Subcutaneous Teclistamab in Combination with Daratumumab for the Treatment of Patients with Relapsed/Refractory Multiple Myeloma: Results from a Phase 1b Multicohort Study

Abstract

Introduction: Teclistamab (Tec) is a B-cell maturation antigen × CD3 T-cell redirecting bispecific antibody. In the phase 1 MajesTEC-1 trial in patients (pts) with heavily pretreated relapsed/refractory multiple myeloma (RRMM), Tec monotherapy was well tolerated and yielded an overall response rate of 65% and very good partial response or better rate of 58% at the recommended phase 2 dose (RP2D) with 6.1 months' median follow-up; responses were durable and deepened over time. Daratumumab (Dara) is a monoclonal antibody that targets CD38 and is approved for the treatment of MM. In addition to direct cytotoxicity, Dara has immunomodulatory effects, including promotion of T-cell expansion and depletion of suppressive CD38+ immunoregulatory cells, making it a rational partner for T-cell redirection. In preclinical studies, the lytic activity of Tec against MM cell lines was enhanced by pretreatment and combination treatment with Dara. By targeting discrete yet complementary antigens, combination of Tec and Dara may improve efficacy in pts with RRMM. We present data for pts with RRMM who received Tec + Dara in a phase 1b multicohort study (TRIMM-2; NCT04108195). Methods: Eligible pts were ≥18 years of age with an MM diagnosis and had received ≥3 prior lines of therapy (including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD. Pts who had received anti-CD38 therapy ≤90 days were excluded. In Tec + Dara cohorts, treatment was administered in 28-d cycles (with step-up dosing for Tec). The primary objectives were to identify the RP2D for the Tec + Dara combination and evaluate its safety. This analysis focuses on subcutaneous (SC) cohorts in the study. Responses were assessed by IMWG 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: A total of 33 pts received SC Tec + Dara in different dosing cohorts: Dara 1800 mg + Tec 1500 µg/kg weekly (n=21), + Tec 3000 µg/kg weekly (n=5), + Tec 300 mg biweekly starting Cycle 3 Day 1 (Tec 150 mg weekly in Cycles 1-2; n=2), and + Tec 3000 µg/kg biweekly (n=5). Nine pts in the Dara 1800 mg + Tec 1500 µg/kg weekly cohort switched to Tec 3000 μg/kg biweekly dosing after Cycle 3 Day 1. As of the data cutoff (Jun 22, 2021), median follow-up across Tec + Dara cohorts was 3.6 months (range 0.1-10.4). Median pt age was 67 years (range 51-78) and 57.6% were female. Median number of lines of prior therapy was 5 (range 2-16); 69.7% of pts were triple-class exposed (prior anti-CD38 therapy was Dara in all 69.7%) and 60.6% were penta-drug exposed. Overall, 97.0% of pts had ≥1 AE of any grade; 66.7% had grade 3/4 AEs. The most common AE was CRS (54.5%; all grade 1/2); median time to onset was 2 days (range 1-6), and median duration was 2 days (range 1-7). Other AEs (≥30% across Tec + Dara cohorts) were neutropenia (36.4%; all grade 3/4), thrombocytopenia (36.4%; grade 3/4 33.3%), anemia (36.4%; grade 3/4 24.2%), diarrhea (36.4%; grade 3/4 3.0%), nausea (30.3%; all grade 1/2), and pyrexia (30.3%; all grade 1/2). Infections occurred in 51.5% of pts (grade ≥3 24.2%). No ICANS events were reported. One pt in the Dara 1800 mg + Tec 3000 µg/kg weekly cohort died due to bacterial pneumonia (unrelated to treatment) during Cycle 1, and 1 in the Dara 1800 mg + Tec 1500 µg/kg weekly cohort died due to progressive disease. Responses in different dosing cohorts are shown in the Table. Across Tec + Dara cohorts, median time to first response was 1.0 month (range 0-1.9). Median duration of response was not reached. Tec + Dara treatment led to proinflammatory cytokine production (induction of interferon-γ and tumor necrosis factor-α) and T-cell activation (upregulation of programmed cell death protein-1 and CD38 on peripheral T cells). The Tec pharmacokinetic profile was similar to that in MajesTEC-1. Data will be updated with longer follow-up at the time of the congress. Conclusions: The combination of Tec + Dara had a manageable safety profile, consistent with the monotherapies, and showed preliminary efficacy in pretreated pts with MM; with longer follow-up, responses may continue to deepen, as has been seen with Tec monotherapy. These promising data warrant further investigation; the randomized phase 3 MajesTEC-3 study will evaluate Tec + Dara vs Dara, pomalidomide, and dexamethasone or Dara, bortezomib, and dexamethasone in pts with RRMM. Figure 1 Figure 1. Disclosures Rodriguez-Otero: Amgen: Honoraria; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Clínica Universidad de Navarra: Current Employment; Regeneron: Honoraria. Dholaria: Takeda: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Jazz: Speakers Bureau; MEI: Research Funding; Angiocrine: Research Funding; Poseida: Research Funding; Celgene: Speakers Bureau. Askari: Janssen: Research Funding. Reece: Karyopharm: Consultancy, Research Funding; GSK: Honoraria; Millennium: Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. van de Donk: Cellectis: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Chari: Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Goldschmidt: MSD: Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Dietmar-Hopp-Foundation: Other: Grant; Sanofi: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Takeda: Consultancy, Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grant; Janssen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Incyte: Research Funding; GSK: Honoraria; Chugai: Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; BMS: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Celgene: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding; Adaptive Biotechnology: Consultancy; Amgen: Consultancy, Honoraria, Other: Grants and/or Provision of Investigational Medicinal Product, Research Funding. Krishnan: City of Hope Cancer Center: Current Employment; JANSSEN: Consultancy, Research Funding; BMS: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; MAGENTA: Consultancy; REGENERON: Consultancy; SANOFI: Consultancy; GSK: Consultancy; Amgen: Speakers Bureau. Martin: Sanofi: Research Funding; Oncopeptides: Consultancy; Janssen: Research Funding; Amgen: Research Funding; GlaxoSmithKline: Consultancy. Mateos: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Bluebird bio: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria; Oncopeptides: Honoraria. Morillo Giles: Janssen: Honoraria; Takeda: Honoraria; Abbvie: Honoraria. Rodriguez: Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Karyopharm: Consultancy, Speakers Bureau. Rosinol: Janssen, Celgene, Amgen and Takeda: Honoraria. San-Miguel: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, Merck Sharpe & Dohme, Novartis, Regeneron, Roche, Sanofi, SecuraBio, Takeda: Consultancy, Other: Advisory board. Sureda: Bluebird: Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Wäsch: Amgen: Consultancy, Honoraria; Pfizer: Consultancy; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Weisel: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Novartis: Honoraria; Pfizer: Honoraria. Verona: Janssen: Current Employment. Wang Lin: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Prior: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Weiss: Janssen: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Wade: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Goldberg: Janssen: Current Employment, Current holder of individual stocks in a privately-held company. Oriol: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hari: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Treatment horizon in multiple myeloma

“…101,102 Combination therapy incorporating teclistamab is ongoing and preliminary results have shown promising results. 103 Elranatamab, (PF-06863135), a humanized bispecific molecule that targets BCMA expressed on MM and engages CD3 on T cells, is being studied in phase 1 study MagnetisMM-1 as monotherapy, and also as combination therapy with lenalidomide and pomalidomide.…”

“…The phase 1/2 MajesTEC‐1 trial in triple‐class exposed RRMM patients showed that at a median follow up of around 9 months, Teclistamab monotherapy achieved ORR of 64% (95% CI: 56–72), with a complete response or better achieved in 30% of pts, and with manageable safety profile 101,102 . Combination therapy incorporating teclistamab is ongoing and preliminary results have shown promising results 103 …”

Trial designs and endpoints for immune therapies in multiple myeloma

“…7 Daratumumab was shown to deplete CD38+ myeloid-derived suppressor cells, Bregs, and Tregs in vitro and promote T-cell clonal expansion, 40 and is now being studied in combination with teclistamab and talquetamab. 41,42 Initial data from these studies are promising but longer follow-up is needed, and cohorts with additional pomalidomide and dexamethasone are accruing.…”

Updates in the Management of Multiple Myeloma from the American Society of Hematology Meeting 2021

“…Overall, the combination was well tolerated with safety comparable with monotherapy. 52 Talquetamab is being studied as monotherapy and in combination with other agents in RRMM.…”