OA-19: Comprehensive genomic characterization of response and resistance to daratumumab- based quadruplet induction in newly diagnosed multiple myeloma patients

Introduction: Quadruplet induction regimens containing daratumumab (dara-quads) are highly efficacious in newly diagnosed multiple myeloma (NDMM), producing high rates of minimal residual disease negativity and long progression-free and overall survival. Though deep clinical responses are observed in patients with conventionally defined high-risk disease, a subset of patients still progress early. We hypothesize that dara-quads may overcome traditional prognostication, with more comprehensive genomic stratification being required for individualized treatment decisions and definition of novel treatment approaches.

Methods: We examined NDMM patients prescribed dara-quad induction at Memorial Sloan Kettering Cancer Center prior to Feb 2023, focusing on genomic characterization.

Results: Among 205 patients analyzed, 84 patients received carfilzomib (DKRd) and 121 bortezomib (DVRd). Overall median follow-up was 1.4 years (y); 4.2y with DKRd (IQR 2.1-4.7, max 5.6) and 1.0y with DVRd (IQR 0.7-1.4, max 3.2). 25 patients progressed following DKRd and 20 following DVRd. 194 had FISH performed, 123 SNP-array, 74 targeted sequencing (MSK-IMPACT-Heme) and 45 whole genome sequencing (WGS).

ISS stage did not predict for PFS or OS, either in the whole cohort, or in individual regimens. The inclusion of genomic assessment improved prognostication; while R-ISS, high-risk cytogenetics as per R-ISS, and R2-ISS each improved PFS prediction (p < 0.01), consideration of every feature assessable by FISH (including del1p, amp1q, t(14;20), MYC-translocations) further increased discrimination (p=0.009), as did considering 2 or more co-occurring high-risk features (p=0.002). There were trends towards potential differences between the regimens based on risk profile.

Using comprehensive genomic assessment (SNP-array, MSK-IMPACT-Heme and WGS) allowed for the assessment of additional genomic features in those with adequate follow-up (predominantly DKRd). Del1p22.1 was strongly predictive of shorter PFS (RPL5, p< 0.0001), as were del22q12.1 (XBP1, p=0.02) and APOBEC-mutational activity (p=0.01). Additional features demonstrated a trend to significance, including del1p12 (TENT5C, p=0.06) and the complex structural variant chromothripsis, which may become significant upon examining a larger cohort.

Conclusions: In the context of highly effective dara-quad induction, ISS stage did not predict for either PFS or OS. Limited cytogenetic assessment improved prognostication, while advanced genomic assessment was highly discriminatory. The current study provides the rationale for more comprehensive genomic assessment in patients receiving dara-quads in order to refine prognostication and consider novel treatment approaches for high-risk patients. With the assistance of an IMS Translational Research Award, we are significantly expanding our cohort of WGS in dara-quad-treated patients, including the integration of single-cell WGS.