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Daratumumab-based combination regimen for patients with relapsed / refractory multiple myeloma, approved by FDA


The U.S. Food and Drug Administration ( FDA ) has approved Darzalex ( Daratumumab ) in combination with Kyprolis ( Carfilzomib ) and Dexamethasone ( DKd ) for the treatment of adult patients with relapsed / refractory multiple myeloma who have received one to three previous lines of therapy.
Darzalex has been approved in combination with two Carfilzomib dosing regimens, 70 mg/m2 once weekly and 56 mg/m2 twice weekly, based on positive results from the phase 3 CANDOR and phase 1b EQUULEUS studies, representing the first-ever approval of an anti-CD38 with Carfilzomib.

CANDOR is the first phase 3 randomized trial to compare DKd versus Carfilzomib and Dexamethasone ( Kd ) in patients with relapsed / refractory multiple myeloma.
The study, which administered Carfilzomib twice weekly, met its primary endpoint of progression-free survival ( PFS ) after a median follow-up of 16.9 months and 16.3 months for the DKd and Kd arms, respectively.
The median PFS had not been reached in the DKd arm and was 15.8 months in the Kd arm ( hazard ratio, HR=0.63; 95% confidence interval [ CI ], 0.46- 0.85; P=0.0014 ), representing a 37% reduction in the risk of disease progression or death for patients treated with DKd versus Kd.
The inclusion of once-weekly dosing of Carfilzomib as an approved DKd regimen was supported by positive results from the open-label, multi-cohort phase 1b EQUULEUS trial, which evaluated Daratumumab in combination with various treatment regimens.

In CANDOR, the safety profile of DKd was generally consistent with the known safety profiles of Daratumumab and Kd, and reflect a median treatment duration of 16.1 months for the DKd arm and 9.3 months for the Kd arm.
Serious adverse events occurred in 56% and 46% of patients who received DKd and Kd, respectively.
The most frequent serious adverse effects in the DKd arm, compared with the Kd arm, was pneumonia ( 14% vs 9% ).
Fatal adverse reactions occurred in 10% of DKd patients and 5% of Kd patients, and the most frequent fatal advers effects was infection ( 5% vs 3% ).

CANDOR evaluated 466 relapsed or refractory patients with multiple myeloma who had received one to three prior lines of therapy from 102 global sites.
Patients were treated until disease progression.
The primary endpoint was progression-free survival, and the key secondary endpoints were overall response rate, minimal residual disease and overall survival.
PFS was defined as time from randomization until disease progression or death from any cause.
All patients received Carfilzomib as a 30-minute intravenous ( IV ) infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle ( 20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter ) and received 40 mg Dexamethasone oral or IV weekly ( 20 mg/m2 for patients aged more than 75 years ).
In the treatment arm, Daratumumab 8 mg/kg was administered IV on days 1 and 2 of cycle 1 and 16 mg/kg IV once weekly for the remaining doses of the first two cycles, then every two weeks for four cycles ( cycles 3 to 6 ), and every four weeks thereafter.
Of the patients randomized in the study, 92% had received a prior proteasome inhibitor, 42% had received prior Lenalidomide, and 33% were Lenalidomide-refractory.

Daratumumab is the first CD38-directed antibody approved globally to treat multiple myeloma. CD38 is a surface protein that is present in high numbers on multiple myeloma cells, regardless of the stage of disease. Daratumumab binds to CD38 and inhibits tumor cell growth causing myeloma cell death.
Daratumumab may also have an effect on normal cells. ( Xagena )

Source: Janssen Pharmaceutical, 2020

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