Abstract

 

Background

GPRC5D-directed therapy has expanded treatment options for relapsed/refractory multiple myeloma (RRMM),

but characteristic oral, dermatologic, nail, and nutritional toxicities may affect tolerability, dose intensity, and

treatment persistence. We performed a systematic review and meta-analysis to quantify the burden of treatment-

relevant, largely nonhematologic toxicity with talquetamab/GPRC5D-directed therapy in RRMM.

 

Methods

We systematically searched PubMed/Medline, Cochrane Library, ClinicalTrials.gov, and major hematology/

oncology meeting proceedings, including ASH, ASCO, EHA/HemaSphere, and SOHO, from 2022 to 2026 for

prospective and real-world RRMM studies of GPRC5D-directed therapy reporting extractable toxicity or treatment-limiting

outcomes. Duplicate trial-family reports were adjudicated by preferentially selecting the latest or

most complete source. Registry-only records and nonextractable abstracts were not pooled. Random-effects

logit-transformed pooled proportions were estimated.

 

Results

Four unique talquetamab cohorts/arms met inclusion criteria for quantitative synthesis. The primary analysis

included two pivotal MonumenTAL-1 prior T-cell redirection–naïve dose cohorts and one German multicenter

real-world cohort; the prior T-cell redirection cohort was analyzed separately as a sensitivity cohort. Taste-

related adverse events/dysgeusia were most frequent, with a pooled incidence of 72.5% (95% CI, 68.1%–76.5%;

k=3; n=433). Other common toxicities included nonrash skin-related adverse events at 66.7% (51.9%–78.8%;

k=2; n=297), nail-related adverse events at 55.2% (49.5%–60.8%; k=2; n=297), weight loss/decreased weight

at 45.6% (37.5%–53.9%; k=3; n=418), rash-related adverse events at 35.4% (27.4%–44.3%; k=2; n=297), dry

mouth/xerostomia at 32.6% (21.7%–45.8%; k=2; n=297), dysphagia at 24.2% (19.7%–29.4%; k=2; n=297), and

decreased appetite at 24.1% (17.4%–32.4%; k=2; n=297). Treatment-limiting outcomes were less frequent: dose

reduction occurred in 11.7% (6.4%–20.5%; k=2; n=297), and discontinuation due to adverse events occurred

in 7.0% (3.8%–12.6%; k=2; n=297). Sensitivity analyses including the prior T-cell redirection cohort produced

similar estimates.

 

Conclusions

Talquetamab/GPRC5D-directed therapy in RRMM is associated with a high burden of taste, skin, nail, and

weight-related on-target/off-tumor toxicities, but adverse event–related discontinuation appears comparatively

uncommon. These findings support proactive counseling, early nutritional and supportive care, dose-modification

strategies, and standardized reporting of treatment-limiting toxicity in future GPRC5D-directed therapy

studies.

 

ASH: American Society of Hematology, ASCO: American Society of Clinical Oncology, CI: confidence interval,

EHA: European Hematology Association, GPRC5D: G protein-coupled receptor class C group 5 member D, MM:

multiple myeloma, SOHO: Society of Hematologic Oncology

 

Keywords

MM, multiple myeloma, talquetamab, GPRC5D-directed therapy, adverse events, treatment persistence