Daratumumab plus carfilzomib and dexamethasone for patients with RRMM

Nearly all patients with multiple myeloma (MM) relapse, despite the introduction of novel compounds improving clinical outcomes. Lenalidomide use as first-line or early maintenance therapy after autologous stem cell transplantation (ASCT), has highlighted the need for effective treatments in lenalidomide-refractory RRMM.

Ajai Chari, from the Tisch Cancer Institute, Mount Sinai School of Medicine, New York, US, and colleagues, conducted a phase Ib study (NCT 01998971) evaluating the use of daratumumab plus carfilzomib with dexamethasone (D-Kd) in patients with RRMM after 1−3 lines of therapy.

The primary endpoints of the study were safety and tolerability of D-Kd. Secondary endpoints included overall survival (OS) and overall response rate (ORR), and exploratory endpoints investigated were progression-free survival (PFS), minimal residual disease (MRD), and pharmacokinetics.

Patient characteristics

Of all patients treated, 62 (73%) had prior ASCT, with 33 (65%) of patients in the lenalidomide refractory arm previously undergoing ASCT. From all enrolled patients, 26 (31%) were refractory to bortezomib, and 21 (41%) of patients in the lenalidomide arm were also refractory to botezomib. 29% of patients were refractory to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD), with 43% of lenalidomide-refractory patients were also refractory to PI and IMiD.

Methods

• Patients treated in 28-day cycles (cycle 1 was 29 days)
• IV daratumumab, 16mg/kg:
  • Weekly during cycles 1 and 2 (days 1, 8, 15, and 22)
  • Fortnightly during cycles 3−6 (days 1 and 15)
  • Every four weeks thereafter
  • Ten patients received a single first dose on cycle 1, day 1. The remaining patients received split doses: 8mg/kg on days 1 and 2, to collect safety and pharmacokinetic data
• Carfilzomib, 30-minute infusion weekly, on days 1, 8, and 15 of each cycle (prior to daratumumab on days when both were administered
  • Initial dose of 20mg/m², escalated to 70mg/m² if deemed tolerable
• Dexamethasone, 40mg (20mg if aged >75 years) per week as a single dose
  • On days of infusion, 20mg was administered before and after

Key findings

• Median follow-up was 16.6 months (range, 0.5−4) overall and 16.4 months (range 0.5−27.2) for the lenalidomide-refractory cohort
• ORR at median follow-up:
  • 84%, with 33% response of CR or better
  • Lenalidomide-refractory cohort: 79%, with 29% response of CR or better
  • Bortezomib-refractory cohort: 84%, with 20% response of CR or better
• VGPR, at median follow-up:
  • 71% VGPR or better
  • Lenalidomide-refractory cohort: 69% VGPR
• OS at 12 months:
  • 82% for all treated patients
  • Refractory subgroups (Lenalidomide, immunomodulatory drug (IMiD)/proteasome inhibitor (PI), bortezomib): 75%
• Median PFS not reached:
  • 12- and 18-month PFS 74% and 66% respectively
  • Lenalidomide-refractory 12- and 18-month PFS were 65% and 56% respectively

Table 2: A total of 45% of patients discontinued treatment

Table 3: Grade III/IV AEs experienced by >20% of patients

Table 4: Other treatment-emergent adverse events (TEAEs) experienced by >20% of patients at any grade

Conclusion

The study found that the combination of daratumumab and weekly Kd showed efficacy in patients with RRMM, inducing a deep and durable response, regardless of prior lenalidomide exposure. The combination was also well-tolerated. No new safety signals were shown for D-Kd, with low neutropenia rates being observed. As the need for novel or combination therapies continues to rise, daratumumab-based regimens will continue to be clinically investigated.