Chari A, et al. ASH 2016:2133
A multicentre, open-label, Early Access Treatment Protocol (EAP) was opened in June 2015 after the MMY2002 study demonstrated the efficacy and safety profile of daratumumab in patients with relapsed/ refractory (R/R) multiple myeloma (MM).1 Results from the EAP were presented at the 2016 ASH Meeting.2
- The objectives of the EAP were to provide early access to daratumumab treatment and to collect safety and patient-reported outcome data in patients with MM who had received ≥3 prior lines of therapy, including a proteasome inhibitor (PI) and an immunomodulatory agent (IMID), or who were double refractory to a PI and an IMID.
- Additional inclusion criteria were:
- Age ≥18 years;
- Documented MM;
- Progression by International Myeloma Working Group criteria; 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:
- Acetaminophen 650–1,000 mg iv or orally (po) one hour prior to infusion;
- An antihistamine (diphenhydramine 25–50 mg iv or po, or equivalent) one hour prior to infusion;
- Methylprednisolone 100 mg iv prior to infusions 1–2 (60 mg iv prior to subsequent infusions); and
- Methylprednisolone 20 mg or equivalent post infusion for two days.
- 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.
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).
- Patient disposition is summarized in Figure 1.
- The median change from baseline in all domains of the EuroQol-five dimensions, five-level questionnaire (EQ-5D-5L) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 scales was 0 after one and two cycles, as well as at patients’ last assessment. (Table 1)
- The exception to this was the EQ-5D-5L visual analogue scale, which showed a median increase of 1 and 2 units after one and two cycles, respectively.
- The total number of patients who experienced an adverse event (AE) was 281 (80.7%).
- Grade ≥3 AEs were reported in 50% of patients. (Table 2)
- The total number of patients who discontinued treatment due to an AE was 13 (3.7%).
- Serious AEs (SAEs) occurred in 35% of patients, including 12% of patients with SAEs that were determined by the investigator to be drug-related.
- Grade 3/4 SAEs occurred in 29.0% of patients. (Table 3)
- A total of 195 patients (56%) experienced infusion-related reactions (IRRs) during the study, and all 195 of them experienced IRRs during their first infusion. (Table 4)
- No subjects discontinued the study due to an IRR.
- AEs in the EAP were consistent with the previously described AE profile of daratumumab in patients with MM who had received ≥3 prior lines of therapy, including a PI and an IMID, or who were double refractory to a PI and an IMID.
- No new safety signals were observed.
- SAEs occurred in one-third of patients, including 12% of patients who experienced a drug-related SAE.
- More than half of patients experienced IRRs, which primarily occurred during the first infusion and were mostly grade 1/2 in severity.
- Patients maintained their health-related quality of life during a median duration of two months of therapy.
References: 1. Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol (ASCO Annual Meeting) 2015;33(Suppl): abstr LBA8512. 2. Chari A, Mark TM, Krishnan A, et al. Results of an early access program (EAP) of daratumumab in United States patients with relapsed or refractory multiple myeloma. ASH Annual Meeting Abstracts 2016:2133.
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.
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.
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.
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.
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.
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.