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249 Genomic Determinants of Clinical Outcomes in Multiple Myeloma with t(11;14)(CCND1;IGH) Treated with Venetoclax

Program: Oral and Poster Abstracts
Type: Oral
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Genomic and Epigenomic Insights into Myeloma Outcomes
Hematology Disease Topics & Pathways:
Research, Translational Research, Plasma Cell Disorders, Bioinformatics, Diseases, Lymphoid Malignancies, Technology and Procedures
Saturday, December 7, 2024: 2:30 PM

Marcella Kaddoura, MD1, J Erin Wiedmeier-Nutor, MD, MPH2, Vikas A. Gupta, MD PhD3, Bachisio Ziccheddu4*, Suganti Shivaram, M.B.B.S5*, Hongwei Tang, PhD6*, Rodrigo Fonseca, MD7*, Michael Durante, MD, PhD8*, Shannon M Matulis, PhD9*, Tomas Jelinek, MD, PhD10*, Ola Landgren11, Constantine S Mitsiades, MD12, P. Leif Bergsagel, MD13, Esteban Braggio, PhD14, Lawrence H. Boise, PhD15, Rafael Fonseca, MD16, Shaji Kumar, MD17, Francesco Maura, MD18 and Linda B. Baughn, PhD5

1Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
2Division of Hematology, Mayo Clinic, Phoenix, AZ
3Winship Cancer Institute of Emory University, Atlanta, GA
4Myeloma Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami
5Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
6Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
7Internal Medicine, Mayo Clinic Arizona, Scottsdale, AZ
8University of Miami Miller School of Medicine, Miami, FL
9Department of Hematology and Medical Oncology and the Winship Cancer Institute, Emory University, Atlanta, GA
10Department of Hematooncology, University Hospital Ostrava and Faculty of Medicine University of Ostrava, Ostrava, Czech Republic
11Sylvester Comprehensive Cancer Center, Miami, FL
12Dana-Farber Cancer Institute, Boston, MA
13Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic, Scottsdale, AZ
14Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ
15Emory University, Atlanta, GA
16Division of Hematology, Mayo Clinic, Paradise Valley, AZ
17Division of Hematology, Mayo Clinic, Rochester, MN
18University of Miami, Coral Gables, FL

Introduction:

Multiple myeloma (MM) with t(11;14)(q13;q32), resulting in CCND1;IGH rearrangement, remains the only subset amenable to targeted therapy with the BCL2 inhibitor, Venetoclax. Nevertheless, not all patients with this translocation respond to treatment and some progress early after initial response. The mechanisms behind this clinical heterogeneity are largely unknown.

Methods:

To investigate mechanisms of heterogeneity in response to Venetoclax, we interrogated 44 whole genome sequencing (WGS) and 24 whole exome sequencing data from a training cohort including 33 patients with t(11;14) MM treated with Venetoclax at the Mayo Clinic. In a validation cohort, we extracted single nucleotide variants (SNV) and indels from 17 MM patients with t(11;14) with available RNAseq data treated with Venetoclax at Emory University.

Results:

In the training cohort the median number of lines of therapy was 4 and Venetoclax drug regimens included combinations with dexamethasone, proteasome inhibitors, anti-CD38 agents, and immunomodulatory agents. After a median follow up of 30 months, the median progression free survival (PFS) was 9 months, and 13 patients (39%) achieved a complete remission (CR) to therapy, while 9 (27%) were refractory (i.e. no response or progressed within the first 60 days).

For our driver discovery analysis, we integrated SNV, indels, copy number variants (CNV) and structural variants (SV). Deletion 17p (del17p) or TP53 mutation, MCL1 gain/amp, and hyper-APOBEC did not correlate with PFS in our cohort (p=0.59, p=0.71, and p=0.05, respectively). In contrast, mutations involving the MAPK pathway (NRAS, KRAS, BRAF, FGFR3) displayed the strongest association with short PFS, which was retained after adjusting for del17p/TP53 mutations, and 1q gain/amp (HR: 4.76, CI: 1.8-12.9, p=0.002). The association between suboptimal response and resistance to Venetoclax in MM patients with MAPK pathway mutations (n=7) was also observed in our validation cohort from Emory University (p=0.046). This is in line with what has been reported in functional studies in acute myeloid leukemia, where RAS pathway promotes MCL1 under the selective pressure of Venetoclax (Zhang et al. Signal Transduct Target Ther 2022).

While MAPK mutations explained most cases of refractory patients (86%), the mechanisms through which initially responding patients subsequently progressed remain unclear. To investigate this, we interrogated 10 patients with pre- and post-treatment samples collected at disease progression (PD). We identified genomic events acquired/selected at PD of genes involved in the anti-apoptotic MCL1/BCL2 and MAPK pathways in 6/10 cases. One patient was refractory to Venetoclax and had double minutes involving BCL2, which caused multiple focal amplifications (>30 copies), likely reflecting extrachromosomal DNA. Another patient progressed with an acquired, focal deletion on BCL2L11. In two patients, the progressing clones harbored mutations in MAPK pathways (one BRAF and the other WNK2). Two patients who relapsed after sustained CR had major branching evolution where a previously undetectable focal deletion of PMAIP1 (NOXA) was seen at PD. Importantly, one of these deletions was a biallelic event. Venetoclax sensitivity assays conducted on PMAIP1 knockout in the MM t(11;14) cell line, KMS12PE, demonstrated significantly reduced cell death across all drug concentrations (p<0.05), validating the loss of NOXA as a mechanism of resistance to Venetoclax in MM. Finally, similarly with what was previously reported in chronic lymphocyte leukemia treated with Venetoclax (e.g., Herling et al Nat Comm 2018), CDKN2A/B monoallelic and biallelic focal deletions were selected post-Venetoclax, at PD in 4 patients while TP53 SNV/deletions were selected from subclonal to clonal in 2 patients at PD.

Conclusion:

In this study, we demonstrate that mutations involving the MAPK pathway identify a population of MM patients with t(11;14)(CCND1;IGH) who are unlikely to respond to Venetoclax. We also show that genomic events involving the MAPK and BCL2/MCL1 pathways are primarily responsible for disease progression after initial response. These findings highlight the critical role of comprehensive genomic profiling through WGS in identifying mechanisms of resistance to targeted therapies in MM, aiding patient selection for Venetoclax, and guiding the development of novel drug combinations.

Disclosures: Gupta: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy; BMS Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Jelinek: Janssen: Consultancy, Other: Honoraria for lectures, Research Funding; Sanofi: Other: Honoraria for lectures, Research Funding; Pfizer: Consultancy, Other: Honoraria for lectures; Bristol Myers Squibb: Other: Honoraria for lectures; GlaxoSmithKline: Consultancy, Other: Honoraria for lectures; Amgen: Research Funding. Landgren: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees. Mitsiades: BMS: Research Funding; Nurix: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; EMD Serono: Research Funding; Oncopeptides: Consultancy; Secura Bio: Consultancy; Nerviano: Consultancy; Genentech: Consultancy; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; H3 Biomedicine/Eisai: Research Funding; Springworks: Research Funding; Abcuro: Research Funding; Novartis: Research Funding; OPNA: Research Funding. Bergsagel: BMS/Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Omeros: Consultancy; Janssen: Consultancy; Cellcentric: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding. Boise: AstraZeneca Abbvie: Consultancy, Honoraria. Fonseca: Patent for FISH in MM - ~$2000/year: Patents & Royalties: Patent for FISH in MM - ~$2000/year; AbbVie, Adaptive, Amgen, Apple, Bayer, BMS/Celgene, Gilead, GSK, Janssen, Kite, Karyopharm, Merck Sharp & Dohme, Juno Therapeutics, Takeda, Arduro Biotech, Oncotracker, Oncopeptides, Pharmacyclics, Pfizer, RA Capital, Regeneron, Sanofi: Consultancy; Celgene, Bristol Myers Squibb, Bayer, Amgen, Janssen, Kite, a Gilead company, Merck Sharp & Dohme, Juno Therapeutics, Takeda, AbbVie, Aduro Biotech, Sanofi, OncoTracker: Honoraria; Antengene: Membership on an entity's Board of Directors or advisory committees. Kumar: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Novartis: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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, Research Funding; Oncopeptides: Other: Independent review committee participation; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune/AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Maura: Medidata: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Baughn: Genentech: Consultancy.

*signifies non-member of ASH