Final analysis from phase III CANDOR trial in adult patients with RRMM

Survival outcomes in patients with multiple myeloma (MM) have improved significantly due to novel agents such as monoclonal antibodies and immunomodulatory drugs. Despite these improvements, MM remains generally incurable.¹ Currently, lenalidomide is one of the most common front-line therapies administered to patients. However, lenalidomide is often administered until disease progression, resulting in patients becoming refractory to the therapy.¹ The need for alternative treatment strategies is important in ensuring optimal clinical outcomes for these patients.

The phase III CANDOR trial (NCT03158688) investigated the efficacy of carfilzomib + daratumumab + dexamethasone (KdD) versus carfilzomib + dexamethasone (Kd) in adult patients with relapsed or refractory (R/R) MM. The primary analysis reported that the trial met its primary endpoint of progression-free survival (PFS). The interim analysis demonstrated that the KdD regime continued to show higher median PFS. Recently, Usmani et al. published the final analysis of the CANDOR trial in Blood Advances with updated safety and efficacy data.¹ We summarize the key findings here.

Study design

This was a randomized, multicenter, open-label, phase III trial in patients aged ≥18 years with RRMM, who had an Eastern Cooperative Oncology Group performance status of 0–2 and had received 1–3 prior lines of therapy. Baseline patient characteristics have previously been reported by the MM Hub. The dosing schedule is highlighted in Figure 1.

Pre-defined patient subgroups included in the analysis were based on the number of prior therapies, as well as exposure and/or refractory to protease inhibitors or immunomodulatory drugs including lenalidomide.

IV, intravenous; Kd, carfilzomib + dexamethasone; KdD, carfilzomib + daratumumab + dexamethasone.
*Adapted from Usmani, et al.¹
†Randomization was stratified based on the international staging system at screening, previous protease inhibitor exposure, number of previous lines of therapy, and previous anti-CD38 monoclonal antibody therapy.

The primary endpoint was PFS, defined as the time from randomization until disease progression or death from any cause. Disease progression was assessed every 28 ± 7 days based on the International Myeloma Working Group criteria. The key secondary endpoints included overall response rate and minimal residual disease (MRD) negativity.

Results

Efficacy

A total of 466 patients were included: 312 in the KdD and 154 in the Kd arm. The median follow-up times were 50.6 and 50.1 months in the KdD and Kd arms, respectively.

• The rates of MRD negativity at 12 months was three-fold higher in patients in the KdD versus the Kd arm (Figure 2).

• Median PFS was higher in the KdD arm compared with the Kd arm (28.4 vs 15.2 months; hazard ratio [HR], 0.64).
• Median overall survival was 50.8 versus 43.6 months in the KdD and Kd arms, respectively (HR, 0.78; p = 0.042).
• There was a trend towards improved overall survival in the KdD versus the Kd arm in several patient subgroups, including:
  • Patients refractory to lenalidomide (not reached vs 38.2 months; HR, 0.69)
  • Patients refractory to proteasome inhibitor (43.2 vs 30 months; HR, 0.70)
  • Patients in KdD arm with high-risk cytogenetics (HR, 0.52) and International Staging System III at screening (HR, 0.58) showed a significant improvement in overall survival.
• The median time to next treatment was higher in the KdD arm compared with the Kd arm (37.4 vs 17.8 months).

CR, complete response; Kd, carfilzomib + dexamethasone; kdD, carfilzomib + daratumumab + dexamethasone; MRD–, measurable residual disease negative.
*Adapted from Usmani, et al.¹

Safety

• Safety outcomes were comparable across treatment arms (Table 1) and were consistent with the outcomes of previous analyses.

Table 1. Treatment-emergent adverse events*

Kd, carfilzomib + dexamethasone; KdD, carfilzomib + daratumumab + dexamethasone; TEAE, treatment-emergent adverse event. *Adapted from Usmani, et al.1
TEAE, (% unless otherwise stated)	KdD (n = 312)	Kd (n = 154)
Any-grade TEAE	99	97
Grade ≥3 TEAE	87	78
Serious TEAE	68	52
Fatal TEAE	11	6
Study discontinuations due to TEAE	34	27

• The most frequently experienced hematologic and non-hematologic treatment-emergent adverse events of any grade are shown in Figure 3.
• Since the primary analysis, no new fatal treatment-related adverse events were reported.

Kd, carfilzomib + dexamethasone; KdD, carfilzomib + daratumumab + dexamethasone; TEAE, treatment-emergent adverse event.
*Adapted from Usmani, et al.¹

Conclusion

The final analysis of the CANDOR trial shows a significantly improved PFS as well as a trend towards improved overall survival in patients treated with KdD. Patients in the KdD arm also showed a consistently higher rate of MRD negativity compared with those in the Kd arm. Overall, the favorable risk-benefit profile of KdD regimen strengthens the rationale for its use as standard of care, particularly in patients who are refractory to lenalidomide or have high-risk cytogenetics.

However, the results of this trial should be interpreted in the context of certain limitations. Firstly, assessment of outcomes was challenging due to the small proportion of patients aged ≥75 years. Furthermore, there were many patients with unknown cytogenetics, which also made it difficult to assess clinical outcomes.