Teclistamab in Combination with Subcutaneous Daratumumab and Lenalidomide in Patients with Multiple Myeloma: Results from One Cohort of MajesTEC-2, a Phase1b, Multicohort Study

Introduction: Teclistamab (tec) is an off-the-shelf, B-cell maturation antigen (BCMA) × CD3 bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing multiple myeloma (MM) cells. The combination of daratumumab (dara) and lenalidomide (len) plus dexamethasone is approved for the treatment of MM. Both dara and len have immunomodulatory effects that may enhance the function of tec, potentially resulting in enhanced antimyeloma activity in a broader population of patients. We present initial safety and efficacy data for patients with MM who received tec in combination with dara and len (tec-dara-len) in a phase 1b multicohort study (MajesTEC-2; NCT04722146).

Methods. Patients were eligible for tec-dara-len if they had received 1–3 prior lines of therapy (LOT), including a proteasome inhibitor and immunomodulatory drug. In this cohort, patients received weekly doses of tec (0.72 or 1.5 mg/kg with step-up dosing) plus the approved schedules of dara 1800 mg + len 25 mg. Responses were investigator assessed per 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 patients received tec-dara-len (0.72 mg/kg, n=13; 1.5 mg/kg, n=19). At the 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). Median age was 62 years (range, 38–75); 87.5% were male. All patients had received prior MM treatment; median prior LOT was 2 (range, 1–3), and 31.3% were anti-CD38 exposed. The most frequent AE was CRS (81.3% [n=26]). All CRS events were grade 1/2, and 95% of the events occurred during cycle 1 treatment doses. Median time to onset was 2 days (range, 1–8) and median duration was 2 days (range, 1–22). No ICANS events were reported. Other frequent AEs (≥25.0% across both dose levels) were neutropenia (75.0% [n=24]; grade 3/4: 68.8% [n=22]), fatigue (43.8% [n=14]; grade 3/4: 6.3% [n=2]), diarrhea (37.5% [n=12]; all grade 1/2), insomnia (31.3% [n=10]; grade 3/4: 3.1% [n=1]), cough (28.1% [n=9]; all grade 1/2), hypophosphatemia (25.0% [n=8]; all grade 1/2), and pyrexia (25% [n=8]; grade 3/4: 6.3% [n=2]). The frequency of febrile neutropenia was 12.5% (n=4). Infections occurred in 24 patients (75.0%; grade 3/4: 28.1% [n=9]). The most common infections were upper respiratory infection (21.9% [n=7]), COVID-19 (21.9% [n=7]), and pneumonia (21.9% [n=7]). Three patients (9.4%) had COVID-19 pneumonia. One patient (3.1%) discontinued due to an AE (COVID-19) considered unrelated to study drugs; this patient died due to COVID-19. The overall response rate (ORR) was 13/13 evaluable patients (median follow-up, 8.61 mo) at 0.72 mg/kg and 13/16 evaluable patients (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 patients 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 similar to 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 was well tolerated, with a safety profile consistent with tec or dara-len individually. Promising ORR supports the potential for this combination to have enhanced early disease control through the addition of tec. These data warrant further investigation. The randomized phase 3 MajesTEC-7 study will compare tec-dara-len vs the combination of dara, len, and dexamethasone in patients with NDMM ineligible or not intended for autologous stem cell transplant as initial treatment.