Ultra high-risk multiple myeloma with early mortality despite quad-class and BCMA-directed therapies: Clinical and molecular insights

Abstract Intdocution: Multiple myeloma (MM) treatment has evolved significantly with the introduction of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), anti-CD38 monoclonal antibodies, and B-cell maturation antigen (BCMA)-directed therapies including CAR-T cells and bispecific antibodies (BsAbs). However, a small but clinically significant subset of patients (pts) demonstrates rapidly progressive disease with resistance to all major therapeutic classes and early death from MM. There is a critical need to understand the clinical and biological features driving this ultra high-risk phenotype to guide future therapeutic development and risk-adapted strategies. Methods: We conducted a retrospective study of pts with MM from two academic centers who experienced early mortality (death within 36 months of diagnosis) despite receiving PIs, IMiDs, anti-CD38 antibodies, and at least one BCMA-directed therapy (CAR-T or BsAb). Demographics, disease characteristics, treatment history, and outcomes were abstracted from clinical records. In a subset of pts DNA and RNA sequencing was performed on bone marrow (BM) FFPE clot sections using a targeted hematologic malignancy panel covering 302 DNA and >1600 RNA genes. DNA sequencing included all coding exons and flanking intronic regions. RNA sequencing utilized hybrid capture technology to detect fusions, transcript variants, gene expression outliers, and immune repertoire metrics. Bioinformatic analyses employed DRAGEN (Illumina), CNVkit for copy number variation, and MiXCR for immune repertoire reconstruction. Error correction included UMI-based deduplication, manual BAM file review, and cross-validation with internal and public variant databases (ClinVar, COSMIC, dbSNP). Results: Sixteen pts were identified with the median age of 62 years (range, 43–70), with 25% identifying as African American. At diagnosis, 31% had extramedullary disease (EMD), and only 25% met International Myeloma Working Group (IMWG) high risk. EMD was present at relapse in 56% of pts. Prior to death, all pts. had received PIs, IMiDs, anti-CD38 antibodies, and BCMA-targeted therapy; 56% underwent autologous transplant. The median line of therapy was 6 (range, 4-6), and 50% received BCMA CAR-T and BsAb respectively. The median time from diagnosis to death was 20 months (range, 8–27) with 38% showing primary refractoriness to the first line induction therapy. Genomic and transcriptomic profiling was performed on 7 BM clot sections with either paired (diagnosis and last relapse, N=3) or at last relapse (N=4). Frequent mutations included TP53 (3/7), DNMT3A (2/7), KMT2C (4/7), NRAS (2/7), and BRAF (2/7), with some cases harboring biallelic hits or co-occurring alterations in signaling and epigenetic regulators. TERT promoter mutations and MYCN amplification were also observed. Several patients demonstrated germline or CHIP-associated mutations (e.g., MED12, ABCG2, CD33, DNMT3A), suggesting a complex clonal architecture. Recurrent translocations included t (4;14) (IGH: NSD2/FGFR3), t (11;14) (CCND1 overexpression), and t (6;14) (IRF4 promoter hijacking), consistent with established high-risk gene expression subtypes. Promoter hijacking events led to marked overexpression of NSD2, FGFR3, IRF4, MYC, and CCND1. Copy number abnormalities were common and included 1q gain, 13q deletion, and losses in 6q, 10q, 16q, and 18. One patient demonstrated a novel TRAPPC3:SOS1 fusion transcript. BCMA mRNA expression was highly variable. While plasma cell markers (CD138, CD38) were typically increased, 3 of 7 patients showed markedly reduced BCMA mRNA (all post BCMA therapy), raising concern for resistance to BCMA-directed therapies via antigen downregulation. Notably, T cell clonality was undetectable in all samples. Conclusions: The study highlights the impact of convergent clinical features (e.g., extramedullary disease, rapid relapse) and molecular characteristics, including TP53 mutations, epigenetic dysregulation, promoter hijacking events, copy number complexity, and variable BCMA expression on poor outcomes of ultra-high-risk pts. These pts cycle through the highly effective therapies quickly and represent an unmet group for improved disease understanding as well as novel therapies.