Moreau P, et al. ASH 2016:489

Background

In a phase I/II study, 32 patients with relapsed or refractory (R/R) multiple myeloma (MM) were treated with daratumumab, lenalidomide, and dexamethasone (DRd), which induced rapid, deep, and durable responses with a manageable safety profile.1 The phase III POLLUX study compared DRd to the combination of lenalidomide and dexamethasone (Rd) in patients with R/R MM. Updated results from the POLLUX study were presented at the 2016 ASH Meeting.2

Study design

  • The POLLUX study was a multicentre, randomized, open-label, active-controlled, phase III study.
  • Patients were stratified by number of lines of therapy, International Staging System stage at study entry, and prior lenalidomide treatment.
  • The primary endpoint was progression-free survival (PFS).
  • Secondary endpoints included time to progression, overall survival, overall response rate (ORR), minimal residual disease (MRD), time to response, and duration of response.
  • The primary analysis included 177 PFS events.
  • MRD was evaluated at three sensitivity thresholds (10–4, 10–5, and 10–6).
  • MRD-negativity rate was defined as the proportion of patients with negative MRD test results at any time during treatment.
  • A stringent, unbiased MRD evaluation was applied:
    • MRD-negativity counts were evaluated against the intent-to-treat (ITT) population;
    • Any patient in the ITT population not determined to be MRD-negative was scored as MRD-positive; and
    • A minimum cell input equivalent to the given sensitivity threshold was required to determine MRD-negativity (i.e., MRD at 10–6 required that ≥1,000,000 cells were evaluated).
  • MRD was assessed at suspected complete response (CR) and three and six months after CR.

Study Design

Key findings

Baseline characteristics and disposition

  • In the updated analysis, evaluations were performed on the subgroup of patients who had received 1–3 prior lines of therapy, which comprised 95% of the DRd arm and 93% of the Rd arm.
  • Baseline demographics were similar between groups.
  • Median age was 65 years in both treatment arms; 10% and 12% of patients were aged ≥75 years in the DRd and Rd groups, respectively.
  • In both treatment arms, 18% of patients had received prior lenalidomide, and 21% of patients were refractory to bortezomib.
  • Cytogenetic profiling was conducted on 161 patients in the DRd arm and on 150 patients in the Rd arm.
    • The majority of patients tested had standard risk cytogenetic profiles (83% in the DRd arm and 75% in the Rd arm).

Efficacy

  • For patients who received 1–3 prior lines of therapy, responses continued to deepen in the DRd group with longer follow-up (median: 18.4 months). (Figure 1)
  • DRd maintained treatment benefit in lenalidomide-naïve patients:
    • The 18-month PFS was 76% in the DRd arm vs. 49% in the Rd arm (HR = 0.37; 95% CI: 0.26–0.51; p <0.0001); and
    • ORR was 93% and 77% in the DRd and Rd arms, respectively (p <0.0001).
  • DRd also improved outcomes in lenalidomide-exposed patients. (Figure 2)
  • A DRd treatment benefit was observed in patients who were refractory to their last line of therapy:
    • The 18-month PFS was 65% in the DRd arm vs. 37% in the Rd arm (HR = 0.45; 95% CI: 0.27–0.74; p = 0.0014); and
    • ORR was 89% and 63% in the DRd and Rd arms, respectively (p = 0.0003).
  • DRd significantly improved outcomes regardless of refractoriness to bortezomib:
    • The 18-month PFS was 65% in the DRd arm vs. 40% in the Rd arm (HR = 0.51; 95% CI: 0.28–0.91; p = 0.021); and
    • ORR was 92% and 68% in the DRd and Rd arms, respectively (p = 0.0024).
  • Patients achieved deeper responses, including MRDnegativity, irrespective of prior lenalidomide exposure or bortezomib refractoriness. (Figure 3)
  • MRD-negative patients (at a sensitivity of 10–5) achieved prolonged PFS in both treatment arms.
  • DRd improved outcomes in both high-risk and standard-risk patients. (Figure 4)

Safety

  • No new safety signals were reported in the study. (Table 1)

Key conclusions

  • DRd significantly improved outcomes for patients with R/R MM and 1–3 prior lines of treatment.
  • This treatment benefit was maintained regardless of prior treatment with lenalidomide or refractoriness to bortezomib.
  • Higher MRD-negative rates were observed in the DRd arm vs. the Rd arm for all subgroups.
  • DRd was superior to Rd in both standard- and high-risk cytogenetic patients.
  • The safety profile was unchanged between treatment arms.
  • These data support the use of DRd, irrespective of prior lenalidomide treatment or bortezomib refractoriness.

References: 1. Plesner T, Arkenau HT, Gimsing P, et al. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood 2016;128:1821–8. 2. Moreau P, Kaufman JL, Sutherland HJ, et al. Efficacy of daratumumab, lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone for relapsed or refractory multiple myeloma among patients with 1 to 3 prior lines of therapy based on previous treatment exposure: updated analysis of POLLUX. ASH Annual Meeting Abstracts 2016:489.

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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.