Real-World Safety and Efficacy of Talquetamab for Patients with Heavily Pretreated Relapsed-Refractory Multiple Myeloma
Authors: Shaikh Hira , Lochner Jonathan , Loeffler Bradley , Friend Reed , Habib Alma , McKenna Marshall , Snyder Jordan , Davis James A , Patrus Gina , Dileo Rachel , Mewawalla Prerna , Green Kimberly M , Poonsombudlert Kittika , Mushtaq Muhammad Umair , Abdallah Al-Ola , Ahmed Nausheen , Atrash Shebli , Hashmi Hamza , Strouse Christopher , Paul Barry , Khan Abdullah Mohammad , Tiger Yun Kyoung 
Published: December 2024

Background: Talquetamab is a G protein-coupled receptor class C group 5 member D (GPRC5D) targeting bispecific T-cell engager (TCE) approved in August 2023 for patients with relapsed-refractory multiple myeloma (RRMM) who have received at least 4 prior lines of therapy (LOT) including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody based on the results of the pivotal MonumenTAL-1 trial. In this multicenter study, we evaluated the real-world safety and efficacy of talquetamab, including patients who would have been ineligible for the MonumenTAL-1 trial.

Methods: RRMM patients who received at least the first full dose of talquetamab monotherapy at one of seven U.S. academic institutions as of 6/1/24 were ascertained from institutional databases and included in this US Myeloma Research Innovations Research Collaborative (USMIRC) analysis. Responses to therapy were evaluated using the International Myeloma Working Group (IMWG) criteria. Adverse events were graded based on the CTCAE v5.0 criteria. The Kaplan-Meier method was used to estimate duration of response (DoR), progression-free (PFS) and overall survival (OS). Chi-square tests were used to compare responders and non-responders.

Results: The 68 patients included in this analysis received a median of 7 (4-17) prior LOT, 45% had high risk cytogenetics (including 1q gain) and 46% had extramedullary disease (EMD). Most were triple class (88%), penta-drug (71%), or B cell maturation antigen (BCMA) directed therapy (BDT) (83%, 52/63) refractory. Cytokine release syndrome (CRS) was observed in 64% (36/56), with 1 grade III/IV event. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 13% (7/56), with 1 grade III/IV event. The most common grade III/IV hematological toxicities were thrombocytopenia (23%, 10/43) and anemia (17%, 8/47). Dysgeusia (73%, 41/56), dry mouth (42%, 23/55), and weight loss ≥10% (27%, 15/55) were common. Nail changes (41%, 23/56), skin-related events (48%), prominently rash, peeling, and dryness were also noted. Infections occurred in 36% (20/56) of patients, most (70%) involving the respiratory tract. One potential treatment-related death was reported; 21% of the patients had died at the time of data cut-off (7/1/24) with 83% of deaths attributed to disease progression.

The best overall response rate (ORR) was 71%. Responses were deep: 51% very good partial response or better (&gt;VGPR), 25% complete response or better (&gt;CR). The median time to first response was 0.9 (0.1-4.0) month and 1.0 (0.4-7.0) month to best response. Overall, responders had lower rates of EMD (33% vs 75%, p&lt;0.01) and TCE exposure (60% vs 100%, p&lt;0.01) compared to the non-responders. ORR was 65%, 71%, and 52% for BDT-refractory, penta-refractory, and those with EMD, respectively.

At a median follow-up of 4.6 (0.5-17.5) months, estimated 6-month OS was 74% (95% CI 59-85). While, the estimated 6-month DoR was 63% (95% CI 42-77) and PFS was 45% (95% CI 30-58) respectively. OS was associated with EMD (HR 3.2, p=0.05) and MONUMENTAL-1 ineligibility (HR 4.5, p=0.01) on univariate analysis. EMD (HR 2.6, p=&lt;0.01) and TCE (HR 3.5, p=0.02) significantly affected PFS on univariate analysis, however only EMD (HR 2.8, p&lt;0.01) was associated with PFS on multivariate analysis.

Of the patients included in our analysis, 40% (26/65) would have been deemed ineligible for the MonumenTAL-1 trial, primarily due to cytopenias, ECOG &gt;2 or renal dysfunction. ORR in this sub-group was 65%.

Conclusion: In this real-world experience of the safety and efficacy of talquetamab for RRMM, results were comparable to that of the MonumenTAL-1 trial even though 40% of patients would not have been eligible. BDT-refractory patients, except for TCE exposed had impressive ORR.