher CRS occurring in 1% to 2% of patients.14,16 These events generally occur during the step-up dosing phase (Figure 1).16
Mitigation strategies for CRS associated with bispecific antibody treatment include step-up dosing and premedication. Median time to onset with bispecific antibodies is 24 hours.16 Treatment during the step-up dosing phase has typically been administered inpatient, although outpatient administration is becoming more common. Because CRS symptoms overlap with infection, a medical history, physical exam, and laboratory investigations should be performed in all cases.16
CRS is managed in a grade-dependent manner using the anti-IL-6 receptor antibody tocilizumab and corticosteroids (Table 2).16,20
Table 2: Grade-Based Management of CRS.
Grade | Treatment | Notes |
1 | Observation | - Consider early tocilizumab use
- If persistent grade 1 (>24–48 h), early use of tocilizumab is encouraged
|
2 | Tocilizumab (8 mg/kg IV) | - If no improvement, consider adding second-line treatment (ie, steroids)
- Supportive care, including oxygen supplementation and fluids, should be implemented
|
3 | Tocilizumab + dexamethasone (10 mg every 6 h) | - Transfer the patient to ICU
- Supportive care as clinically indicated
- Consider high-dose steroids and salvage CRS treatment (ie, anakinra)
|
4 | Tocilizumab + high-dose steroids | - Transfer the patient to ICU
- Supportive care as clinically indicated
- Consider high-dose steroids and salvage CRS treatment (ie, anakinra)
|
Skin Toxicities
Case: 71-year-old man with RRMM |
- Diagnosed in March 2016 with IgG lambda ISS stage II symptomatic hyperdiploid MM
- Treatment:
- First line: Treated on the ENDURANCE/ECOG E1A11 clinical trial with carfilzomib/lenalidomide/dexamethasone (KRd) and followed by melphalan-conditioned (200 mg/m²) autologous stem cell transplant (ASCT), resulting in a stringent complete response (sCR) followed by maintenance therapy with lenalidomide
- Second line: After a 5-year remission, he relapsed and was treated with elotuzumab, pomalidomide, and dexamethasone
- Third line: After a 9-month response, he progressed and was treated with daratumumab-VCD for 1 cycle, but continued to progress
- Fourth line: He was then treated with selinexor, carfilzomib, and dexamethasone, but progressed 7 months later
- Fifth line: He then underwent treatment on study with teclistamab plus nirogacestat but came off of study due to intolerance 8 months later
- Sixth line: Talquetamab monotherapy
- He had transient mucositis pain early in the first few weeks
- At approximately 6 weeks, he developed palmar plantar erythema that progressed to mild desquamation with peeling skin on his palms and soles, mild erythema, and tenderness
|
Rash and non-rash dermatologic toxicities are common with GPRC5D-targeted bispecific antibodies. Between 30% and 40% of patients treated with talquetamab experienced rash with a median onset of 20 to 27 days, depending on dose and schedule of talquetamab. Non-rash dermatologic toxicities, including skin exfoliation, dry skin, pruritus, and palmar-plantar erythrodysesthesia syndrome, occurred in 36% to 73% of patients. (Figure 2).11,18 Topical ammonium lactate cream along with heavy moisturizer can be used to prevent and manage palmoplantar peeling.
Figure 2: Summary of Talquetamab-Associated Adverse Events.

CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome.
“I’m not going to wait till someone has a [skin] side effect, so I advise patients to use those heavy moisturizers, those barrier creams.”
-Donna Catamero, NP
Patients undergoing treatment with talquetamab should be educated on the potential for skin toxicity prior to treatment. Mitigation strategies include keeping skin clean and dry, moisturized, and hydrated. Early intervention should be considered. Early or prophylactic use of emollients and sunscreen is recommended.16 Rash occurring in the first treatment cycle is managed with topical corticosteroids per institutional guidelines with consideration for short-course oral corticosteroids to reduce the risk of rash progression. A consultation with dermatology can be considered.18 For severe rash, treatment may need to be withheld.21 Rashes that occur beyond cycle 2 or that are refractory to emollients or low-potency steroids should be immediately referred to dermatology.16
“With the hand-foot peeling, what I will prescribe for my patients is ammonium lactate 12% lotion, and I’m asking patients to put that on the soles and the palms and do that twice a day for that skin peeling. And these will typically resolve in several weeks with these interventions.”
- Donna Catamero, NP
Nail disorders were observed in 55% of patients on MonumenTAL-1 and included discoloration, disorder, onycholysis, onychomadesis, onychoclasis, nail dystrophy, nail toxicity, and nail ridging. Median time to onset was between 64 and 69 days, and median AE duration was between 74 and 122 days. Nail soaks, topical moisturizers, and topical corticosteroids can be used for management. Other strategies include vitamin E oil, systemic hydration, biotin, triamcinolone ointment, and protective nail coverings. Dose reductions, delays, or treatment holidays may help improve nail toxicities, although evidence is limited.18
Oral Toxicities
Case: 65-year-old woman with RRMM |
- Diagnosed 9 years ago with IgG kappa MM containing t(11;14), del(13q), and trisomy 5
- She was induced with bortezomib, cyclophosphamide, and dexamethasone followed by a high-dose melphalan-conditioned (200 mg/m2) ASCT followed by maintenance lenalidomide therapy
- Relapsed several times and was treated with the following:
- Second line: Daratumumab, pomalidomide, and dexamethasone
- Third line: Carfilzomib, cyclophosphamide, and dexamethasone
- Fourth line: Belantamab mafodotin (poorly tolerated)
- Fifth line: Talquetamab
- First step-up dose: May of 2024
- Bi-weekly dosing schedule
- Day 22 of cycle 1, she had noted dysgeusia and mild burning when she ate or drank anything acidic
- Weight loss of 5 pounds
|
Dysgeusia, dysphagia, and xerostomia are common in patients undergoing treatment with talquetamab. Dysgeusia occurred in 72% to 77%, dysphagia in 24% to 25%, and xerostomia in 27% to 51% of patients on MonumenTAL-1, depending on the dose/schedule. Median time to onset was 13 to 20 days for dysgeusia, 21 to 28 days for dysphagia, and 19 to 26 days for xerostomia.18 The incidence of both skin and oral toxicities appears to be lower with GPRC5D-directed bispecific antibodies compared to GPRC5D-directed CAR T-cell therapy (Figure 2).14
Oral symptoms can be difficult to manage, impair quality of life, and cause treatment discontinuation. Patients should be managed with supportive care, including increased hydration, oral rinses, saliva substitutes, and sugar-free gum to stimulate saliva flow. Modifying dosage and frequency can facilitate keeping patients on therapy.16,22
“I think it’s super important to really educate our patients prior to starting talquetamab, to set expectations, and let them know that if they get significant dysgeusia or oral toxicity, that we, down the road, have remedies that we can institute with dose modifications, if necessary, and often with a lot of success.”
-Jeffrey Matous, MD
Oral adverse events can coincide and result in weight loss. Nutritional supplements that enhance oral intake and prevent bodyweight reduction may be necessary. Assess the potential for other oral comorbidities and encourage regular dental review. A consultation with a nutritionist should be encouraged.14,16,18
“Because I’m really concerned about the weight loss and we know that these oral toxicities can greatly affect a patient’s quality of life, I add in a nutritional consult.…I have them seen during that step-up dosing because we’re going to probably need to make some dietary modifications, so we want to make sure that patients have high-caloric, high-protein diets so that we can avoid the weight loss.”
-Donna Catamero, NP
Conclusion
GPRC5D-directed immunotherapies represent an advance in the care and treatment of RRMM with talquetamab being the only non-BCMA-directed T-cell-redirecting therapy currently available in the US. While certain AEs associated with GPRC5D-directed therapies can be challenging, education to set expectations along with aggressive support and early intervention, including modifying dose and/or frequency, can improve patients’ quality of life and reduce treatment discontinuations due to intolerance.14,16,18
References
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- Lesokhin AM, Tomasson MH, Arnulf B, et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023;29(9):2259-2267. doi:10.1038/s41591-023-02528-9
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- Rodriguez-Otero P, van de Donk NWCJ, Pillarisetti K, et al. GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review. Blood Cancer J. 2024;14(1):24. doi:10.1038/s41408-023-00966-9
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- Rodriguez-Otero P, Usmani S, Cohen AD, et al; International Myeloma Working Group. International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma. Lancet Oncol. 2024;25(5):e205-e216. doi:10.1016/S1470-2045(24)00043-3
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- Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-638. doi:10.1016/j.bbmt.2018.12.758
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- Chari A, Oriol A, Krishnan A, et al. Efficacy and safety of less frequent/lower intensity dosing of talquetamab in patients with relapsed/refractory multiple myeloma: results from the phase 1/2 MonumenTAL-1 study. Blood. 2023;142(Supplement 1):1010. doi: 10.1182/blood-2023-181228