Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favorable safety profile in this population of patients.

— Sagar Lonial, MD, and colleagues

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In the phase II SIRIUS trial reported in The Lancet, Sagar Lonial, MD, of Winship Cancer Institute, Emory University, and colleagues found that the CD38-targeted monoclonal antibody daratumumab (Darzalex) produced durable responses in patients with multiple myeloma who had received at least three lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who were double refractory to proteasome inhibitor and immunomodulatory therapy.¹ Results of this trial supported the recent U.S. Food and Drug Administration approval of daratumumab in this setting. Daratumumab is the first monoclonal antibody approved for the treatment of multiple myeloma.

Study Details

In this open-label trial, 106 patients from 26 sites in Canada, Spain, and the United States received daratumumab at 16 mg/kg/week for 8 weeks in cycles 1 and 2, every 2 weeks for 16 weeks in cycles 3 to 6, and every 4 weeks thereafter. The study began in September 2013 and is ongoing. The primary endpoint was overall response rate.

Patients had a median age of 64 years (45% ≥ 65 years); 51% were women; 79% were white and 14% were black; Eastern Cooperative Oncology Group performance status was 0 in 27%, one in 65%, and two in 8%; International Staging System stage was I in 25%, II in 38%, and III in 38%; cytogenetics included t(4;14) in 10%, del17p in 17%, and del13q in 32%; baseline creatinine clearance was ≥ 60 mL/min in 57%; 13% had at least one extramedullary plasmacytoma; and median time since initial diagnosis was 4.8 years (range = 1.1–23.8 years). Patients had received a median of five previous lines of therapy (> 3 for 82%, range = 2–14), and 80% had previously received autologous stem cell transplantation.

Previous proteasome inhibitors consisted of bortezomib (Velcade) in 99% and carfilzomib (Kyprolis) in 50%, and previous immunomodulatory therapy consisted of lenalidomide (Revlimid) in 99%, pomalidomide (Pomalyst) in 63%, and thalidomide (Thalomid) in 44%. All patients had previously received dexamethasone. Overall, 95% were refractory to both a proteasome inhibitor and an immunomodulatory drug; 97%, to the last line of therapy; 77%, to alkylating agents; 82%, to bortezomib/lenalidomide; 40%, to bortezomib/lenalidomide/carfilzomib; 54%, to bortezomib/lenalidomide/pomalidomide; and 31%, to bortezomib/lenalidomide/carfilzomib/pomalidomide.

Responses

Patients received a median of four cycles of treatment (range = 1–16), with 38% receiving at least six cycles. Median follow-up was 9.3 months for the current analysis.

Based on independent review committee assessment, partial response or better was observed in 31 patients (29.2%, 95% confidence interval [CI] = 20.8%–38.9%), including stringent complete response in 3 (2.8%, 95% CI = 0.6%–8.0%), very good partial response in 10 (9.4%, 95% CI = 4.6%–16.7%, and partial response in 18 (17.0%, 95% CI = 10.4%–25.5%). Another 4.7% had minimal response, and 43.4% had stable disease. Median time to first response was 1.0 month (range = 0.9–5.6 months), and median duration of response was 7.4 months (95% CI = 5.5 months to not estimable).

Response was observed in all patient subgroups examined, including 30 of 101 patients (29.7%, 95% CI = 21.0%–39.6%) refractory to both proteasome inhibitors and immunomodulatory drugs; 20 of 70 (28.6%, 95% CI = 18.4%–40.6%) refractory to at least three of bortezomib, lenalidomide, carfilzomib, and pomalidomide; and 2 of 12 (16.7%, 95% CI = 2.1%–48.4%) who were refractory to bortezomib, lenalidomide, carfilzomib, pomalidomide, and thalidomide. Response was observed in 3 of 14 patients (21.4%, 95% CI = 4.7%–50.8%) with extramedullary disease, 4 of 20 (20%, 95% CI = 5.7%–43.7%) with high-risk cytogenetics, 11 of 42 (26.2%, 95% CI = 13.9%–42.0

Survival

Median progression-free survival was 3.7 months (95% CI = 2.8–4.6 months). Overall survival at 12 months was 64.8% (95% CI = 51.2%–75.5%); median overall survival was not reached (95% CI = 13.7 months to not estimable), including not reached in responders and 13.7 months (95% CI = 8.6 months to not estimable) in nonresponders. At a subsequent cutoff for an updated safety analysis in June 2015, median overall survival was 17.5 months (95% CI = 13.7 months to not estimable).

Adverse Events

The most common adverse events of any grade were fatigue (40%), anemia (33%), nausea (29%), and thrombocytopenia (25%). The most common grade 3 or 4 adverse events were anemia (24%), thrombocytopenia (19%), and neutropenia (12%). Grade ≥ 3 anemia (32% vs 3%) and thrombocytopenia (24% vs 6%) were more common in nonresponders vs responders; rates of grade ≥ 3 neutropenia were similar (12% vs 13%). Red blood cell transfusion was required in 38% of patients; platelet transfusion, in 13%; and granulocyte colony-stimulating factor, in 8%.

Serious adverse events occurred in 30% of patients. Infusion-related reactions occurred in 42% (37% during first infusion), including grade 3 reactions in 5%. Treatment was discontinued in five patients (5%) due to adverse events, with none considered related to treatment.

The investigators concluded: “Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favorable safety profile in this population of patients.” ■

Disclosure: The study was funded by Janssen Research & Development. For full disclosures of the study authors, visit www.thelancet.com.

Reference

1. 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 387:1551-1560, 2016.