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1150 Efficacy of Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Relapsed or Refractory Myeloma Based on Prior Lines of Therapy: Updated Analysis of CastorClinically Relevant Abstract

Myeloma: Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Immunotherapy
Monday, December 5, 2016: 5:15 PM
Hall AB (San Diego Convention Center)

Maria-Victoria Mateos, MD, PhD1, Jane Estell, B.Med (Honours), FRACP, FRCPA2*, Wolney Barreto, PhD3*, Paolo Corradini, MD4*, Chang-Ki Min, MD5*, Eva Medvedova, MD6, Ming Qi7*, Jordan Schecter8*, Himal Amin8*, Xiang Qin7*, William Deraedt9*, Tineke Casneuf9*, Christopher Chiu7*, A. Kate Sasser7* and Ajay Nooka, MD, MPH10*

1University Hospital of Salamanca/IBSAL, Salamanca, Spain
2Haematology Department, Concord Cancer Centre, Concord Hospital, Concord, NSW, Australia
3Hospital Santa Marcelina, Sao Paulo, Brazil
4Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy
5Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Korea, The Republic of
6Oregon Health & Science University, Portland, OR
7Janssen Research & Development, LLC, Spring House, PA
8Janssen Research & Development, LLC, Raritan, NJ
9Janssen Research & Development, Beerse, Belgium
10Winship Cancer Institute, Emory University, Atlanta, GA

Introduction: Daratumumab is a first-in-class monoclonal antibody targeting the plasma cell antigen, CD38, that demonstrated significant activity in combination with bortezomib and dexamethasone (DVd) compared with bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of CASTOR, a randomized phase 3 study of relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). In this abstract, we report on subgroup analyses according to the number of prior lines of therapy received, and include outcomes based on cytogenetic status, in order to identify the patient population who derived the most benefit from the DVd combination.

Methods: Eligible patients (pts) received at least 1 prior line of therapy and were randomized (1:1) to 8 cycles (q3w) of Vd with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). For each cycle, bortezomib 1.3 mg/m2 SC was administered on Days 1, 4, 8, and 11, and dexamethasone 20 mg PO was given on Days 1, 2, 4, 5, 8, 9, 11, 12. Progression-free survival (PFS) was the primary endpoint. Numbers of prior lines of therapy were determined by the site investigator according to the IMWG consensus guidelines. High-risk cytogenetic status based on local laboratory assessments was defined as having at least one of the following abnormalities via karyotyping or fluorescence in-situ hybridization: del17p, t(4;14), or t(14;16). Minimal residual disease (MRD) was evaluated on bone marrow aspirate samples that had been prepared with Ficoll using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA).

Results: Median follow-up was 7.4 months. In the 1 to 3 prior lines (1-3 PL) subgroup (DVd, n=229; Vd, n=219), PFS was significantly longer with DVd vs Vd (median: not reached [NR] vs 7.3 mo; HR, 0.39; 95% CI, 0.28-0.55; P<0.0001); estimated 12-month PFS rates were 62.2% vs 29.3%, respectively. Median time to progression (TTP) among 1-3 PL pts was NR vs 7.4 months, respectively (HR, 0.29; 95% CI, 0.20-0.43; P<0.0001). Overall response rate (ORR) was significantly higher with DVd vs Vd (84% vs 67%; P<0.0001) and was associated with higher rates of very good partial response (VGPR) or better (62% vs 32%; P<0.0001). Among 1-3 PL pts with standard-risk cytogenetic status, PFS was significantly prolonged in DVd vs Vd (HR, 0.38; 95% CI, 0.25-0.58; P<0.0001), and estimated 12-month PFS rates were 58.7% vs 27.0%, respectively. PFS was also significantly longer in pts with high-risk cytogenetics who received DVd vs Vd (HR, 0.46; 95% CI, 0.22-0.97; P=0.0367; Figure), with estimated 12-month PFS rates of 63.2% vs 26.7%, respectively. Lastly, the rate of MRD-negative patients was significantly higher (4 fold or greater) at all evaluated thresholds (10-4, 10-5, and 10-6) among the 1-3 PL subgroup.

In the 1 prior line (1 PL) subgroup (DVd, n=122; Vd, n=113), PFS was also significantly improved for DVd vs Vd (median: NR vs 7.5 mo; HR, 0.31; 95% CI, 0.18-0.52; P<0.0001); estimated 12-month PFS rates were 77.5% vs 29.4%, respectively. Median TTP among 1 PL pts was NR vs 8.4 months, respectively (HR, 0.28; 95% CI, 0.16-0.49; P<0.0001). ORR in pts with 1 PL was significantly higher for DVd vs Vd (89% vs 74%; P=0.0029), including higher rates of VGPR or better being observed for DVd vs Vd (71% vs 42%; P<0.0001).

Updated efficacy and safety data, including analyses of MRD status across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting.

Conclusions: The treatment benefit of DVd vs Vd was maintained across 1-3 PL and 1 PL pts. Responses for DVd were deep and durable and correlated with significantly improved outcomes vs Vd. Despite small group sizes, treatment benefit of DVd vs Vd was also observed in high-risk cytogenetic pts receiving 1-3 PL. These data continue to support the addition of daratumumab to a standard-of-care regimen in RRMM.


Figure: Progression-free Survival in High-risk Patients (Defined by Cytogenetic Abnormalities) who Received 1 to 3 Prior Lines of Therapy


Disclosures: Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Estell: Janssen: Membership on an entity's Board of Directors or advisory committees. Corradini: Celgene, Janssen, Novartis, Roche, Takeda, Sanofi, Servier, Gilead: Honoraria; Takeda: Consultancy. Medvedova: Oregon Health and Science University: Employment. Qi: Janssen: Employment. Schecter: Janssen: Employment, Equity Ownership. Amin: Janssen: Employment. Qin: Janssen: Employment. Deraedt: Janssen: Employment; Johnson & Johnson: Equity Ownership. Casneuf: Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu: Janssen: Employment. Sasser: Janssen: Employment; Johnson & Johnson: Equity Ownership. Nooka: Amgen, Novartis, Spectrum: Consultancy.

*signifies non-member of ASH