Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Myeloma pathogenesis and novel targets
Hematology Disease Topics & Pathways:
Biological, Genomics, Adults, Translational Research, Non-Biological, Bioinformatics, Plasma Cell Disorders, Clinically Relevant, Diseases, Computational Biology, Therapies, Lymphoid Malignancies, Monoclonal Antibody Therapy, Biological Processes, Technology and Procedures, Imaging, Study Population
Multiple myeloma (MM) remains an all but incurable plasma cell malignancy. Patients with relapsed MM are treated with a growing list of multi-drug regimens that typically result in transient responses followed by subsequent lines of therapy, ultimately leading to multidrug resistance. Accordingly, improved understanding of how the evolution of resistance to one class of drugs affects response to other classes is needed to inform optimal sequencing therapy for patients. We employed RNA-seq profiling paired with ex vivo drug sensitivity as well as associated clinical studies to examine rational sequencing of the nuclear export inhibitor, Selinexor (SEL). Our data indicate that the biology associated with resistance to the monoclonal antibody Daratumumab (DARA) is associated with sensitivity to SEL.
Bone marrow biopsies (BMBX) of MM patients treated at Moffitt Cancer Center (protocols MCC14690/MCC18608) were co-cultured with collagen and patient-derived serum and stroma for an organotypic ex vivo drug sensitivity assay using single agents and combinations. Viability of cells during 96h-exposures was assessed using digital imaging and used to calculate LD50 and AUC. Matching aliquots of MM cells had RNA and whole exome sequencing performed through ORIEN/AVATAR. Gene set enrichment analysis (GSEA) was conducted using both AUC and LD50 with KEGG, cancer hallmarks, and unsupervised gene clustering as gene sets. Clinical correlative studies were performed for patients treated on the Phase 1b/2 STOMP study evaluating SEL in various triplet combinations (ClinicalTrials.gov: NCT02343042) and patients treated with SEL, DEX and bortezomib on the Phase 2b XPORT-MM-028 study (NCT04414475). Patients were stratified based on previous anti-CD38 antibody exposure for comparisons of overall response rate (ORR), and progression-free survival (PFS).
MM cells from 72 patients were tested ex vivo with SEL. MM cells from patients collected after clinical relapse from a DARA-based regimen as the immediate prior line (n=9) were more sensitive to SEL than cells from DARA-naïve patients (n=56) and cells with intervening therapy from DARA-based therapy had an intermediate sensitivity (n=7) (median AUC=60.4, 68.1, and 66.6 respectively) (Figure 1A). Transcriptome-wide correlations between gene expressions and ex vivo drug sensitivity were identified with RNA sequencing from samples tested with SEL (n=66) or DARA (n=105). Remarkably, the overlay of gene clusters correlated with ex vivo sensitivity/resistance showed opposing patterns, meaning high expression of genes that convey resistance to DARA were associated with sensitivity to SEL (Figure 1B). GSEA showed MYC targets, oxidative phosphorylation and DNA repair pathways were positively correlated with DARA resistance and SEL sensitivity ex vivo, while the opposite was observed for inflammatory pathways (Figure 1C). Among relapsed MM patients, samples from DARA-refractory patients (n=8) had increased expression of MYC and XPO1, and decreased CD38 compared to DARA-naïve (n=29) (Figure 1D). Investigation of protein level expression of these biomarkers in core biopsies through IHC is under investigation. These data highlight that the biology of DARA-resistance is associated with SEL sensitivity.
We next wanted to determine if this phenotype is observed clinically. Examination of patients on the STOMP trial, testing SEL-based triplets, showed that patients receiving an anti-CD38 antibody in their immediate prior line to SEL (n=31) had improved PFS compared to those with an anti-CD38 antibody in an earlier prior line (n=23) (15 mo [95%CI: 8.7 - not evaluable (NE)] vs. 8.9 mo [4.9-NE]). Similarly, patients treated on the XPORT-MM-028 study who had an anti-CD38 antibody in their immediate prior line (n=15) had an ORR rate of 47% (95% CI: 21-73%) compared to 8% (0-39%) for those with an anti-CD38 antibody in an earlier prior line (n=12), and a median PFS not reached (95% CI: 7 mo-NE) compared to 3.5 mo (3.4-NE).
Ex vivo SEL sensitivity was increased and clinical response to SEL was more favorable for patients immediately after DARA, demonstrating direct clinical correlation of our ex vivo methods. Further, these data introduce a biologic rationale for how DARA-resistant MM cells are more sensitive to SEL and implicate sequential use of SEL-containing regimes for patients immediately after acquired resistance to DARA.
Disclosures: Zhang: M2Gen: Current Employment. Hampton: M2Gen: Current Employment. DeCastro: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Van Domelen: Karyopharm: Current Employment, Current equity holder in publicly-traded company. Chai: Karyopharm: Current Employment. Walker: Karyopharm Therapeutics Inc.: Current Employment. Siqueira Silva: AbbVie Inc.: Research Funding; Karyopharm Therapeutics Inc.: Research Funding. Landesman: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Baz: Merck: Research Funding; GlaxoSmithKline: Consultancy, Honoraria; Oncopeptides: Consultancy; BMS, sanofi, Karyopharm, Janssen, AbbVie: Consultancy, Research Funding. Shain: Adaptive Biotechnologies Corporation: Consultancy, Speakers Bureau; Janssen oncology: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithLine, LLC: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi Genzyme: Consultancy, Speakers Bureau; Novartis Pharmaceuticals Corporation: Consultancy; Karyopharm Therapeutics Inc.: Honoraria, Research Funding.
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