Humoral Immune Reconstitution Following Therapy with Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), Autologous Hematopoietic Cell Transplantation (AHCT) and MRD-Response-Adapted Treatment Cessation

Introduction Quadruplet induction, AHCT, and measurable residual disease (MRD) response-adapted consolidation yields unprecedented depth of response in newly diagnosed multiple myeloma (NDMM). Immune reconstitution (IR) in patients (pts) receiving limited duration intensive therapy has not been well described.

Methods NDMM pts treated on MASTER (NCT03224507) received induction with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd; 4 cycles), followed by AHCT and 0, 4 or 8 cycles of Dara-KRd consolidation guided by serial assessments of bone marrow MRD by next-generation sequencing (NGS, ClonoSEQ®). Pts with two consecutive MRD <10^-5 ceased therapy and entered active surveillance for MRD resurgence (MRD-SURE). The primary objective of this study is to evaluate humoral IR of MRD-SURE pts by characterizing quantitative changes in the repertoire of immunoglobulin (Ig) genes (IgH, IgK and IgL) by NGS and serum gamma globulin levels.

Results After induction, the IgH repertoire was small and lacked diversity (median unique sequences (mus) 11,330/10⁶, IQR 5,711-23,143). Of 63 evaluable pts who received AHCT and >=4 cycles of consolidation, a substantial expansion of the IgH repertoire was seen 90 days after AHCT (75,375 mus/10⁶, IQR 49,361-113,305, P< 0.001) with a contraction after consolidation (15,795 mus/10⁶, IQR 5,571-33,732, P< 0.001). Pts who received post-AHCT consolidation (N=27) had a smaller IgH repertoire at MRD-SURE entry compared to pts entering MRD-SURE after AHCT (N=28) (15,082 v 76,266 mus/10⁶, p< 0.001), with near but incomplete recovery after 6 months (mo) of treatment cessation (83,954 v 107,715 mus/10⁶, p=0.037) and no difference at 18 mo (109,989 v 115,246 mus/10⁶, P=0.72) (Figure 1). Similar findings were seen for IgK and IgL. The serum protein gamma fraction was depressed (median 0.3 g/dL, IQR 0.23-0.41) in pts entering MRD-SURE post-AHCT, but rose off therapy reaching plateau after 12 months. Gamma globulin recovery was delayed in patients receiving consolidation (Figure 2). Risk of grade≥3 infection while on Dara-KRd was 3.8/100*patient*month during induction, and 2.2/100*patient*month during post-AHCT consolidation (overall 2.9/100*patient*month). Risk of grade≥3 infection reduced substantially to 0.22/100*patient*month during the first 6 months and 0.12/100*patient*month during subsequent 12 months of MRD-SURE (overall 0.15/100*patient*month).

Conclusions Quadruplet, anti-CD38 mAb-containing therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Pts who received post-AHCT consolidation had delayed IR as compared to those who did not, however the Ig repertoire steadily recovered, with no statistically significant difference 18 mo after treatment cessation. Grade ≥3 infection risk is very low after treatment cessation, as the Ig gene repertoire expands prior to recovery of immunoglobulin levels. Further evaluation of IR after MRD-adapted therapy is warranted as new immunotherapeutic agents are incorporated in therapy.

Schmidt:Janssen: Consultancy; Sanofi: Consultancy. Silbermann:Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Bal:Adaptive Biotechnologies: Consultancy. Dhakal:Karyopharm Therapeutics: Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Natera: Consultancy; BMS: Honoraria, Research Funding; Arcellx: Research Funding; Carsgen: Research Funding; Cartesian: Research Funding; Fate: Research Funding; Takeda: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Dholaria:Gamida Cell: Consultancy; Wugen: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; BEAM Therapeutics: Consultancy; Angiocrine: Research Funding; Arivan: Consultancy; Molecular Templates: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Vanderbilt University Medical Center: Current Employment; MJH Biosciences: Honoraria; Jazz Pharmaceuticals: Consultancy; Orca Bio: Research Funding; BMS: Research Funding; MEI Pharma: Research Funding. Chhabra:GlaxoSmithKline: Honoraria; Sanofi: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Giri:CareVive: Honoraria, Research Funding; Pack Health: Research Funding; OncLive: Honoraria. Costa:Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.