IMiD-Free Triplet Leads to Prolonged PFS in Relapsed/Refractory Myeloma

Saad Z. Usmani, MD, FACP

Findings from the phase III CANDOR trial have defined a new triplet option for patients with relapsed/refractory multiple myeloma, especially for those with lenalidomide (Revlimid)-exposed or -refractory disease, explained lead study author Saad Z. Usmani, MD, FACP.

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

The addition of the anti-CD38 antibody reduced the risk of disease progression or death by 37%, according to data presented at the 2019 ASH Annual Meeting. At a median follow-up of 17 months, the median progression-free survival (PFS) was not yet reached in the KdD arm versus 15.8 months with Kd alone (HR, 0.63; 95% CI, 0.464-0.854; P = .0014). Furthermore, the median overall survival (OS) had yet to be reached in either arm (HR, 0.75; 95% CI, 0.49-1.13; P = .08).

Among the study population, 42.3% had received prior lenalidomide, and 33% of patients were lenalidomide-refractory. Notably, the median PFS with KdD was not reached in either lenalidomide-exposed patients (HR, 0.52; 95% CI, 0.34-0.80) or lenalidomide-refractory patients (HR, 0.45; 95% CI, 0.28-0.74).

Regarding safety, the rates of grade ≥3 adverse events (AEs) were higher in the KdD arm versus the Kd arm. There were 5 treatment-related deaths, all occurring in the KdD arm. However, the treatment-related discontinuation rates were comparable between the arms at 22.4% and 24.8%, respectively.

“These data give us another important triplet option for patients with relapsed/refractory myeloma. For lenalidomide-exposed and -refractory patients, this is an important regimen,” said Usmani. “This was a definitive, regulatory phase III trial, which will hopefully lead to the approval of the 3-drug regimen for use in the United States.”

In an interview with OncLive, Usmani, chief of Plasma Cell Disorders and director of Clinical Research in Hematologic Malignancies at Levine Cancer Institute, Atrium Health, discussed the results of the CANDOR trial and the impact of these data on clinical practice in multiple myeloma.

OncLive: Could you provide background on the CANDOR trial?

Usmani: We've seen that the addition of daratumumab to other approved combinations improves patient outcomes. Each phase III trial [we’ve seen with daratumumab] has read out favorably. The phase III ALCYONE study compared the addition of daratumumab to bortezomib (Velcade), melphalan, and prednisone (VMP) with VMP alone. At the 2019 ASH Annual Meeting, we saw an OS benefit with the addition of daratumumab at 36 months. Additionally, based on the data from the phase III ENDEAVOR trial, we know carfilzomib and dexamethasone appears to be better than bortezomib and dexamethasone. As such, we wanted to develop another immunomodulatory (IMiD) drug—free regimen for patients who received 1 to 3 prior lines of therapy.

Patients in the United States who are progressing on lenalidomide maintenance don't have many triplet options. All of the approved therapies we have in that setting are combinations with lenalidomide, such as carfilzomib, lenalidomide, and dexamethasone (KRd); elotuzumab (Empliciti) and Rd; and ixazomib (Ninlaro) and Rd. When patients have had previous exposure to lenalidomide or are progressing on lenalidomide, we don’t have many options because those patients were not included in those randomized trials.

In the phase Ib EQUULEUS (MMY1001) study, daratumumab was evaluated in combination [with a number of regimens, including] weekly carfilzomib. The trial enrolled more than 100 patients, and almost all of those patients [had been] exposed or refractory to lenalidomide. We saw a high response rate and [an encouraging median PFS]. [Based on these data], there was good rationale to proceed with the phase III CANDOR trial.

What was the design of the trial, and what were the findings that you presented at the 2019 ASH Annual Meeting?

We enrolled 466 patients on the trial. Patients were randomized 2:1 to receive either KdD or Kd alone. Specifically, 312 patients were randomized to the KdD arm and the rest were assigned to Kd. Treatment was continued until relapse, progression, or intolerance. Medium PFS was the primary endpoint of the study. About 90% of patients had been exposed to bortezomib, 42% had been exposed to lenalidomide, and 33% were refractory to lenalidomide. Other endpoints of the trial included OS, overall response rates (ORR), and minimal residual disease (MRD) negative—complete response (CR) rates at 12 months, [among others]. After a median follow-up of 17 months, the median PFS with KdD wasn’t reached versus 15.8 months with Kd. The ORR was 84% versus 74% with KdD and Kd, respectively. At 12 months, the MRD-negative CR rates were 12.5% and 1.3% with KdD and Kd, respectively. We didn’t see a difference in OS.

In terms of safety, higher rates of grade 3 AEs were observed on the 3-drug arm compared with the 2-drug arm. Most of these AEs were related to infection. Five treatment-emergent grade 5 events were reported on the KdD arm versus 0 on the Kd arm. Of the 5 events, 4 were infection related. Interestingly, the grade ≥2 cardio failure rate appeared to be lower in the KdD arm compared with the Kd arm.

We also had prespecified subset analyses for lenalidomide-exposed and -refractory patients; in the Kd arm, the median PFS was 12 months and 11 months, respectively. The median PFS had not been reached in the 3-drug arm.

Could you elaborate on the MRD analysis?

MRD was studied a little differently in this trial. The analysis was done as a landmark analysis at 12 months. We’ll have additional follow-up data to see whether MRD was sustained or not. For the analysis, we stuck to the stringent International Myeloma Working Group guidelines. We reported on MRD-negative CR rates, which means we weren’t checking MRD unless the patient was in a CR. With subsequent follow-up, serial MRD assessments will be an important benchmark to follow for future studies.

How are these data going to impact clinical practice?

From a practical standpoint, it's very likely that community physicians may follow the weekly schedule that was studied in the phase I trials rather than this particular schedule for patient convenience. Given the rate of infection, the use of Immunoglobulin G [antibodies] and prophylactic antibiotics for the older, more frail patients may be an issue we have to consider from a supportive care standpoint.

At the 2019 ASH Annual Meeting, many of us raised concerns about coming up with some sort of an algorithm to identify patients who are at high risk for recurring infections. Maybe we should be giving [these patients] prophylactic [agents]. We need to do a better job of identifying those who need [them].

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). Blood. 2019;134(suppl_2; abstr LBA-6). doi: 10.1182/blood-2019-132629.