ECOG-ACRIN EAA172: Phase 1/2 study of daratumumab, bortezomib, dexamethasone (DVd) with or without venetoclax in relapsed/refractory multiple myeloma (RRMM) with assessment for t(11;14) status.

Michael A. Thompson Advocate Aurora Health, Milwaukee, WI info_outline Michael A. Thompson, Susanna J. Jacobus, Shaji Kumar, Murali Janakiram, Sagar Lonial, Matthias Weiss, Natalie Scott Callander, S. Vincent Rajkumar

Authors Michael A. Thompson Advocate Aurora Health, Milwaukee, WI info_outline Michael A. Thompson, Susanna J. Jacobus, Shaji Kumar, Murali Janakiram, Sagar Lonial, Matthias Weiss, Natalie Scott Callander, S. Vincent Rajkumar Organizations Advocate Aurora Health, Milwaukee, WI, Dana-Farber Cancer Institute, Boston, MA, Mayo Clinic, Rochester, MN, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, Winship Cancer Institute of Emory University, Atlanta, GA, ThedaCare, Appleton, WI, University of Wisconsin, Fitchburg, WI Abstract Disclosures Research Funding U.S. National Institutes of Health Pharmaceutical/Biotech Company Background: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), present in approximately 20% of cases. MM cells with t(11;14) usually have a favorable high BCL-2 level and inferior outcomes compared to standard risk MM. Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in MM cell lines and primary samples. VEN has single agent activity in relapsed/refractory MM (RRMM) with an acceptable safety profile, especially in t(11;14) MM; however, non- t(11;14) MM patients may benefit from single agent VEN and VEN incorporated in multi-agent RRMM regimens. Dexamethasone (d) promotes Bcl-2 dependence in MM resulting in sensitivity to VEN and this combination with bortezomib (Vd-VEN) has an acceptable safety profile with high response rates in heavily pre-treated MM. Combination therapy with daratumumab and bortezomib (DVd) has become a standard of care in RRMM. Our hypotheses are that the addition of VEN will improve upon this standard and be most effective in the t(11;14) positive subset. Methods: Eligibility criteria include RRMM with measurable disease, not bortezomib refractory, platelet count > 100K. t(11;14) is an integral biomarker with status (positive or negative) established at registration. After a Ph1 study to determine the recommended phase 2 VEN dose, patients are randomized to DVd +/- VEN [stratified by prior lines of therapy and R-ISS]. The primary Ph2 objectives are to compare 8-cycle minimal residual disease (MRD) negative rate and to inform the role of t(11;14) as a biomarker. The Ph2 design proposed by Freidlin et al. follows a decision algorithm as outlined in the table below. Simulations were run to establish an optimal sample size given various parameters including biomarker prevalence and power to make appropriate decisions for a Ph3 design. Target Ph2 accrual is 240 patients with a 1/3 positive:2/3 negative t(11;14) split. Clinical trial information: NCT03701321 Ph2 Design Decision Algorithm. Step Population Approach If Result Then Rate difference (RD) = DVd+VEN - DVd 1 t(11;14) positive Hypothesis Testing: 1-sided alpha=0.10 Ho: RD</=0 Ha: RD>0 Not Significant Step 2A Significant Step 2B 2A All patients Hypothesis Testing: alpha=0.05 Not Significant No further study Significant Standard Ph3 2B t(11;14) negative Confidence Interval: 2-sided 80% for RD CI below 10% Biomarker-enrichment Ph3 CI includes 10% Biomarker stratified Ph3 CI above 10% Standard Phase 3