Two bispecific antibody therapies are demonstrating significant efficacy across different stages of multiple myeloma treatment, offering new hope for patients ranging from newly diagnosed cases to those with heavily pretreated disease, according to data presented at the 2024 ASCO Annual Meeting.
Talquetamab Proves Effective in Post-CAR-T Setting
A retrospective analysis of 21 patients with relapsed or refractory multiple myeloma treated with talquetamab (Talvey) showed promising results even in a challenging patient population. The study included patients who had received a median of 7 prior lines of treatment, with 85.7% being triple-class refractory and 57.1% being penta-class refractory.
Notably, 76.2% of patients had received prior CAR-T cell therapy, and 85.7% did not meet eligibility criteria for the pivotal MonumenTAL-1 trial due to factors including poor performance status, cytopenias, and recent gene-modified cell therapy. Despite these challenging characteristics, talquetamab achieved an objective response rate of 71.4% and a complete response rate of 28.6% at a median follow-up of 2 months.
"Our data suggests that patients with poor functional status, multiple medical comorbidities, and recent gene-modified adoptive cell therapy benefit from treatment with [talquetamab] without increased rates of [adverse events]," the researchers noted.
The response rates varied by prior treatment history. Patients who had received prior BCMA CAR-T cell therapy showed a 100% objective response rate with a 30.8% complete response rate. Those treated with prior BCMA bispecific antibodies had a 50% response rate, while patients who received both prior BCMA CAR-T and bispecific antibody treatment achieved a 75% response rate with 50% complete responses.
Safety Profile Consistent with Previous Studies
The safety profile of talquetamab was consistent with the MonumenTAL-1 trial data. Cytokine release syndrome occurred in 57% of patients, with most cases being grade 1 or 2. The median time to onset was 4 days after the first dose, with a median duration of 3.5 days. Immune effector cell-associated neurotoxicity syndrome affected 19% of patients, and 14% experienced infections.
Skin-related adverse events occurred in 61.9% of patients, while dysgeusia was observed in 76.2% of cases. Treatment delays occurred in 38% of patients, primarily due to cytokine release syndrome, neurotoxicity, and infections. Importantly, no treatment-related deaths were reported.
Teclistamab Combination Shows Promise in Newly Diagnosed Patients
In the frontline setting, the phase 3 MajesTEC-7 trial's safety run-in cohort evaluated teclistamab (Tecvayli) combined with daratumumab (Darzalex) and lenalidomide (Revlimid) in 26 patients with newly diagnosed multiple myeloma ineligible for transplant. The median patient age was 72.5 years, with 80.8% aged 70 years or older.
The combination demonstrated remarkable efficacy with a 92.3% overall response rate. Complete responses or better were achieved in 80.8% of patients, and very good partial responses or better occurred in 92.3% of cases. No disease progressions were observed in this cohort during the follow-up period.
Dr. Salomon Manier from Lille University Hospital noted that the median time to first response was just 1.0 month, with a median time to best response of 6.5 months. The estimated 12-month duration of response and progression-free survival rates were 100% and 96.2%, respectively.
Managing Infection Risk in Combination Therapy
The teclistamab combination showed a manageable but notable safety profile. All patients experienced treatment-emergent adverse events, with 92.3% having grade 3 or 4 events. Infections occurred in all 26 patients, with 30.8% experiencing grade 3 or 4 infections, most commonly COVID-19.
"Most of these [infection] events occurred during the first 3 cycles, so very early," Dr. Manier explained. "We can see that the cumulative exposure to [teclistamab plus daratumumab and lenalidomide] over time did not increase the incidence of grade 3/4 infections [much]. So this emphasized the need for [intravenous immunoglobulin] supplementation and infection prophylaxis that should be initiated early."
Hypogammaglobulinemia affected 80.8% of patients, and 73.1% received intravenous immunoglobulin replacement. Cytokine release syndrome occurred in 61.5% of patients, mostly during cycle 1, with all cases resolving.
Optimizing Treatment Sequencing
The MajesTEC-7 trial also evaluated different treatment sequencing strategies in additional safety run-in cohorts. Cohorts that included a daratumumab, lenalidomide, and dexamethasone lead-in showed increased neutropenia, grade 3 cytokine release syndrome, and serious infections compared to the primary cohort.
"The hypothesis is that the administration of lenalidomide prior to and during the bispecific step-up schedule may have increased the T-cell fitness and the T-cell activation and bone marrow suppression," Dr. Manier explained. Based on these findings, the randomized phase will proceed with lenalidomide initiated in cycle 2 rather than as a lead-in therapy.
These studies collectively demonstrate that bispecific antibodies are expanding treatment options across the multiple myeloma treatment landscape, from newly diagnosed patients to those with heavily pretreated, refractory disease. The key to success appears to be careful patient monitoring, appropriate supportive care measures, and optimal treatment sequencing to maximize efficacy while managing toxicities.
