P30 single cohort results from majestec-2: teclistamab (tec) in combination with subcutaneous daratumumab (dara) and lenalidomide (len) in patients with multiple myeloma (mm)

Introduction: DARA and LEN plus dexamethasone is approved for treating MM. Both DARA and LEN have immunomodulatory effects that may enhance the function of TEC, potentially resulting in improved antimyeloma activity in a broader population of patients (pts). Here we report preliminary safety and efficacy results from MajesTEC-2 (NCT04722146) of TEC combined with DARA and LEN (TEC-DARA-LEN) in pts with MM). Methods: Pts who received 1–3 prior lines of therapy (LOT), including a proteasome inhibitor and immunomodulatory drug, were eligible for TEC-DARA-LEN. In this cohort, pts were given weekly doses of TEC (0.72 or 1.5 mg/kg with step-up dosing) combined with an approved regimen of DARA 1800 mg+LEN 25 mg. Investigator responses were assessed by International Myeloma Working Group criteria, and adverse events (AEs) by CTCAE v5.0, except for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) which were graded per ASTCT guidelines. Results: 32 pts (87.5% male; median age, 62 years) received TEC-DARA-LEN (0.72 mg/kg, n=13; 1.5 mg/kg, n=19). At data cutoff (July 11, 2022), median follow-up was 5.78 months (mo; range, 1.0–10.4) and median treatment duration was 4.98 mo (range, 0.10–10.35). 18.8% were refractory to DARA and 28.1% refractory to LEN and median prior LOT was 2 (range, 1–3). Most frequent AE was CRS (81.3% [n=26]; grade [gr] 1/2) and 95% of the events occurred during cycle 1 treatment doses. Median time to onset was 2 days and median duration was 2 days. No ICANS events were reported. Other frequent AEs (≥25.0% across both dose levels) were neutropenia (75.0% [n=24]; gr 3/4: 68.8% [n=22]), fatigue (43.8% [n=14]; gr 3/4: 6.3% [n=2]), diarrhea (37.5% [n=12]; all gr 1/2), insomnia (31.3% [n=10]; gr 3/4: 3.1% [n=1]), cough (28.1% [n=9]; all gr 1/2), hypophosphatemia (25.0% [n=8]; all gr 1/2), pyrexia (25% [n=8]; gr 3/4: 6.3% [n=2], and febrile neutropenia (12.5% [n=4]). Infections occurred in 24 pts (75.0%; gr 3/4: 28.1% [n=9]) and most common were upper respiratory infection (21.9% [n=7]), COVID-19 (21.9% [n=7]), and pneumonia (21.9% [n=7]). 3 pts (9.4%) had COVID-19 pneumonia. 1 pt (3.1%) discontinued due to an AE (COVID-19) and died due to COVID-19. Overall response rate (ORR) was 13/13 evaluable pts (median follow-up: 8.61 mo) at 0.72 mg/kg and 13/16 evaluable pts (median follow-up was less mature at 4.17 mo) at 1.5 mg/kg. Very good partial response or better was achieved in 12 pts at the 0.72 mg/kg dose and was not mature for the 1.5 mg/kg group. Median time to first response was 1.0 mo (range, 0.7–2.0). Preliminary pharmacokinetic concentrations of TEC in combination with DARA-LEN were comparable with those seen with TEC monotherapy. TEC-DARA-LEN treatment led to proinflammatory cytokine production (induction of interleukin-6, soluble interleukin-2Rα, interferon-γ, and tumor necrosis factor-α) and T-cell activation (upregulation of programmed cell death protein-1 and CD38 on peripheral T cells). Conclusions: TEC-DARA-LEN has a safety profile consistent with TEC or DARA-LEN individually. Promising ORR findings support the potential of combined treatment on enhanced early disease control through the addition of tec. The phase 3 MajesTEC-7 study will compare TEC-DARA-LEN vs the combination of DARA, LEN, and dexamethasone in pts with NDMM ineligible or not intended for autologous stem cell transplant as initial treatment.