Triple Therapy Demonstrates Early Activity in Refractory Myeloma

Bone marrow aspirate cytology of multiple myeloma: ©David A Litman - stock.adobe.com

The oral, novel combination regimen of mezigdomide (CC-92480), tazemetostat (Tazverik), and dexamethasone led to early signals of activity and a tolerable safety profile in patients with highly refractory multiple myeloma, according to preliminary findings from the phase 1b/2a CA057-003 trial (NCT05372354) presented at the 21st International Myeloma Society Annual Meeting.

No new safety signals were identified with this regimen across the cohort of 15 treated patients. The rate of grade 3/4 nonhematologic treatment-emergent adverse effects (TEAEs) was low, and no dose-limiting toxicities were observed. Any-grade infections were reported in 60.0% of patients, including upper respiratory tract infections (26.7%) and pneumonia (20.0%). Grade 3 infections were reported in 3 patients, with 1 patient experiencing a grade 5 infection (pulmonary sepsis) at the 1.0-mg dose.

The combination was associated with an overall response rate (ORR) of 53.3% across all dose levels, with responses observed in patients who had received prior CAR T-cell therapy or bispecific T-cell engagers. At the 1.0-mg dose of mezigdomide (n = 9), the ORR increased to 66.7%.

Study author Luciano J. Costa, MD, PhD, associate director of clinical research at the O’Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, explained that, “the results of this study provide a strong rationale for further exploration of mezigdomide in combination with tazemetostat and other novel therapeutic agents for the treatment of patients with relapsed/refractory multiple myeloma.”

Prior research has demonstrated the potential efficacy of mezigdomide in combination with dexamethasone in this patient population. The phase 1/2 CC-92480-MM-001 trial (NCT03374085) demonstrated the clinical activity of the combination in heavily pretreated patients, providing the rationale for combining mezigdomide with other antimyeloma therapies.

Study Design

The CA057-003 study employs a dose-escalation portion followed by dose expansion to determine the recommended phase 2 dose. The primary objective of the study is to evaluate safety and tolerability, and secondary objectives include efficacy and pharmacokinetic assessments. Exploratory end points focus on minimal residual disease evaluation and biomarker analysis.

In the dose-finding cohort, patients received oral mezigdomide at doses ranging from 0.3 mg to 1.0 mg on days 1 through 21 of each 28-day cycle, in combination with oral tazemetostat at 800 mg twice daily and oral dexamethasone at 40 mg (20 mg for patients older than 75 years of age) weekly. The goal of this portion of the trial was to determine the optimal dosing regimen for this combination in a heavily pretreated patient population.

In cohort A, patients received the combination of mezigdomide, tazemetostat, and dexamethasone. Additional cohorts were designed to explore other combinations, such as mezigdomide plus dexamethasone and either BMS-986158 or trametinib (Mekinist), to further evaluate the safety and efficacy of novel combinations in this population.

Baseline Patient Characteristics

A total of 15 patients with relapsed/refractory multiple myeloma were enrolled. The median age of the cohort was 63 years (range, 51-80), and most patients (66.7%) were male. In terms of race, 66.7% of patients were White, and 26.7% of patients were Black or African American.

At the time of enrollment, the median time since initial diagnosis was 8.3 years (range, 2.4-13.3). Regarding performance status, 86.7% of patients had an ECOG performance status (PS) of 1, and the remaining 13.3% of patients had a PS of 0. When stratified by International Staging System stage, 46.7% of patients were stage I, 33.3% were stage II, and 20.0% were stage III. Forty percent of patients had extramedullary disease at study entry, and an equal percentage (40.0%) had high-risk cytogenetics, including 17p deletion, translocation (4,14) or (14,16), and amplification of 1q21.

All patients had been previously treated with a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody. Additionally, 66.7% of patients had prior exposure to T-cell–redirecting therapies, including 33.3% of patients who had received CAR T-cell therapy. Furthermore, 80.0% of the cohort was triple-class refractory, and 80.0% of patients were quadruple-class refractory, underscoring the significant level of treatment resistance within this population.

Safety Profile

The most common hematologic TEAEs observed across all treated patients included neutropenia (any-grade, 60.0%; grade 3, 20.0%; grade 4, 26.7%), anemia (26.7%; 13.3%; 0%), and thrombocytopenia (20.0%; 0%; 0%). Nonhematologic TEAEs included fatigue (53.3%; 6.7%; 0%), cough (33.3%; 0%; 0%), and back pain (20.0%; 6.7%; 0%).

Grade 3/4 TEAEs were observed across different dose levels of mezigdomide. At the 0.3-mg dose level (n = 3), 100% of patients experienced a grade 3/4 TEAE. Hematologic TEAEs were common, with neutropenia occurring in 66.7% of patients at this dose. Nonhematologic TEAEs included dyspnea, back pain, respiratory failure, muscular weakness, and infections, each reported in 33.3% of patients.

At the 0.6-mg dose level (n = 3), 33.3% of patients experienced a grade 3/4 TEAE. Neutropenia was the only hematologic TEAE observed at this dose level, occurring in 33.3% of patients. No nonhematologic grade 3/4 TEAEs were reported at this dose.

At the 1.0-mg dose level, 77.8% of patients experienced a grade 3/4 TEAE. Hematologic TEAEs were frequent at this dose level, with neutropenia occurring in 44.4% of patients and anemia occurring in 22.2% of patients. Nonhematologic TEAEs included dyspnea (33.3%), fatigue (11.1%), pain in extremity (11.1%), tenosynovitis (11.1%), insomnia (11.1%), and infections (22.2%), which included pneumonia in 11.1% of patients and a urinary tract infection in 11.1% of patients. The distribution of TEAEs highlights that the 1.0-mg dose level was associated with the highest frequency of grade 3/4 AEs, particularly hematologic toxicities.

Observable Responses

Among responders, 6.7% of patients achieved a stringent complete response (sCR), 26.7% of patients experienced a very good partial response (VGPR), 20.0% of patients had a PR, and 6.7% of patients achieved minimal response (MR). Stable disease (SD) was observed in 20.0% of patients, and 20.0% of patients experienced progressive disease (PD).

Of responders who received mezigdomide at 1.0 mg, 11.1% achieved an sCR, 44.4% had a VGPR, 11.1% experienced a PR, and 11.1% had an MR. Additionally, 1 patient (11.1%) demonstrated SD, and another patient (11.1%) experienced PD.

The median time to first response across all doses was 0.95 months (range, 0.9-3.0). The median duration of response was not reached (95% CI, 3.71 months-not available), indicating a sustained benefit in some patients. Notably, some responses lasted for 10 or more treatment cycles, indicating durable efficacy in certain cases.

Pharmacokinetics

In the study, mezigdomide exposure increased in a dose-linear manner across the range of doses, and co-administration with tazemetostat did not affect mezigdomide levels. Pharmacodynamic activity demonstrated that substrate degradation, B-cell depletion, and serum free light chain reduction were dose dependent, with the most pronounced effects seen at the 1.0-mg mezigdomide dose. Additionally, T-cell activation and proliferation were observed from day 8 of cycle 1, with maximum activity generally occurring at the 1.0-mg dose of mezigdomide.

Disclosures: Dr Costa reports receiving honoraria from Adaptive Technologies, BMS/Celgene, and Janssen; performing consultancy roles for Amgen, BMS/Celgene, Janssen, Pfizer, and Sanofi; and receiving grants/funding from Amgen, BMS/Celgene, Caribou Biosciences, and Janssen.

REFERENCE:

Costa LJ, Popat R, Siegel D, et al. Mezigdomide, tazemetostat, and dexamethasone in patients with relapsed/refractory multiple myeloma: preliminary results from the CA057-003 trial. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-29.