Benefits of Daratumumab Triplets in Myeloma Sustained With Longer Follow-Up

Maria-Victoria Mateos, MD, PhD

The benefits of 2 FDA-approved daratumumab (Darzalex)—based triplet regimens were sustained in long-term data from 2 pivotal phase III studies presented at the 2016 ASH Annual Meeting.^1,2

In November 2016, the FDA approved daratumumab in combination with lenalidomide (Revlimid) and dexamethasone or bortezomib (Velcade) and dexamethasone for patients with relapsed multiple myeloma following at least 1 prior therapy, based on findings from the phase III CASTOR and POLLUX studies.

CASTOR

At the recent ASH meeting, CASTOR and POLLUX updates were presented, respectively, by Maria-Victoria Mateos, MD, PhD, consultant physician, hematology department, Hospital Universitario de Salamanca, and Saad Z. Usmani, MD, Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System.The CASTOR study randomized 498 patients with relapsed or refractory multiple myeloma to bortezomib and dexamethasone alone (n = 247) or with daratumumab (n = 251). Patients had received a median of 2 prior lines of therapy. Overall, 66% had received prior bortezomib, 76% received a prior immunomodulatory drug (IMiD), and 48% had received prior proteasome inhibitors and IMiD. The median age was 64 years (range, 30-88).

Patients were randomized 1:1 to receive 8 cycles of bortezomib/dexamethasone with or without 16 mg/kg of daratumumab. Bortezomib was administered subcutaneously at 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21-day cycle for a maximum of 8 cycles. Patients received 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of the first 8 bortezomib treatment cycles. Patients in the daratumumab group were administered an IV infusion of the antibody at 16 mg/kg weekly for the first 3 cycles, on day 1 of cycles 4 to 9, and then every 4 weeks. Treatment was administered until disease progression or unacceptable toxicity.

In the primary analysis, the 12-month progression-free survival (PFS) rate was 60.7% with daratumumab, bortezomib, and dexamethasone versus 26.9% for bortezomib and dexamethasone alone. After a median follow-up of 7.4 months, the median PFS was not reached in the daratumumab arm compared with 7.2 months in the control group (HR, 0.39; 95% CI, 0.28-0.53; P <.0001).

The overall response rate (ORR) with the addition of daratumumab was 82.9% compared with 63.2% in the control group (P <.001). The very good partial response (VGPR) or better rate was 59.2% with daratumumab versus 29.1% in the control arm (P <.001). The complete response (CR) rate was 19.2% with daratumumab versus 9.0% with the doublet (P = .001).

The median follow-up for the data Mateos presented at ASH was 13 months (range, 0-21.3). The 12-month PFS was 60% in the daratumumab arm versus 22% in the control arm.

“The progression-free survival benefit continues to be maintained for daratumumab in combination with bortezomib and dexamethasone over time. More patients in the [daratumumab arm] achieved deeper responses with longer follow-up,” said Mateos.

The ORR was 84% in the daratumumab arm, including a 7% stringent CR (sCR) rate, 19% CR rate, 35% VGPR rate, and 22% PR rate. The ORR in the bortezomib/dexamethasone arm was 63%, comprising an sCR rate of 2%, CR rate of 8%, VGPR rate of 19%, and partial response (PR) rate of 34%.

The PFS benefit was sustained regardless of the number of prior lines of treatment. Among patients who had 1 prior line of treatment, the 12-month PFS rate was 77% in the daratumumab arm versus 25% in the control arm (HR, 0.22; 95% CI, 0.14-0.34; P <.0001). The ORR rates were 91% versus 74%, respectively (P = .0014).

In the group of patients who had received 2 to 3 prior lines of therapy, the 12-month PFS rate was 44% for the daratumumab cohort versus 22% for the control arm (HR, 0.51; 95% CI, 0.36-0.73; P = .0002). The ORR rates were 79% versus 58%, respectively (P = .0022).

Additionally, Mateos said, “MRD negative rates for daratumumab plus bortezomib/dexamethasone were more than 3-fold higher across all sensitivity thresholds in comparison with bortezomib/dexamethasone alone.”

Daratumumab plus bortezomib/dexamethasone also improved outcomes regardless of cytogenetic risk. Among high-risk patients, the median PFS was 11.2 months in the daratumumab arm versus 7.2 months in the control arm (HR, 0.49; 95% CI, 0.27-0.89; P = .0167). The ORR rates were 82% versus 62%, respectively (P = .039).

Among standard-risk patients, the median PFS was not yet reached in the daratumumab arm and was 7 months in the bortezomib/dexamethasone group (HR, 0.29; 95% CI, 0.20-0.43; P <.0001). The ORR rates were 85% versus 64%, respectively (P = .0003).

Mateos reported that the overall survival data are not yet mature, but that the curves are beginning to separate.

There were no new safety signals with longer term follow-up. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported for 79% of the daratumumab arm versus 63% of the control arm. Discontinuations related to TEAEs occurred in 9% of patients in each arm. The rate of infusion related reactions remained stable with longer follow-up at 45%.

POLLUX

“These data further support the use of this newly approved regimen of daratumumab plus bortezomib/dexamethasone in relapsed/refractory multiple myeloma,” said Mateos.The international, open-label POLLUX trial randomized 569 patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide/dexamethasone (n = 286) or lenalidomide plus dexamethasone alone (n = 283). Patients characteristics were well balanced between the study arms. The median age across the trial was 65 years and the median number of prior treatment lines for each cohort was 1.

Daratumumab was dosed at 16 mg/kg IV once weekly during cycles 1 and 2, every 2 weeks during cycles 3 to 6, and once only (on day 1) of cycles 7 onward. Oral lenalidomide was administered at 25 mg daily for the first 3 weeks of each cycle and dexamethasone was dosed at 40 mg weekly (20 mg weekly in patients older than 75 or with a BMI <8.5). Treatment cycles for both study arms were 28 days. Patients were treated until progression or unacceptable toxicity.

The primary analysis occurred at a median follow-up of 13.5 months. The median PFS was not yet reached in the daratumumab arm versus 18.4 months with lenalidomide/dexamethasone alone (HR, 0.37; 95% CI, 0.27-0.52; P <.001). The ORR was 92.9% versus 76.4%, respectively (P <.001). The VGPR or better rate was 75.8% with daratumumab versus 44.2% in the control arm (P <.001) and the CR rates were 43.1% and 19.2%, respectively (P <.001).

At ASH, Usmani reported updated efficacy results observed after a median follow-up of 17.3 months (range, 0-24.5 months). The median PFS was still not reached in the daratumumab arm versus 17.5 months in the lenalidomide/dexamethasone arm (HR, 0.37; 95% CI, 0.28-0.50; P <.0001).

“Daratumumab plus lenalidomide and dexamethasone significantly improves outcomes for patients with myeloma in this early relapse setting,” said Usmani.

The ORR was 93% in the daratumumab arm, comprising an sCR rate of 23%, a CR rate of 23%, a VGPR rate of 32%, and a PR rate of 15%. In the control arm, the ORR was 76%, comprising an sCR rate of 8%, a CR rate of 12%, a VGPR rate of 25%, and PR rate of 32%.

“Responses continued to deepen in the daratumumab plus lenalidomide and dexamethasone arm with longer follow-up,” said Usmani.

He added that the daratumumab arm had a higher depth of response when measuring MRD negativity, and that MRD negative status was associated with improved outcomes.

The daratumumab regimen also had superior efficacy regardless of the time between last line of therapy and start of study treatment. In patients who received their last therapy within the previous 12 months, the 18-month PFS rate was 70% in the daratumumab arm versus 37% in the control arm (HR, 0.38; 95% CI, 0.26-0.55; P <.0001). In patients whose last treatment was more than 12 months ago, the 18-month PFS rate was 83% versus 60%, respectively (HR, 0.37; 95% CI, 0.23-0.61; P <.0001).

Patients who were refractory to their last line of therapy had an 18-month PFS rate of 65% with daratumumab versus 36% with lenalidomide/dexamethasone alone (HR, 0.47; 95% CI, 0.29-0.76; P = .0015). The ORR in these patients was 87% versus 64%, respectively (P = .0011).

Outcomes were better with daratumumab regardless of cytogenetic risk. Among standard-risk patients, the median PFS was not reached in the daratumumab arm versus 17.1 months in the control arm (HR, 0.30; 95% CI, 0.18-0.49; P <.0001). The ORR was 95% versus 82%, respectively (P = .0020).

In the high-risk group, the median PFS was not reached in the daratumumab arm versus 10.2 months in the lenalidomide/dexamethasone arm (HR, 0.44; 95% CI, 0.19-1.03; P = .0475.) The ORR rates were 85% versus 67%, respectively.

Usmani suggested that the fact that the median PFS had not yet been reached with daratumumab in the high-risk group may differentiate the POLLUX regimen from the CASTOR regimen. “It does appear that daratumumab plus lenalidomide and dexamethasone is improving the poor prognostication that is conferred by high-risk cytogenetics.”

The overall survival data are not yet mature, although the curves are beginning to separate, Usmani noted.

Regarding safety, Usmani said, “We do not see any new safety signals. The data are very consistent with the data that have already have already been published.”

References

1. Mateos M-V, Estell J, Barreto W, et al. Efficacy of daratumumab, bortezomib, and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory myeloma based on prior lines of therapy: updated analysis of CASTOR. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 1150.
2. Usmani SZ, Dimopoulos M, Belch A, et al. Efficacy of daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma patients with 1 to 3 prior lines of therapy: updated analysis of POLLUX. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 1151.