FDA Approves Daratumumab Plus Carfilzomib/Dexamethasone in Relapsed/Refractory Myeloma

The FDA has approved daratumumab (Darzalex) for use in combination with carfilzomib (Kyprolis) and dexamethasone (KdD) for the treatment of patients with relapsed/refractory multiple myeloma who have received 1 or more prior lines of therapy.¹

“We are extremely pleased that multiple myeloma patients in the United States will now have yet another treatment option, as this is the eighth overall US FDA approval for [daratumumab] and the fifth in the relapsed/refractory setting. In addition, [daratumumab] is now the first CD38 antibody approved for use in combination with carfilzomib,” Jan van de Winkel, PhD, chief executive officer of Genmab, stated in a press release.

The combination regimen has been approved in 2 carfilzomib dosing regimens: 70 mg/m² once weekly and 56 mg/m² twice weekly. The regulatory decision was based on positive data from the phase 3 CANDOR (NCT03158688) trial and the phase 1b EQUULEUS trial (MMY1001; NCT01998971).

In CANDOR, patients with relapsed/refractory disease who had received 1 to 3 prior lines of therapy were randomized 2:1 to receive either KDd (n = 312) or carfilzomib/dexamethasone alone (Kd; n = 154).

Results from the trial showed that the addition of the anti-CD38 antibody led to a 37% reduction in the risk of disease progression or death. At a median follow-up of 17 months, the median progression-free survival (PFS) was not yet reached with KdD versus 15.8 months with Kd alone (HR, 0.63; 95% CI, 0.46-0.85; P = .0014).² Moreover, the median overall survival (OS) had not yet been reached in either treatment arm (HR, 0.75; 95% CI, 0.49-1.13; P = .08).

The open-label phase 3 trial, previous treatment with anti-CD38 antibodies and carfilzomib was permitted, as long as the patient achieved at least a partial response, did not relapse in 60 or fewer days from treatment discontinuation, and had a 6-month or longer treatment-free interval at the time of starting study treatment. Overall, 90% of patients received prior bortezomib (Velcade) and 42% of patients had previously been given lenalidomide (Revlimid). One-third (33%) of patients were refractory to lenalidomide.

All treatments were administered over 28-day cycles. Daratumumab, at a dose of 16 mg/kg, was given on days 1, 8, 15, and 22, of cycles 1 and 2, every 2 weeks during cycles 3 to 6, and every 4 weeks during cycle 7 and beyond. Notably, for patient convenience, the initial dose of daratumumab was split into two 8-mg/kg doses and given on cycle 1, day 1 and cycle 2, day 2.

Carfilzomib and dexamethasone were administered at the same dose and schedule in both arms. Participants were given carfilzomib on days 1, 2, 8, 9, 15, and 16 of each treatment cycle. For cycle 1 only, participants received a 20-mg/m² loading dose of carfilzomib on days 1 and 2; however, the agent was administered at a dose of 56 mg/m² for all subsequent treatments thereafter. Dexamethasone was given at a dose of 40 mg on days 1, 8, 15, and 22 of each treatment cycle. During weeks when patients received carfilzomib and/or daratumumab infusions, a split dose of 20 mg each of dexamethasone was given.

The primary end point of the trial was PFS, and key secondary end points included overall response rate (ORR), minimal residual disease (MRD) negativity status, complete response (CR) rate at 12 months, OS, duration of response, and safety.

In the participants who were exposed to lenalidomide, the median PFS had not been reached in the KdD arm versus 12.1 months in the Kd arm (HR, 0.52; 95%, 0.34-0.80); in those refractory to lenalidomide, the median PFS was not reached versus 11.1 months, respectively (HR, 0.45; 95% CI, 0.28-0.74).

Additionally, an ORR of 84.3% was reported in the KdD arm versus 74.7% in the Kd arm (P = .0040). The rates of CR or better were 28.5% versus 10.4% with KdD and Kd, respectively. The median time to first response was 1 month in both arms. Among patients receiving KdD, the MRD-negative rate at 12 months was 12.5% versus 1.3% with Kd.

With regard to safety, a total of 308 patients in the KdD arm and 153 patients in the Kd arm were included in the analysis.

Results showed that the overall toxicity profile with the regimens were comparable to what has been previously reported with the use of these agents as monotherapy. The median treatment duration was 70.1 weeks in the KdD arm and 40.3 weeks in the Kd arm.

The rates of grade 3 or higher adverse effects (AEs) were 56.2 % versus 45.8% in the KdD and KD arms, respectively, while the rates of serious AEs were 56.2% versus 45.8%, respectively. Treatment discontinuation rates because of toxicities were 22.4% versus 24.8% with KdD and KD, respectively. In the KdD arm, 3.9% of patients experienced grade 3 or higher cardiac failure versus 8.5% of those in the Kd arm. Cardiac failure resulted in carfilzomib discontinuation in 3.9% versus 4.6% of those on the KdD Kd arms, respectively.

Moreover, 5 treatment-related deaths were reported; all were reported on the tripley arm; 1 each were due to pneumonia, sepsis, septic shock, acinetobacter infection, and cardiorespiratory arrest.

In the EQUULEUS trial, investigators evaluated daratumumab in combination with various backbone therapies in patients with relapsed/refractory multiple myeloma and showed that the pharmacokinetic concentrations of daratumumab at 16 mg/kg were comparable at the end of weekly dosing, regardless of whether it was a split-dose or a single infusion.³ Additionally, the safety profiles were similar across both dosing regimens.

In a subgroup analysis of the trial, a total of 85 patients with relapsed/refractory disease were treated with KdD. Participants had received 1 to 3 previous lines of therapy, including bortezomib and an immunomodulatory (IMiD) agent. Per study protocol, daratumumab was given intravenously at a single first dose of 16 mg/kg (n = 10) or at a split first dose of 8 mg/kg on days 1 and 2 of cycle 1 (n = 75). Participants were also treated with carfilzomib at 20 mg/m² IV on day 1 of cycle 1, and dexamethasone IV or orally at a 40-mg weekly dose on days 1, 8, 15, and 22.

Notably, baseline characteristics were comparable between the lenalidomide-refractory subgroup (n = 51) and the overall population (n = 85). The primary end points of the trial were safety and tolerability; secondary endpoints were ORR and OS.

At a median follow-up of 12.0 months for both populations, the safety profiles were similar across both treatment groups. In the overall population, the most common hematologic treatment-emergent AEs (TEAEs) included thrombocytopenia (67%), anemia (47%), neutropenia (29%), and lymphopenia (25%). Nonhematologic TEAEs included nausea (40%), upper respiratory tract infection (39%), asthenia (38%), vomiting (37%), dyspnea (34%), pyrexia (33%), insomnia (31%), diarrhea (31%), hypertension (25%), cough (25%), headache (22%), and back pain (22%). Moreover, grade 3 or 4 TEAEs that were reported 20% or more of participants included thrombocytopenia (31%), anemia (21%), neutropenia (21%), and lymphopenia (22%).

Additionally, infusion-related reactions (IRRs) were observed in half (50%; n = 5) of patients who received the single daratumumab infusion versus 36% (n = 27) of those who received the first split dose and 4% (n = 3) who were given the second split dose. The median infusion time was 7.1 hours (range, 6.5-8.9) versus 4.3 hours (range, 3.9-10.6) on the first split dose and 4.2 hours (range, 3.9-8.6) on the second split dose. The IRR rates and infusion times proved to be consistent between the single and split first dose regimens for subsequent infusions.

Data also indicated that the split and single daratumumab doses had comparable pharmacokinetic profiles. Overall, the results supported the feasibility of the split-dosing regimen and showed its potential to improve patient convenience for initial dosing.

Regarding efficacy, the ORR in the overall population who received with the triplet regimen was 84% versus 79% in the lenalidomide-refractory population and 90% in the population of patients who were exposed to lenalidomide but not refractory. MRD-negative rates were 36%, 20%, and 50% in the overall, lenalidomide-refractory, and lenalidomide-exposed-but-not-refractory populations, respectively.

Moreover, the median PFS for the overall and lenalidomide-exposed populations were not estimable versus 14.1 months for the lenalidomide-refractory population; the 12-month PFS rates were 71%, 87%, and 62%, respectively. For patients who were refractory to a proteasome inhibitor (PI) and an IMiD agent, the median PFS was not estimable and the 12-month PFS rate was 51%.

The median OS was not estimable in the overall and lenalidomide-exposed populations. In the lenalidomide-refractory population, the median OS was 21.1 months (95% CI, 18.8-NE) versus 18.8 months (95% CI, 18.8-NE) in the PI/IMiD-refractory groups; the 12-month OS rates were 82%, 90%, 75%, and 75%, respectively. Follow-up for OS is ongoing.

Daratumumab is currently indicated as a single agent for patients with myeloma who have previously received 3 or more lines of therapy; in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone for those who have received 1 or more prior lines of therapy; in combination with pomalidomide (Pomalyst) and dexamethasone for those with myeloma who have received at least 2 prior lines of treatment, including lenalidomide and a PI; and in combination with bortezomib, melphalan, and prednisone for the treatment of those with newly diagnosed myeloma who are not candidates for autologous stem cell transplant.

References

1. Genmab announces Janssen granted US FDA approval of Darzalex (daratumumab) in combination with carfilzomib and dexamethasone in relapsed or refractory multiple myeloma. News release. Genmab. August 20, 2020. Accessed August 20, 2020. https://bit.ly/3aKjsea.
2. Usmani SZ, Quach H, Mateos M-V, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study CANDOR (NCT03158688). Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract LBA6. bit.ly/2LEwAGf.
3. Chari AJ, Martinez-Lopez J, Mateos MV, et al. Daratumumab (DARA) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide (len)-refractory patients (pts) with relapsed multiple myeloma (MM): subgroup analysis of MMY1001. J Clin Oncol. 2018;36 (suppl 15):8002. doi:10.1200/JCO.2018.36.15_suppl.8002