On August 20, 2020, carfilzomib and daratumumab were approved for use in combination with dexamethasone for treatment of adults with relapsed or refractory multiple myeloma who have received one to three lines of therapy.1-3
Supporting Efficacy Data
Approval was based on findings in two clinical trials of carfilzomib and daratumumab with dexamethasone: the phase III, open-label CANDOR trial (ClinicalTrials.gov identifier NCT03158688) and the phase Ib EQUULEUS trial (NCT01998971).
In the CANDOR trial,2-4 466 patients with relapsed or refractory disease who had received one to three prior lines of therapy were randomly assigned 2:1 to receive intravenous (IV) carfilzomib in the 20/56 mg/m2 twice-weekly regimen (see recommended dosing below), IV daratumumab (see recommended dosing below), and dexamethasone (DKd; n = 312) or carfilzomib in the same regimen and dexamethasone (Kd; n = 154). Efficacy was assessed by independent review committee evaluation of progression-free survival using International Myeloma Working Group response criteria.
An objective response was observed in 84% of the DKd group, including a complete response in 28%, vs 75% of the Kd group, including a complete response in 10% (P = .004). The median duration of response was not reached (95% confidence interval [CI] = not estimable to not estimable) vs 16.6 months (95% CI = 13.9 months to not estimable). Median progression-free survival was not reached (95% CI = not estimable to not estimable) vs 15.8 months (95% CI = 12.1 months to not estimable), yielding a hazard ratio of 0.63 (95% CI = 0.46–0.85, P = .0014).
In the EQUULEUS trial,2,3 85 patients with relapsed or refractory disease who had received one to three prior lines of therapy received DKd with carfilzomib given in the 20/70 mg/m2 once-weekly regimen (see recommended dosing below).
KEY POINTS
- Carfilzomib and daratumumab were approved for use in combination with dexamethasone for treatment of adults with relapsed or refractory multiple myeloma who have received one to three lines of therapy.
- The recommended regimens of carfilzomib plus daratumumab and dexamethasone are:
Once-weekly 20/70 mg/m2 regimen: carfilzomib IV as a 30-minute infusion on days 1, 8, and 15 of each 28-day cycle at a dose of 20 mg/m2 on cycle 1, day 1—and, if tolerated, increased to 70 mg/m2 on cycle 1, day 8 and thereafter; OR
Twice-weekly 20/56 mg/m2 regimen: carfilzomib IV as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, at a dose of 20 mg/m2 on days 1 and 2 of cycle 1—and, if tolerated, increased to 56 mg/m2 on cycle 1, day 8 and thereafter.
Efficacy was based on the overall response rate as assessed by independent review committee using International Myeloma Working Group response criteria. The overall response rate was 81% (95% CI = 71%–89%), including a stringent complete response in 21% and a complete response in 14%. The median duration of response was 27.5 months (95% CI = 20.5 months to not estimable).
How It Is Used
The recommended dosage regimens of carfilzomib when administered in combination with daratumumab and dexamethasone are:
Once-weekly 20/70 mg/m2 regimen: carfilzomib IV as a 30-minute infusion on days 1, 8, and 15 of each 28-day cycle at a dose of 20 mg/m2 on cycle 1, day 1—and, if tolerated, increased to 70 mg/m2 on cycle 1, day 8 and thereafter; OR
Twice-weekly 20/56 mg/m2 regimen: carfilzomib IV as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, at a dose of 20 mg/m2 on days 1 and 2 of cycle 1—and, if tolerated, increased to 56 mg/m2 on cycle 1, day 8 and thereafter.
The recommended dosage of daratumumab when administered in combination with carfilzomib and dexamethasone is 16 mg/kg IV administered as split dosing of 8 mg/kg on days 1 and 2 of cycle 1, followed by standard dosing of 16 mg/kg for subsequent doses, administered weekly from weeks 2 to 8, every 2 weeks from weeks 9 to 24, and every 4 weeks from week 25 and thereafter.
Carfilzomib prescribing information provides instructions on hydration, electrolyte monitoring, premedication and concomitant medication, thromboprophylaxis, antiviral prophylaxis, dosages for hepatic impairment and end-stage renal disease, and dose reductions for adverse reactions. Detailed instructions on dosage modification and management are provided for adverse reactions, including hematologic toxicity, renal toxicity, and other nonhematologic toxicity.
Daratumumab should be administered by a health-care provider with immediate access to emergency equipment and appropriate medical support to manage infusion-related reactions. Patients should be typed and screened prior to starting treatment. Prescribing information provides details of infusion rates, preinfusion and postinfusion medication, and antiviral prophylaxis. No dose reductions of daratumumab are recommended. Prescribing information provides detailed instructions on management of infusion-related reactions.
Safety Profile
The most common adverse events of any grade occurring in at least 20% of patients treated with carfilzomib and daratumumab in the two combination therapy trials were infusion-related reactions, anemia, diarrhea, fatigue, hypertension, pyrexia, respiratory tract infection, thrombocytopenia, neutropenia, lymphopenia, cough, dyspnea, insomnia, headache, and back pain.
Among patients receiving DKd vs Kd with the carfilzomib 20/56 mg/m2 twice-weekly regimen in the CANDOR trial, the most common grade 3 or 4 adverse events in the DKd group were thrombocytopenia (25% vs 16% in Kd group), anemia (17% vs 14%), pneumonia (13% vs 9%), and infusion-related reactions (12% vs 5%).
OF NOTE
The most common adverse events of any grade occurring in patients treated with carfilzomib and daratumumab in the two combination therapy trials were infusion-related reactions, anemia, diarrhea, fatigue, hypertension, pyrexia, respiratory tract infection, thrombocytopenia, neutropenia, lymphopenia, cough, dyspnea, insomnia, headache, and back pain.In the DKd group, serious adverse events occurred in 56% of patients, the most common being pneumonia (14%), pyrexia (4.2%), influenza (3.9%), and sepsis (3.9%). Adverse events led to dose reduction of carfilzomib in 25% of patients. Adverse events led to discontinuation of carfilzomib in 21% of patients, the most common causes being cardiac failure (1.9%) and fatigue (1.9%), and to discontinuation of daratumumab in 9% of patients, the most common cause (> 1%) being pneumonia. Infusion-related reactions occurred in 13% of patients following the first carfilzomib dose and in 12% of patients following the first daratumumab dose. Fatal adverse events within 30 days of the last dose of any study treatment occurred in 10% of patients, the most common cause being infection (4.5%).
Among patients receiving DKd with the carfilzomib 20/70 mg/m2 once-weekly regimen in the EQUULEUS trial, the most common grade 3 or 4 adverse events were hematologic adverse events, the most frequent being thrombocytopenia (32%). The most common grade 3 or 4 nonhematologic adverse events were fatigue (18%) and infusion-related reactions (12%). Pulmonary hypertension occurred in 4.7% of patients.
Serious adverse events occurred in 48% of patients, the most common being pneumonia (4.7%), upper respiratory tract infection (4.7%), and basal cell carcinoma (4.7%). Adverse events led to dose reduction of carfilzomib in 31% of patients. Adverse events led to discontinuation of carfilzomib in 19%, the most common cause being asthenia (2%), and to discontinuation of daratumumab in 8% of patients (no cause occurring in more than one patient). Infusion-related reactions occurred after the first dose of carfilzomib in 13% of patients. For patients receiving the split first dose of daratumumab, infusion-related reactions occurred in 36% and 4% on the first and second day of administration. Fatal adverse events within 30 days of the last dose of any study treatment occurred in 3.5% of patients, with causes including general physical health deterioration and multiorgan failure secondary to pulmonary aspergillosis.
Carfilzomib has warnings/precautions for cardiac toxicities; acute renal failure; tumor-lysis syndrome; pulmonary toxicity, including acute respiratory distress syndrome, acute respiratory failure, and acute diffuse infiltrative pulmonary disease; pulmonary hypertension; dyspnea; hypertension, including hypertensive crisis; venous thrombosis; infusion-related reactions; hemorrhage; thrombocytopenia; hepatic toxicity and hepatic failure; thrombotic microangiopathy; posterior reversible encephalopathy syndrome; progressive multifocal leukoencephalopathy; increased fatal and serious toxicities in combination with melphalan and prednisone in newly diagnosed transplant-ineligible patients; and embryofetal toxicity.
Daratumumab has warnings/precautions for infusion-related reactions, interference with cross-matching and red blood cell antibody screening, neutropenia, thrombocytopenia, and embryofetal toxicity. Patients should be advised not to breastfeed while receiving carfilzomib or daratumumab.
References
1. U.S. Food and Drug Administration: FDA approves carfilzomib and daratumumab with dexamethasone for multiple myeloma. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-carfilzomib-and-daratumumab-dexamethasone-multiple-myeloma. Accessed September 2, 2020.
2. Kyprolis (carfilzomib) for injection prescribing information, Onyx Pharmaceuticals, August 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/202714s030lbl.pdf. Accessed September 2, 2020.
3. Darzalex (daratumumab) injection prescribing information. Janssen Biotech, August 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761036s029lbl.pdf. Accessed September 2, 2020.
4. Dimopoulos M, Quach H, Mateos MV, et al: Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): Results from a randomised, multicentre, open-label, phase 3 study. Lancet 396:186-197, 2020.
