Dacetuzumab (SGN-40), Lenalidomide, and Weekly Dexamethasone in Relapsed or Refractory Multiple Myeloma: Multiple Responses Observed in a Phase 1b Study.

Dacetuzumab (SGN-40) is a humanized monoclonal antibody that targets CD40. In prior phase 1 studies, antitumor activity was demonstrated with dacetuzumab monotherapy in patients with non-Hodgkin lymphoma and stabilization of disease was noted in multiple myeloma (MM) patients. Preclinical data demonstrate that the addition of lenalidomide to dacetuzumab markedly enhances dacetuzumab-mediated ADCC and apoptosis in both MM cell lines and patient isolates through modulation of NK cell activity.

A phase 1b, dose-escalation study of dacetuzumab, lenalidomide, and low-dose dexamethasone has been initiated in patients with relapsed or refractory MM. Patients were enrolled in a 3+3 dose-escalation scheme and were given cohort-specific doses of weekly IV dacetuzumab (4, 8, or 12 mg/kg) in addition to oral lenalidomide (25 mg, Days 1-21 every 28 days), and weekly oral dexamethasone (40 mg). At the conclusion of dose escalation, the highest tolerated dose combination was used to treat an expansion cohort, approximately half of whom were lenalidomide-naïve. The maximum number of cycles permitted was 8, or 2 cycles beyond a complete response (CR).

Thirty-six patients from 8 centers were enrolled and treated, 15 patients in 3 dose-escalation cohorts and 21 patients in the expansion cohort at the 12 mg/kg dacetuzumab dose level. The median age of patients was 65 years (range 48-83) with a median of 3.4 years since diagnosis (range 1-11); patients were heavily pretreated (median of 4 prior systemic regimens [range 2-14]). The median number of cycles received was 4 (range 1-8), although 14 patients remain on treatment. The most common adverse events (AEs) in the study were fatigue (47%), neutropenia (28%), thrombocytopenia (25%), diarrhea (22%), constipation (19%), and headache (19%), the majority of which were Grade 1 or 2 in severity. Two patients discontinued treatment due to dose-limiting toxicity (DLT) during Cycle 1: one patient developed Grade 3 herpes zoster (4 mg/kg); a second patient developed Grade 4 renal failure requiring dialysis (12 mg/kg). This patient had IgA myeloma with a rising M-protein and deteriorating kidney function at study entry; the patient's renal function eventually improved and dialysis was no longer required. Another patient discontinued treatment due to a serious AE that was not considered a DLT (tumor lysis syndrome). Of 33 patients who have had Investigator-assessed response evaluations according to the European Group for Bone Marrow and Transplantation criteria, 13 patients (39%) achieved an objective response (1 CR, 12 partial responses [PR]); other responses were 4 (12%) minimal responses (MR), 10 patients (30%) had stable disease (SD), 2 patients (6%) had progressive disease (PD), and 4 patients (12%) were not evaluable. Responses that occurred among lenalidomide-naïve patients (n=18) were 1 CR, 9 PR, 1 MR, 3 SD, 2 PD, and 2 not evaluable. Among patients who have previously received lenalidomide (n=18), the responses were 3 PR, 3 MR, 7 SD, and 2 not evaluable; additionally, 3 patients who are receiving treatment have not yet been assessed for response.

The combination regimen of dacetuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated at all doses studied. Evidence of anti-myeloma activity with this combination is encouraging as antitumor activity was observed in patients with MM who have previously received lenalidomide as well as lenalidomide-naïve patients.

Agura:Seattle Genetics, Inc.: Research Funding. Off Label Use: Dacetuzumab is an investigational agent. Niesvizky:Proteolix: Research Funding, data monitoring committee; Seattle Genetics, Inc: Research Funding; Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Honoraria, Speakers Bureau. Munshi:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Research Funding. Hussein:Seattle Genetics, Inc.: Research Funding. Parameswaran:Seattle Genetics, Inc.: Research Funding. Tarantolo:Seattle Genetics, Inc.: Research Funding. Whiting:Seattle Genetics, Inc.: Employment, Equity Ownership. Drachman:Seattle Genetics, Inc.: Employment, Equity Ownership. Zonder:Pfizer: Consultancy; Seattle Genetics, Inc.: Research Funding; Millennium: Research Funding; Amgen: Consultancy; Celgene: Speakers Bureau.