PracticeUpdate: Haematology & Oncology

EUROPEAN HEMATOLOGY ASSOCIATION 2016 CONGRESS 20

Adding daratumumab to bortezomib and dexamethasone improves outcomes of relapsed or refractory multiple myeloma significantly Daratumumab improved progression-free survival, time to progression, and objective response rates significantly in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone, reports an interim outcome of the phase 3, randomised, controlled CASTOR trial. A ntonio Palumbo, MD, of the University of Turin, Italy, explained that daratumumab, a human anti-CD38 immune globulin G κ monoclonal antibody, induces deep and durable responses with a favourable safety profile in patients with relapsed or refractory multiple myeloma. In addition, prespecified subgroup analyses on progression-free survival demonstrated that the treatment effect of daratumumab + bortezomib + dexamethasone over bortezomib + dexamethasone was consistent across all selected subgroups.

Most common (>25%) treatment-emergent adverse events with daratumumab + bortezomib + dexamethasone and bortezomib + dexamethasone were thrombocytopenia (59%/44%), peripheral sensory neuropathy (47%/ 38%), diarrhoea (32%/22%), and anaemia (26%/31%), respectively. Most common (>10%) grade 3/4 treatment-emergent adverse events with daratumumab + bortezomib + dexamethasone and bortezomib + dexamethasone were thrombocytopenia (45%/33%), anaemia (14%/16%), and neutropenia (13%/4%), respectively. Seven percent of patients who received daratumumab + bortezomib + dexameth- asone and 9% of those who received bortezomib + dexamethasone discontinued due to a treatment-emergent adverse event. Daratumumab-associated infusion-related reactions (45% of patients) occurred mostly during the first infusion (98% of patients with an infu-

Dr Palumbo and colleagues are performing the first randomised con- trolled study of daratumumab (CASTOR). Their aim is to compare the efficacy and safety of daratumumab + bortezomib and dexamethasone versus bortezomib and dexamethasone alone in patients with relapsed or refractory multiple myeloma. Patients who received at least one prior line of therapy were ran- domised 1:1 to eight cycles every 3 weeks of bortezomib 1.3 mg/m 2 subcutaneously on days 1, 4, 8, and 11; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 with or without daratumumab (16 mg/kg intravenously once weekly in cycles 1–3, day 1 of cycles 4–8, then every 4 weeks until progression). The primary endpoint was progression-free survival. A total of 498 patients (daratumumab + bortezomib + dexametha- sone, n=251; bortezomib + dexamethasone, n=247) were randomised. Baseline demographics and disease characteristics were well balanced between the two groups. Patients received a median of two prior lines of therapy (range one to ten). Sixty-six percent received prior bortezomib; 76% received a prior immunomodulatory drug; 48% received a prior proteasome inhibitor and an immunomodulatory drug; 33% were refractory to an immunomodulatory drug; and 32% were refractory to their last line of prior therapy. After a median follow-up of 7.4 months, daratumumab significantly improved median progression-free survival (61% reduction in risk of progression/death) for daratumumab + bortezomib +dexamethasone versus bortezomib + dexamethasone. Addition of daratumumab to bortezomib + dexamethasone also delayed median time to disease progression significantly versus bortezomib + dexamethasone (not reached vs 7.3 months; hazard ratio 0.30; 95% CI 0.21–0.43; P < 0.0001). Daratumumab increased overall response rate significantly (objec- tive response rate 83% vs 63%, P < 0.0001), in addition to doubling the rates of very good partial responses or better (59% vs 29%, P < 0.0001) and complete responses or better (19% vs 9%, P = 0.0012) for daratumumab + bortezomib + dexamethasone vs bortezomib + dexamethasone, respectively. The median duration of response was not reached for daratumumab + bortezomib + dexamethasone versus 7.9 months for bortezomib + dexamethasone. All planned sensitivity analyses demonstrated that daratumumab + bortezomib + dexamethasone was better than borte- zomib + dexamethasone, which was consistent with results from the primary analysis.

sion-related reaction). Most were grade 1/2 (grade 3/4, 9%/0%). Dr Palumbo concluded that daratumumab improved pro- gression-free survival, time to progression, and objective re- sponse rate in combination with bortezomib and dexamethasone significantly versus bortezomib + dexamethasone alone. Daratumumab + bortezomib + dexamethasone doubled rates of both very good partial response or better and stringent complete response/complete response ver- sus bortezomib + dexamethasone alone. The safety of daratumumab + bortezomib + dexamethasone is consistent with the known safety profile of daratumumab, bortezomib, and dexamethasone. The addition of daratumumab to bortezomib and dexamethasone should be considered a new standard of care for patients with relapsed or refractory multiple myeloma receiving bortezomib + dexamethasone alone.

© EHA 2016

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY