Mateos MV, et al. ASH 2016:1150

Background

An early phase study of daratumumab in combina­tion with bortezomib showed deep and durable responses in patients with multiple myeloma (MM). The combination was also well tolerated with man­ageable adverse events.1 The CASTOR study compared the combination of daratumumab, bortezomib, and dexamethasone (DVd) to bortezomib and dexametha­sone (Vd) alone in patients with relapsed/refractory (R/R) MM. Updated results from the CASTOR study were presented at the 2016 ASH Meeting.2

Study design

  • The CASTOR study was a multicentre, randomized, open-label, active-controlled, phase III study that enrolled 498 patients.
  • Premedication for the DVd treatment group con­sisted of dexamethasone 20 mg, acetaminophen, and an antihistamine.
  • Patients were stratified by number of lines of thera­py (1 vs. 2 or 3 vs. >3), International Staging System stage (I, II, and III), and prior bortezomib treatment (no vs. yes).
  • The study planned to enrol 480 patients.
  • The primary endpoint was progression-free survival (PFS).
  • Secondary endpoints included time to progression, overall survival (OS), overall response rate (ORR), and minimal residual disease (MRD).
  • The primary analysis included 177 progression-free survival (PFS) events.
  • MRD was evaluated by a clonoSEQ next-generation sequencing-based assay in a central lab at three sensitivity thresholds, for patients with suspected complete response (CR) and also for patients who maintained CR at Cycles 9 and 15.

Key findings

Baseline characteristics and disposition

  • Baseline demographics were similar between groups.
  • Median age was 64 years in both treatment arms; 9% and 14% of patients were aged ≥75 years in the DVd and Vd groups, respectively.
  • The majority of patients had received 1–3 prior lines of therapy, which comprised 91% of the DVd arm and 89% of the Vd arm.
  • Cytogenetic profiling was conducted on 167 patients in the DVd arm and 186 patients in the Vd arm.
  • The majority of patients tested had standard risk cytogenetic profiles (74% in the DVd arm and 73% in the Vd arm).

Efficacy

  • Responses continued to deepen in the DVd group with longer follow-up (median 13.0 months). (Figure 1)
  • An additional 7% of patients in the DVd arm achieved at least a CR with longer follow-up.
  • DVd was superior to Vd regardless of prior lines of therapy, with the greatest benefit observed in patients with one prior line of therapy. (Figure 2)
  • In patients who received one prior line of therapy, DVd provided a treatment benefit regardless of prior bortezo­mib exposure.
  • More patients achieved a deeper response with DVd after one prior line of treatment.
    • In patients with one prior line of treatment, ORR was 91% in the DVd arm vs. 74% in the Vd arm (p = 0.0014); and
    • In patients with 2–3 prior lines of treatment, ORR was 79% in the DVd arm vs. 58% in the Vd arm (p = 0.0022).
  • MRD-negative rates for the DVd arm were at least threefold higher than the Vd arm across all thresholds. (Figure 3)
  • MRD-negativity was associated with better PFS outcomes in both treatment arms.
  • DVd improved PFS regardless of cytogenetic risk. (Figure 4)
  • Overall survival (OS) data were immature; however, pre­liminary data favoured DVd (HR = 0.63; 95% CI: 0.42–0.96).
    • There were 37 OS events (15%) in the DVd arm and 58 events (24%) in the Vd arm.
    • In patients who received one prior line of therapy, HR = 0.42; 95% CI: 0.19–0.93.
    • In patients who received 1–3 prior lines of therapy, HR = 0.54; 95% CI: 0.34–0.84.

Safety

  • Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 79% of patients in the DVd arm vs. 63% in the Vd arm. (Table 1)
  • Discontinuations due to TEAEs occurred in 9% of patients in both treatment arms.
  • No new infusion-related reactions were reported (inci­dence remained stable at 45% with longer follow-up).

Key conclusions

  • A PFS benefit was continually maintained with DVd over time.
  • DVd was superior to Vd regardless of prior lines of therapy.
  • The largest magnitude of benefit with DVd was observed in patients with one prior line of therapy, who had a 78% reduction in the risk of progression or death with DVd vs. Vd.
  • More patients in the DVd arm achieved deeper responses with longer follow-up, including higher CR and MRD-negative rates.
    • MRD-negativity translated into longer PFS.
  • DVd was superior to Vd regardless of cytogenetic risk or time since last therapy.
  • These data support the use of DVd for patients with R/R MM, with most benefit observed in patients with one prior line of therapy.

References: 1. Mateos MV, Moreau P, Comenzo R, et al. An open-label, multicenter, phase 1B study of daratumumab in combination with pomalidomide-dexamethasone and with backbone regimens in patients with multiple myeloma. EHA Annual Meeting Abstracts 2015:P275. 2. Mateos MV, Estell J, Barreto W, et al. Efficacy of daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma based on prior lines of therapy: updated analysis of CASTOR. ASH Annual Meeting Abstracts 2016:1150.

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june2016
Contributors

Dr. Berinstein
Neil Berinstein, MD, FRCPC, ABIM
Dr. Neil Berinstein earned his premedical degree and medical doctorate from the University of Manitoba and received further specialty and research training at the University of Toronto and Stanford University. Dr. Berinstein currently holds multiple academic and professional positions, including Professor in the Department of Medicine at the University of Toronto, and is an active staff member of the Hematology Oncology Site Group in the Odette Cancer Program at the Sunnybrook Health Sciences Centre. He is currently the Director of Translational Research at the Ontario Institute for Cancer Research. Dr. Berinstein specializes in the management and research of patients with lymphoproliferative disorders, including non-Hodgkin lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, and myeloma.

Dr. Cheson
Bruce D. Cheson, MD, FACP, FAAS, FASCO
Dr. Bruce Cheson completed his internship and residency in Internal Medicine at the University of Virginia Hospitals and then a clinical and research fellowship in Hematology at New England Medical Center Hospital. He is former Editor-in-Chief of Clinical Advances in Hematology and Oncology and Clinical Lymphoma, Leukemia and Myeloma, and a former Associate Editor of the Journal of Clinical Oncology. From 2002 to 2006, he was on the Oncologic Drug Advisory Committee to the U.S. Food and Drug Administration. He is past-Chair of the Lymphoma Committee of the Cancer and Leukemia Group B/Alliance, the Scientific Advisory Board of the Lymphoma Research Foundation, and the American Joint Committee on Cancer (AJCC) Subcommittee on Lymphoma. Currently, Dr. Cheson is Professor of Medicine, Head of Hematology, and Deputy Chief of Hematology-Oncology at Georgetown University Hospital, Lombardi Comprehensive Cancer Center. Dr. Cheson’s clinical interests focus on the development and evaluation of new therapeutic approaches for hematologic malignancies.

Dr. Connors
Joseph Connors, MD, FRCPC
Dr. Joseph Connors earned his medical degree from Yale University. He completed his residency training in Internal Medicine and chief residency at the University of North Carolina in Chapel Hill. Prior to completing his Medical Oncology Fellowship at Stanford University, he worked at the Indian Health Service in Alaska for two years. In 1981, he accepted a position in Medical Oncology at the BC Cancer Agency. He has been a member of the Faculty of Medicine at the University of British Columbia since that time, reaching the position of Clinical Professor in 1997. At present, he is a Clinical Professor in the Department of Medicine, Division of Medical Oncology, at the University of British Columbia and the Chair of the Lymphoma Tumour Group for the BC Cancer Agency. Dr. Connors’ clinical activities and research efforts are focused in the area of lymphoid cancers. He is best known for his clinical investigations into the treatment of Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma.

Dr. LeBlanc
Richard LeBlanc, MD, FRCPC
Dr. Richard LeBlanc is a hematologist and medical oncologist at Hôpital Maisonneuve-Rosemont in Montreal, Quebec. He is also a Clinical Assistant Professor of Medicine at the University of Montreal. Dr. LeBlanc obtained his medical degree at Laval University and is certified in Internal Medicine, Hematology, and Medical Oncology. He worked as a research fellow at the Dana Farber Cancer Institute in Boston from 2000 to 2002. Dr. LeBlanc was recruited by Hôpital Maisonneuve-Rosemont to help improve medical care, research, and teaching in multiple myeloma. Dr. LeBlanc holds the Myeloma Canada Chair at the University of Montreal. He is the Director of the Myeloma Cell Bank at Hôpital Maisonneuve-Rosemont, which is affiliated with the Quebec Leukemia Cell Bank. He is also the Medical Director of the Clinical Immunology Laboratory at Hôpital Maisonneuve-Rosemont. Finally, Dr. LeBlanc is a member of the Scientific Advisory Board of Myeloma Canada.

Dr. Owen
Carolyn Owen, MD, FRCPC
Dr. Carolyn Owen completed postgraduate training in internal medicine and hematology at the University of Ottawa and the University of British Columbia, respectively, followed by a research fellowship in molecular genetics at Barts and the London School of Medicine and Dentistry in London, U.K. Her research focused on familial myelodysplasia and acute myeloid leukemia. She is currently an Assistant Professor at the Foothills Medical Centre and Tom Baker Cancer Centre, University of Calgary, and her clinical interests are low-grade lymphoma and chronic lymphocytic leukemia. She is also the local principal investigator in Calgary for several clinical trials in these areas.

Dr. Peters
Anthea Peters, MD, FRCPC
Dr. Anthea Peters obtained her medical degree from the University of Saskatchewan in 2006. She then completed her residencies in Internal Medicine at the University of Alberta and in Hematology at the University of Calgary. Dr. Peters joined the Division of Hematology at the University of Alberta as a Clinical Scholar in July 2011. Her main area of interest is in lymphoma.