Maximizing Myeloma Outcomes With GPRC5D-Directed Therapy: Practical Expert Case Studies and Best Practices

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. 

Class Side Effects of T-Cell-Redirecting Therapies

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).

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.

Skin Toxicities

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.

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

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

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

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

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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