Talquetamab + Pomalidomide in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Preliminary Efficacy Results from the Phase 1b MonumenTAL-2 Study

Introduction: Talquetamab (tal) is a T-cell redirecting bispecific antibody (BsAb) targeting GPRC5D and CD3. GPRC5D is a novel antigen that is highly expressed on malignant plasma cells but has low expression on B cells and normal plasma cells. Tal has demonstrated deep and durable responses, including in high-risk populations, and a clinically manageable safety profile in patients (pts) with relapsed/refractory multiple myeloma (RRMM) in the MonumenTAL-1 study (NCT03399799/NCT04634552). Pomalidomide (pom) is an established immunomodulatory drug (IMiD) that has direct on-tumor apoptotic activity and enhances immune activity. Combining pom with T-cell redirection therapy may lead to synergistic antimyeloma effects. We report initial efficacy and safety results of tal + pom from the MonumenTAL-2 study.

Methods: MonumenTAL-2 (NCT05050097) is a multi-arm, phase 1b study of tal in combination with antimyeloma agents in pts with MM. Pts received the recommended phase 2 doses of subcutaneous tal 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), with step-up dosing, + oral pom 2 mg daily (dose escalation to 4 mg daily permitted) starting in cycle 2. Pts received ≥2 prior lines of therapy (LOT) including a proteasome inhibitor and an IMiD; prior T-cell redirection therapies including BsAbs and chimeric antigen receptor (CAR)-T along with prior pom exposure were permitted. CRS and ICANS were graded by ASTCT criteria; all other adverse events (AEs) were graded by CTCAE v5.0. Response was assessed by IMWG criteria. Efficacy endpoints are presented as individual cohorts (QW and Q2W); safety is presented across both cohorts.

Results: As of June 5, 2023, 35 patients were enrolled with a median follow-up of 11.4 months (range, 1.2-14.9) in the QW cohort (N=16) and 7.7 months (range, 1.6-10.8) in the Q2W cohort (N=19). Median ages were 69.5 years (range, 49-78) and 63.0 years (range, 43-76), respectively; 41.7% and 33.3% of pts had high-risk cytogenetics (del[17p], t[4;14], or t[14;16]) and 12.5% and 10.5% of pts had extramedullary disease, respectively. Median prior LOT were 3 in both cohorts; 25.0% and 21.1% were triple-class refractory, respectively, and 6.3% were penta-drug refractory (all in QW cohort). Prior treatments included CAR-T (18.8% and 0%), BsAb (6.3% and 0% [0% refractory]), and anti-CD38 Ab (75.0% and 73.7% [56.3% and 36.8% refractory]) in the QW and Q2W cohorts, respectively; 31.3% and 15.8% had prior pom exposure (18.8% and 5.3% refractory). All pts had ≥1 AE; most common were dysgeusia (77.1%), CRS (74.3%; most grade 1/2, 2.9% grade ≥3), and neutropenia (60.0%). Grade 3/4 AEs occurred in 88.6% of pts; most common were neutropenia (48.6%), anemia (25.7%), and thrombocytopenia (20.0%). Nail, skin, and rash toxicities occurred in 65.7%, 40.0%, and 20.0% of pts (majority grade 1/2 with no discontinuations), respectively. ICANS occurred in 2 pts (both grade 1). Infections occurred in 71.4% of pts (22.9% grade 3/4); most common were pneumonia (20.0%) and COVID-19 (14.3%). AEs led to dose reduction or schedule change of tal in 34.3% of pts and dose reduction of pom in 31.4% of pts. Two pts (5.7%) in the Q2W cohort had AEs, myocardial infarction and pulmonary embolism (PE), that led to treatment discontinuation (not drug related). One death due to PE occurred (same pt who discontinued treatment). ORR was 86.7% and 83.3% in the QW and Q2W cohorts, respectively, with ≥CR in 60.0% and 44.4% and ≥VGPR in 86.7% and 77.8%, respectively. ORRs were consistent across pt subgroups (>80% independent of prior pom or CAR-T exposure). Median time to first response was 1.0 month (range, 0.9-2.1) in the QW cohort and 1.3 months (range, 0-4.8) in the Q2W cohort. At 6 months, 100% of responders were still responding in both cohorts. Median DOR and PFS were not reached, with 6-month PFS rates of 93.3% (QW) and 88.9% (Q2W).

Conclusions: In this first reported combination of a GPRC5D-targeted therapy and an IMiD, tal + pom showed rapid, deep responses in pts with RRMM and ≥2 prior LOT. The safety profile of the combination, including grade 3/4 hematologic toxicity, was consistent with the individual agents, with no evidence of additive hematologic toxicities; additionally, there were low rates of treatment discontinuation due to AEs. The promising efficacy and manageable safety profile of this combination further supports tal as a versatile combination partner and warrants further evaluation of this regimen.