OBJECTIVES: In the TOURMALINE-MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib-lenalidomide-dexamethasone (IRd) showed different magnitudes of progression-free survival (PFS) benefit vs placebo-Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT). METHODS: RNA sequencing data were used to investigate the basis of these differences. RESULTS: The PFS benefit of IRd vs placebo-Rd was greater in patients with tumors expressing high c-MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c-MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c-MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81. CONCLUSIONS: PFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c-MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE-MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537.

3rd Department of Internal Medicine Semmelweis University Budapest Hungary

Department of Haematology and Stem Cell Transplantation St István and St László Hospital of Budapest Budapest Hungary

Department of Haematology Christchurch Hospital Christchurch New Zealand

Department of Hematology University Hospital Hôtel Dieu University of Nantes Nantes France

Division of Hematology Mayo Clinic Rochester MN USA

Hematologic Oncology Dana Farber Cancer Institute Boston MA USA

Hematology and Oncology University Hospital Brno Brno Czech Republic

Hematology IUC Oncopole Toulouse France

Institute of Hematology and Medical Oncology Seràgnoli Bologna University School of Medicine S Orsola's University Hospital Bologna Italy

Instituto Português de Oncologia do Porto Francisco Gentil Entidade Pública Empresarial Porto Portugal

Millennium Pharmaceuticals Inc Cambridge MA USA

Southern Alberta Cancer Research Institute University of Calgary Calgary AB Canada

Translational Genomics Research Institute Phoenix AZ USA

University Hospital of Ulm Ulm Germany

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ClinicalTrials.gov
NCT01564537