Introduction: The first-in-class bispecific antibodies tec (targeting BCMA) and tal (targeting GPRC5D) have demonstrated deep, durable responses as monotherapies in pts with RRMM. Dara, an anti-CD38 monoclonal antibody, and len, an immunomodulatory drug (IMiD), have been shown to enhance T-cell cytotoxic activity against myeloma cells alone or in combination with other agents. We evaluated immune-cell profiles in pts with NDMM vs those with RRMM in the MajesTEC-2 (NCT04722146) and MonumenTAL-2 (NCT05050097) studies to identify differential immune signatures between pts with NDMM and RRMM treated with either tec-dara-len or tal-dara-len.

Methods: Pts in MajesTEC-2 received subcutaneous (SC) tec 1.5 mg/kg QW after step-up dosing (0.06 and 0.3 mg/kg) plus the approved schedules of dara 1800 mg + len 25 mg. In MonumenTAL-2, pts with RRMM received SC tal 0.3 mg/kg QW, and pts with NDMM received either 0.6 mg/kg Q2W or 0.8 mg/kg Q4W plus the approved schedules of dara 1800 mg + len 25 mg. Dexamethasone was given concurrent with the first 3 full IMiD-containing cycles. Peripheral blood and bone marrow samples were collected at baseline and post treatment at cycle 2 and/or 3 for evaluation of immune cells (CD3+, CD4+, CD8+, regulatory T cells [Tregs], and natural killer [NK] cells), T-cell receptor (TCR) sequencing, cytokine profiles, and assessment of activation/exhaustion markers by flow cytometry. Analyses include all pts for whom samples were available (MajesTEC-2: NDMM, n=11; RRMM, n=19 and MonumenTAL-2: NDMM, n=18; RRMM with ≥3 prior lines of therapy [pLOT] or 1-3 pLOT, n=20).

Results: Overall, pharmacodynamics following tec/tal-dara-len treatment revealed enhanced T-cell recovery plus an increase in effector memory T cells compared with tec/tal monotherapy and consistent with tec, tal, and dara mechanisms of action (MOA) and T-cell restimulation post len (including CD38 subsets), consistent with len MOA. While a reduction of immunosuppressive Tregs and of NK cells with tec/tal-dara (consistent with dara MOA) was observed, the addition of len resulted in increased numbers of NK cells. We sought to further assess whether a differential immune profile exists between pts with NDMM and RRMM treated with tec-dara-len or tal-dara-len. At baseline, pts with NDMM demonstrated a favorable immune fitness profile, indicated by higher absolute counts of peripheral T-cell numbers and NK cells and higher TCR diversity, higher proportions of T cells expressing CD38 (likely due to lack of prior dara exposure), and lower proportions of T cells expressing markers associated with T-cell activation/exhaustion compared with pts with RRMM. Longitudinally, pts with NDMM treated with tec/tal-dara-len showed greater recovery in number of peripheral CD3+ T cells compared with those with RRMM. With tec/tal-dara treatment, early induction of T-cell activation markers was greater in pts with NDMM than in pts with RRMM; specifically, len administration transiently restimulated T cells expressing HLA-DR. In addition, higher induction of pro-inflammatory cytokines such as IFNγ and sIL-2Rα, was seen in pts with NDMM compared with RRMM, suggesting a greater activation capacity in pts with NDMM with both tec/tal-dara-len. Tec/tal-dara-len led to a reduction of the proportion of CD38-expressing T-cell subsets in pts with NDMM and RRMM; the addition of len resulted in a transient upregulation of CD38 on T cells, but continuous dara dosing lowered the proportions of these cells. Further, reduction of NK cells with tec/tal-dara was observed in NDMM and RRMM, with minimal differences in NK cell recovery following the addition of len. Importantly, pts with NDMM exhibited higher T-cell clonal expansion capacity and a lower repertoire similarity post tal-dara-len compared with pts with RRMM, suggesting therapy-induced T-cell expansion.

Conclusions: This combined analysis was conducted to provide insights into the differential immune profiles in pts with NDMM vs RRMM treated with tec/tal-dara-len to enhance understanding of the therapeutic benefits and guide future treatment strategies, which are being evaluated in the phase 3 MajesTEC-7 study (NCT05552222). The more favorable immune profile observed in pts with NDMM vs RRMM suggests that earlier treatment with novel combinations, such as tec-dara-len and tal-dara-len, may improve pt outcomes. Correlations with efficacy will be presented at the meeting.

Disclosures

Cortes:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Hodkinson:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Kumar:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Skerget:Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Mason:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Shearin:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Ludlage:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Koster:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Kane:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Renaud:Janssen: Current Employment, Current holder of stock options in a privately-held company. Kampfenkel:Janssen: Current Employment, Current holder of stock options in a privately-held company. Heuck:Janssen Research & Development, LLC: Current Employment, Current equity holder in publicly-traded company. Thakkar:Johnson & Johnson: Current Employment, Current holder of stock options in a privately-held company. Zishan:Johnson & Johnson: Consultancy. Searle:Shattuck Labs, Sanofi, BMS, DarkBlue Therapeutics: Consultancy; Pfizer, Janssen, Jazz, Abbvie: Speakers Bureau; Janssen, Abbvie, Beigene, BMS, Nurix: Honoraria. Quach:Pfizer: Consultancy; Roche: Consultancy; Sanofi: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Research Funding; Johnson & Johnson: Consultancy. Ravi:Guidepoint: Consultancy. Janowski:Janssen, Pfizer, Beigene: Consultancy. Berdeja:Janssen: Honoraria, Speakers Bureau; 2 Seventy Bio; AbbVie; Amgen; BMS; C4 Therapeutics; Caribou Biosciences; CARsgen; Cartesian Therapeutics; Celularity; CRISPR Therapeutics; Fate Therapeutics; Genentech; GSK; Ichnos Sciences; Incyte; Janssen; Juno Therapeutics; K36 Therapeutics; Karyopharm: Research Funding; AstraZeneca; BMS; Caribou Biosciences; Galapagos; Janssen; K36 Therapeutics; Kite Pharma; Legend Biotech; Pfizer; Regeneron; Roche; Sanofi-Aventis; Sebia; Takeda: Consultancy. Matous:BeiGene; Pharmacyclics: Consultancy. Nooka:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectar Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: 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; Sebia: 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, Research Funding; Aduro Biotech: Research Funding; Arch Oncology: Research Funding; Cellectis: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; K36 Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding. Cochrane:Beigene: Research Funding. D'Souza:Kedrion, Pfizer, Janssen, Bristol Myers Squibb, BMS, Janssen, and Prothena.: Consultancy; AbbVie, Sanofi, Novartis, Janssen, Regeneron, Takeda, TeneoBio, Caelum, and Prothena: Research Funding. Voorhees:Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lava Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ramasamy:Sanofi: Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: 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, Other: Support for attending meetings/travel; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel; Abbvie: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Recordati: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel; Menarini Stemline: Membership on an entity's Board of Directors or advisory committees. Perrot:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; GSK: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria; Menarini Stemline: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Takeda: Honoraria, Research Funding. Spencer:F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding. Parmar:Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant; Janssen Biotech: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Other: travel grants. Vishwamitra:Johnson and Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company.

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2024
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