Chari A, et al. ASH 2016:2142

Background

Daratumumab is a CD38-directed monoclonal antibody indicated for the treatment of patients with relapsed/ refractory (R/R) multiple myeloma (MM). CD38 is expressed on airway smooth muscle cells, and infusion-related reactions (IRRs) in registration studies of daratumumab were marked by symptoms similar to those of allergic rhinitis (e.g., cough, wheezing, rhinor­rhea). Anecdotal reports indicated that premedication with montelukast, a leukotriene receptor antagonist, may reduce the IRR rate associated with daratumumab therapy. At the 2016 ASH Meeting, Chari et al. pre­sented results from the Early Access Treatment Protocol (EAP) that investigated the efficacy of montelukast pre­medication on IRR reduction in patients with R/R MM who were treated with daratumumab.1

Study design

  • The EAP was a multicentre, open-label study.
  • The objectives of this study were to provide early access to daratumumab treatment, to collect safety data (including IRRs), and to allow the use of monte­lukast as a premedication for daratumumab therapy.
  • Inclusion criteria were:
    • Age ≥18 years;
    • Documented MM;
    • Progression by International Myeloma Working Group criteria following the most recent therapy;
    • Three or more prior lines of therapy including a proteasome inhibitor (PI) and an immunomodu­latory agent (IMID), or disease double refractory to a PI and an IMID; and
    • An Eastern Cooperative Oncology Group perfor­mance status (ECOG PS) of 0–2.
  • Exclusion criteria were:
    • Known chronic obstructive pulmonary disease (COPD);
    • Persistent asthma;
    • Ongoing MM therapy;
    • Prior exposure to anti-CD38 antibody therapy;
    • Absolute neutrophil count ≤0.5 × 109/L;
    • Platelet count <50 × 109/L; and
    • Creatinine clearance ≤20 mL/min/1.73 m2.
  • Patients received daratumumab at a dose of 16 mg/kg intravenously (iv) every week for eight weeks, then every two weeks for 16 weeks, and then every four weeks until disease progression, unacceptable toxic­ity, or 60 days after U.S. approval.
  • Pre- and post-infusion medications were adminis­tered as per study MMY2002.
  • Premedications administered one hour (± 15 minutes) prior to the daratumumab infusion included:
    • Methylprednisolone 100 mg (or equivalent) iv for the first two infusions, and 60 mg with subsequent infusions;
    • Acetaminophen 650–1,000 mg; and
    • Diphenhydramine 25–50 mg (or equivalent anti­histamine drug).
  • Postmedication included a corticosteroid (methyl­prednisolone 20 mg or equivalent) and was given on the two consecutive days following daratumum­ab infusions.2
  • Montelukast was not recommended but was allowed at the investigator’s discretion.
  • For subjects with a higher risk of respiratory complications (predicted % forced expiratory volume in one minute <75%), the following post-infusion medications were considered:
    • Diphenhydramine (25–50 mg) or equivalent on the two days following all daratumumab infusions;
    • Short-acting β2 adrenergic receptor agonists such as salbutamol aerosol;
    • Inhaled corticosteroids ± long-acting β2 adrenergic receptor agonists for subjects with asthma; and
    • Long-acting bronchodilators such as tiotropium or salbu­tamol ± inhaled corticosteroids for subjects with COPD.

Key findings

Baseline characteristics and disposition

  • In total, 400 patients were screened and 348 patients were enrolled and dosed.
  • Patients were enrolled at 39 U.S. sites from July to November 2015.
  • The median age was 65 years (range: 27–94).
  • The majority of patients were male (59%), Caucasian (72%), and had an ECOG PS of 1 (58%).
  • Patients received a median eight doses of daratumumab (range: 1–17), and the median treatment exposure time was 1.9 months (range: 0.03–6.0).

Safety

  • A total of 195 patients (56%) experienced IRRs during the study, and all 195 of them experienced IRRs during their first infusion. (Table 1)
  • The most common IRRs were respiratory or thoracic symp­toms, which occurred in 31% of patients.
  • Sixty patients received montelukast during therapy, including 50 patients who received montelukast 10 mg given >30 minutes prior to the first infusion. (Table 2)
  • Median time for the first infusion was 6.7 and 7.6 hours for patients who did or did not receive montelukast, respectively, while times for subsequent infusions were similar in both groups.
  • A total of 24 patients experienced IRRs that were consid­ered serious adverse events, but no patient discontinued the study due to an IRR.

Key conclusions

  • The findings of the EAP study were similar to those observed in the MMY2002 registration study conducted on the same patient population.2
  • The observed IRR rate during the first daratumumab infusion was one-third lower in patients who received 10 mg of montelukast >30 minutes prior to the first infusion vs. patients who did not receive montelukast.
    • Respiratory and gastrointestinal symptoms were lower in patients who received montelukast, while chills were observed at a similar rate in both groups.
  • The median time for the first infusion was 0.9 hours shorter in patients who received montelukast.
  • Because the use of montelukast was limited to a small number of centres, the role of montelukast in reducing IRRs cannot be determined from these uncontrolled observations.
  • Additional studies to determine if montelukast mitigates the IRRs associated with the first infusion of daratumumab are needed.

References: 1. Chari A, Mark TM, Krishnan A, et al. Use of montelukast to reduce infusion reactions in an early access program (EAP) of daratumumab in United States patients with relapsed or refractory multiple myeloma. ASH Annual Meeting Abstracts 2016:2142. 2. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2016;387(10027):1551–60.

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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.