Practical use of talquetamab in relapsed/refractory multiple myeloma: the Memorial Sloan Kettering Cancer Center experience Open Access

Talquetamab is a G protein–coupled receptor family C class 5 member D (GPRC5D)–targeting bispecific antibody that was granted accelerated approval for triple-class relapsed/refractory multiple myeloma (RRMM) based on results of the MonumenTAL-1 trial.¹ Although it led to deep and durable responses in heavily pretreated patients, talquetamab was associated with unique on-target, off-tumor toxicities due to high expression of GPRC5D in hard-keratinized structures such as the skin, nails, and tongue.² These adverse events (AEs) can significantly affect quality of life, and optimal strategies for their prevention and mitigation are yet to be identified. Herein, we report the real-world experience at our center on the safety and efficacy of talquetamab, highlighting the characterization and management of on-target, off-tumor toxicities.

Our single-center retrospective cohort included all patients with RRMM at Memorial Sloan Kettering Cancer Center who received ≥1 full subcutaneous dose (0.4 or 0.8 mg/kg) of commercially available talquetamab. Step-up dosing and toxicity prophylaxis/management were mostly based on institutional guidelines. We assessed treatment responses per International Myeloma Working Group criteria (IMWG)³; immune-related AEs, including cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), and immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome, per American Society for Transplantation and Cellular Therapy guidelines⁴; and all other toxicities per Common Terminology Criteria for Adverse Events version 5.0. The primary study objective was to evaluate the incidence, severity, management, and recovery of nonhematologic, nonimmune–related AEs, categorized as follows: (1) weight loss (≥5% decrease from baseline); (2) oral toxicities (taste changes, dry mouth, and dysphagia); and (3) dermatologic toxicities (nail-related, rash-related, and nonrash skin AEs). We examined toxicity management by tracking supportive interventions and talquetamab regimen adjustments, including treatment interruption (dose holds/delays), modification (reductions in dosing frequency/intensity), or discontinuation. Secondary objectives included assessing hematologic/immune-related AEs, response rates, progression-free survival (PFS), and overall survival (OS). Descriptive statistics summarized baseline data, response rates, and safety outcomes. Time-to-event outcomes were estimated using the Kaplan-Meier method, with medians and 95% confidence intervals (CIs) reported. All analyses were conducted using R version 4.4.1.

Between August 2023 and October 2024, a total of 51 patients (55% female and 65% White) received talquetamab (14% as bridging therapy before chimeric antigen receptor T-cell therapy). The median patient age was 66 years (range, 41-85), with 14 (25%) having renal impairment (creatinine clearance <60 mL/min per 1.73 m²), 7 (14%) with Eastern Cooperative Oncology Group performance status of 2, and 19 (37%) with grade ≥3 cytopenias at treatment initiation. Patients received a median of 7 prior lines of therapy (range, 4-17), with triple-class refractory disease in 48 (94%) and penta-refractory disease in 17 (33%). Notably, 22 patients (43%) had extramedullary disease, 30 (59%) had high-risk cytogenetics per IMWG criteria, and 36 (71%) had a prior T-cell–redirecting therapy. After inpatient step-up dosing, 34 patients (67%) received talquetamab 0.8 mg/kg every 2 weeks (Q2W), whereas 17 (33%) received 0.4 mg/kg weekly as their full dose (Table 1).

At data cutoff (31 January 2025), the median follow-up for safety outcomes was 5.2 months (interquartile range [IQR], 2.9-7.5). Figure 1A-B displays the incidence, severity, and recovery rates of nonimmune–related AEs. Weight loss occurred in 35 patients (69%), including 4 (8%) grade 3 events, with a median percentage weight loss of 7.45% (IQR, 3.6%-13%) for the entire cohort. Among affected patients, 7 (20%) had partial recovery, and 10 (29%) full recovery to baseline weight. Taste changes (eg, dysgeusia, hypogeusia, or ageusia) were reported by 35 patients (69%), with only 10 (29%) demonstrating partial/full recovery. Dry mouth was observed in 31 patients (61%), and 18 (58%) experienced partial/full recovery. Dysphagia was seen in 22 patients (43%), and 16 (73%) reported partial/full recovery. Regarding dermatologic toxicities, rash-related AEs were observed in 10 patients (20%), all of whom experienced resolution during the study period. Nonrash skin toxicities (eg, dryness, pruritus, fissures, blistering, or exfoliation) were reported by 35 patients (69%), with 19 (54%) demonstrating partial/full recovery. Nail-related AEs (eg, discoloration, ridging/splitting/brittleness, or lifting/shedding/loss) occurred in 25 patients (49%); of those affected, 8 (32%) experienced resolution. These AEs occurred at similar rates regardless of the standard full-dose regimen used.

Figure 1C shows management strategies used for weight loss, oral toxicities, and dermatologic AEs. Nearly half of patients (47%) had at least 1 dose held/delayed, most commonly due to active infections (22%) and oral toxicities/weight loss (12%). As for treatment modifications, 18% had a dosing frequency reduction (10% from 0.8 mg/kg Q2W to Q4W; 8% from 0.4 mg/kg weekly to Q2W), and 10% had a dosing intensity reduction (8% from 0.8 to 0.4 mg/kg Q2W; 2% from 0.4 to 0.2 mg/kg weekly). Moreover, 8% permanently discontinued talquetamab. Oral toxicities/weight loss accounted for 13 of 18 events (72%) of treatment modification/discontinuation (Figure 1D). At last follow-up, 6 of 13 patients (46%) who underwent reductions in dosing frequency or intensity had ongoing responses, accompanied by numerically higher rates of recovery from weight loss (64% vs 41%) and taste changes (38% vs 23%) than those who did not. All 4 patients who discontinued talquetamab due to intolerable toxicity ultimately experienced disease progression.

Table 1 summarizes immune-related AEs, hematologic toxicities, and infections. CRS was observed in 28 patients (55%), of whom 27 (53%) experienced grade 1/2 events. ICANS was documented in 7 patients (14%), including 6 (12%) grade 1/2 events. One patient developed grade 3 immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome, which prompted talquetamab discontinuation. At day 30 after treatment initiation, grade ≥3 anemia, thrombocytopenia, and neutropenia were seen in 14%, 31%, and 22% of patients, respectively, decreasing to 3%, 8%, and 3% by day 90. Meanwhile, grade ≥3 lymphopenia rates (37% at day 30 and 26% at day 90) remained relatively high. Infections were reported in 32 patients (63%), including 19 (37%) grade ≥3 events, with nearly all (97%) achieving full resolution.

The median follow-up for efficacy outcomes was 12.3 months (IQR, 6.3-16). Among 45 patients with measurable disease, the overall response rate was 56%, including 42% who achieved a very good partial response or better. The 6-month PFS and OS rates were 45.5% (95% CI, 32.9-62.8) and 87.6% (95% CI, 78.8-97.4), respectively. The median PFS was 5.6 months (95% CI, 3.8-7.6), whereas the median OS was not reached at the time of data cutoff (95% CI, 11.4 months to not reached).

To our knowledge, this single-center retrospective study represents one of the most comprehensive real-world reports to date on talquetamab-associated toxicities in RRMM. Overall, the incidence of most on-target, off-tumor AEs was comparable to that observed in the MonumenTAL-1 trial. Although rash was noticed in 20% of the patients, all events were mild to moderate and resolved with the use of topical agents. In contrast, nonrash skin AEs were reported in over two-thirds of patients, with only half of them experiencing recovery despite widespread use of emollients/moisturizers and individualized trials of additional interventions. One patient developed severe skin desquamation requiring permanent discontinuation of therapy. Nail-related changes were observed in half of the study population, typically causing mild cosmetic disfigurement, and did not prompt any regimen adjustments, although resolution was documented in only one-third of affected patients. Notably, oral AEs, including taste changes, dry mouth, and dysphagia, and associated weight loss were the most common and severe toxicities, affecting 50% to 70% of the patients, with only 30% to 50% of them experiencing partial/full recovery with supportive interventions such as dietary modifications, high-calorie supplements, and appetite stimulants. Oral toxicities/weight loss represented by far the leading reason for treatment modification/discontinuation, highlighting the significant impact on quality of life for these patients. Importantly, our data suggest that, after achieving response to talquetamab, adjusting dose and/or frequency of treatment may be a viable strategy to optimize toxicity profile without compromising efficacy, because approximately half of patients who underwent treatment modification had ongoing responses at the last follow-up. The improvement/resolution dynamics of GPRC5D-related AEs described here align with previously reported findings from reduced dosing frequency/intensity cohorts of talquetamab-treated patients.⁵ 

CRS and ICANS occurred early, were mostly low grade, and reversible. Although most cytopenias were short lived, persistent lymphopenia at day 90 along with severe infections in one-third of patients, which was relatively more frequent than in the MonumenTAL-1 trial, underscore the importance of continued antiviral/pneumocystis prophylaxis and IV immunoglobulin supplementation to reduce infection risk.⁶ Our study population exhibited higher baseline rates of severe cytopenias, impaired performance status, renal dysfunction, penta-refractory disease, and prior exposure to T-cell–redirecting therapies than those in MonumenTAL-1, all of which likely contributed to an increased susceptibility to infections. We also noted inferior PFS and OS, which is not unexpected given the higher prevalence of the aforementioned features and other aggressive disease characteristics (such as ≥5% circulating plasma cells, extramedullary disease, and high-risk cytogenetics) in our real-world cohort.

Retrospective design, modest sample size, and short follow-up are some of the limitations of our study that preclude a comprehensive subgroup analysis or the identification of statistically significant difference in outcomes. Dosing and frequency of treatment varied based on physician preference, and the timing of the complete vs partial resolution of some toxicities could not be accurately differentiated by review of medical records. Furthermore, our study did not incorporate data on supportive strategies for hematologic toxicities (eg, transfusions, growth factor use, antimicrobial prophylaxis, and IV immunoglobulin supplementation). Future studies on talquetamab should focus on the need for de-escalation and/or cessation of therapy guided by the quality of response and associated toxicities. Our center is participating in larger efforts, including the American Society of Hematology research collaborative and IMWG immunotherapy database, to better understand treatment patterns and AE management.

Contribution: B.A.C., C.R.T., and H. Hashmi designed the study; B.A.C. led chart review and data collection; R.S.F, E.M.J., K.M., and B.A.C. assisted in data collection; T.S. assisted in database organization and review; H. Hashmi and B.A.C. performed statistical analysis; H. Hashmi and B.A.C. wrote the manuscript; C.R.T. and S.U. are team leads and oversaw the project; S.R., K.H.M, H. Hassoun, I.S.S., A.X.W., S.M., A.M.L., GL.S, N.K., H.J.L., M.S., U.A.S., M.H., S.A.G., and S.Z.U. reviewed the manuscript and provided feedback on the study.

Conflict-of-interest disclosure: C.R.T. reports research funding from Janssen and Takeda; personal fees from MJH Life Sciences; and has received honoraria for consultancy/participated in the advisory boards for Janssen and Sanofi. T.S. reports receiving honoraria from Roche-Genentech. A.M.L. reports nonfinancial support from Pfizer; grants and personal fees from Janssen, outside the submitted work; serves on the data safety monitoring board for ArcellX; and also has a patent (US20150037346A1) with royalties paid. G.L.S. receives research funding from Janssen, Amgen, Bristol Myers Squibb (BMS), and BeyondSpring Inc.; serves on the data safety monitoring board for ArcellX; and receives research funding to the institution from Janssen, Amgen, BMS, Beyond Spring, and GPCR. N.K. reports research funding through Amgen, Janssen, Epizyme, and AbbVie; consults for Clinical Care Options, OncLive, and Intellisphere; and participated in advisory board for Janssen and MedImmune. H.J.L. has served as a paid consultant for AbbVie, Immix Biopharma, Legend Biotech, Alexion, and Prothena; and has received research funding from Nexcella Inc., Janssen, Alexion, Protego, and Prothena. M.S. served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, Inc, and Omeros Corporation; received research funding from Angiocrine Bioscience, Inc, Omeros Corporation, Amgen Inc, BMS, and Sanofi; served on ad hoc advisory boards for Kite, a Gilead company, and Miltenyi Biotec; and received honoraria from i3Health, Medscape, CancerNetwork, and IDEOlogy. H. Hassoun reports grants from Celgene, Takeda, and Janssen, outside the submitted work. K.H.M. reports grant support from the American Society of Hematology (ASH), the Multiple Myeloma Research Foundation, and the International Myeloma Society. U.A.S. reports research support from Celgene/BMS and Janssen; personal fees/honoraria from the Association of Cancer Care Centers, MashUp MD, Janssen Biotech, Sanofi, BMS, MJH Life Sciences, Intellisphere, Phillips Gilmore Oncology Communications, i3 health, and RedMedEd; and nonfinancial support from the ASH Clinical Research Training Institute and the Transdisciplinary Research in Energetics and Cancer Training Workshop (R25CA203650; principal investigator: Melinda Irwin). M.H. reports research funding from GlaxoSmithKline (GSK), BeiGene, AbbVie, and Daiichi Sankyo, and has received honoraria for consultancy/participated in the advisory boards for Curio Science LLC, Intellisphere LLC, BMS, Janssen, and GSK. S.A.G. reports personal and advisory role fees (scientific advisory board) from Actinium, Celgene, BMS, Sanofi, Amgen, Pfizer, GSK, JAZZ, Janssen, Omeros, Takeda, and Kite, outside the submitted work. S.M. reports research funding from the National Cancer Institute/National Institutes of Health, Janssen Oncology, BMS, Allogene Therapeutics, Fate Therapeutics, Caribou Therapeutics, and Takeda Oncology; consulting fees from EviCore, Optum, BioAscend, Janssen Oncology, BMS, AbbVie, HMP Education, and Legend Biotech; and honoraria from OncLive, Physician Education Resource, MJH Life Sciences, and Plexus Communications. S.Z.U. received research funding from Amgen, AbbVie, Array Biopharma, BMS, Celgene, Gilead, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; is a consultant for AbbVie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Gracell, Janssen, Oncopeptides, Pfizer, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio; and is also a speaker with Amgen, BMS, Janssen, and Sanofi. H. Hashmi reports consultancy for Karyopharm, Amgen, and Janssen. The remaining authors declare no competing financial interests.

Correspondence: Hamza Hashmi, Myeloma and Cell Therapy Service, Memorial Sloan Kettering Cancer Center, 530 East 74th St, New York, NY 10021; email: hashmih1@mskcc.org; and Carlyn Rose Tan, Myeloma Service, Memorial Sloan Kettering Cancer Center, 530 East 74th St, New York, NY 10021; email: tanc4@mskcc.org.