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Daratumumab regimen shows promise in relapsed, refractory multiple myeloma
The addition of daratumumab to pomalidomide and dexamethasone appeared safe and effective for patients with relapsed or refractory multiple myeloma, according to results from the phase 1 EQUULEUS study.
Despite advances in treatment options for multiple myeloma, patients with successive relapses or those who are refractory tend to have poor outcomes.
“There is still a need for novel drugs to be approved,” Ajai Chari, MD, director of clinical research in the multiple myeloma program at Tisch Cancer Institute at Mount Sinai School of Medicine, told HemOnc Today. “We need to do combination therapies to try to improve those numbers. So, that leaves a lot of room for improvement.”
The FDA previously approved daratumumab (Darzalex, Janssen) — a human monoclonal antibody targeting CD38 — for use with dexamethasone and lenalidomide (Revlimid, Celgene) or bortezomib for patients with myeloma who received at least one prior treatment.
The agent also is approved as monotherapy for patients with myeloma who received at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent.
As HemOnc Today previously reported, the FDA expanded the approval of daratumumab for use with pomalidomide (Pomalyst, Celgene) and dexamethasone for patients who received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
The FDA based the approval on results of the phase 1 EQUULEUS study, an open-label, nonrandomized, multicenter, multiarm, phase 1b study.
In this report, Chari and colleagues evaluated the safety and efficacy of the daratumumab plus pomalidomide-dexamethasone treatment arm from that study.
The researchers administered the following regimen to 103 patients with relapsed or refractory multiple myeloma:
- 16 mg/kg IV daratumumab weekly in cycles 1 through 2, followed by every 2 weeks in cycles 3 through 6, and every 4 weeks thereafter;
- 4 mg oral pomalidomide daily on days 1 through 21; and
- 40 mg dexamethasone administered weekly, and before and after the daratumumab infusions to further reduce the risk for infusion-related reactions.
Safety served as the primary endpoint. Secondary endpoints included overall response rate and minimal residual disease by next-generation sequencing.
All patients received prior antimyeloma treatment, and 74% of patients had undergone a prior autologous stem cell transplant. Patients received a median of four prior therapies. Most patients (76%) received three or more prior therapies.
Treatment-emergent adverse events included neutropenia (80%), anemia (54%), fatigue
(52%), diarrhea (43%), thrombocytopenia (42%), cough (38%), leukopenia (37%), constipation (34%), dyspnea (32%), nausea (31%), pyrexia (30%), back pain (28%), upper respiratory tract infection (28%) and muscle spasms (27%).
The most common grade 3 and grade 4 treatment-emergent adverse events included neutropenia (77%), anemia (28%), leukopenia (24%), thrombocytopenia (19%), lymphopenia (14%), fatigue (12%), pneumonia (10%), febrile neutropenia and dyspnea (8% each), and hyperglycemia, back pain and fall (6% each).
Aside from increased neutropenia, the safety profile of daratumumab plus pomalidomide-dexamethasone appeared consistent with that of the individual therapies.
“Although the rates of grade 3 neutropenia are approaching almost 80%, the rates of infection were comparable to what we have seen before,” Chari said. “It reflects the nature of this heavily pretreated population.”
Common infusion-related reactions, which occurred in 50% of patients, included chills (15%), cough (11%), dyspnea (11%), nausea (9%), throat irritation (7%) and nasal congestion (7%).
ORR was 60% (95% CI, 50.1-69.7) — including 8% of patients with stringent complete response, 9% with complete response, 25% with very good partial response and 18% with partial response. Researchers reported a clinical benefit rate of 62%.
Overall, 25% of patients demonstrated stable disease and 3% had progressive disease.
ORR appeared consistent across prespecified subgroups.
Among patients with a complete response or better, 36% were minimal residual disease-negative at a threshold of 10¯ and 29% at a threshold of 10¯.
Median duration of response was not estimable (95% CI, 13.6-NE) among the 62 responders.
Median PFS was 8.8 months (95% CI, 4.6-15.4), with a 12-month PFS rate of 42% (95% CI, 31.5-51.9).
At a median follow-up of 13.3 months, median OS was 17.5 months (95% CI, 13.3-NE), with estimated survival rates of 89% (95% CI, 81.2-93.8) at 3 months, 79% (95% CI, 69.3-85.6) at 6 months, and 66% (95% CI, 55.6-74.8) at 12 months.
Chari noted this regimen and daratumumab monotherapy are being evaluated in a variety of myeloma disease states.
“The definitive phase 3 trial will be done of pomalidomide-dexamethasone plus or minus daratumumab, called the APOLLO study, is ongoing,” Chari added. “For now, the approval of this combination by the FDA gives another opportunity for patients and physicians to be able to derive benefit from this combination.” – by Kristie L. Kahl
For more information:
Ajai Chari, MD, can be reached at Tisch Cancer Institute, Mount Sinai School of Medicine, 1 Gustave Levy Place, Box 1185, New York, New York 10029; ajai.chari@mountsinai.org.
Disclosures: Janssen Research & Development sponsored this study. Chari reports research funding from and consultant/advisory roles with Amgen, Array Biopharma, Celgene, Janssen, Millennium/Takeda and Novartis. Please see the full study for a list of all other authors’ relevant financial disclosures.