Long-term follow-up from POLLUX | Daratumumab in combination with lenalidomide and dexamethasone for relapsed or refractory multiple myeloma

The phase III POLLUX (NCT02076009) study, comparing the efficacy of lenalidomide and dexamethasone (Rd) to that of Rd combined with daratumumab (DRd), has uncovered the promising clinical activity of DRd in patients with relapsed or refractory (R/R) multiple myeloma (MM; RRMM). Combination of the anti-CD38 monoclonal antibody, daratumumab, with the Rd regimen demonstrated favorable progression free survival (PFS) and overall response rates (ORR) in RRMM.¹ In September 2018, the MM Hub reported the interim results from POLLUX study, which highlighted the potential of DRd. Nizar J Bahlis, Charbonneau Cancer Research Institute, University of Calgary, Calgary, CA, and colleagues recently published results from a long-term efficacy and safety analysis of POLLUX after a median follow-up of more than 3.5 years.²

Study overview²

• Adult patients with RRMM (N = 569) were randomly assigned (1:1) to receive:
  • Rd (n = 286)
    • Lenalidomide (orally): 25 mg on Days 1–21 of each 28-day cycle
    • Dexamethasone (orally): 40 mg weekly
  • DRd (n = 283)
    • Rd, as above
    • Daratumumab (intravenously): 16 mg/kg weekly for 8 weeks, every 2 weeks for 16 weeks, and every 4 weeks thereafter until progression
  • Values are henceforth given as DRd vs Rd
  • Patient characteristics¹:
    • Median age: 65 years in both arms
    • Median time from diagnosis: 3.48 years vs 3.95 years
    • Patients who were refractory to last line of therapy: 28.0% vs 26.9%
    • Patients who had received prior autologous stem cell transplantation: 62.9% vs 63.6%
    • 52% of patients had received one prior therapy, 18% had received prior lenalidomide, and 21% were refractory to bortezomib (in both arms)
  • Primary endpoint: PFS
  • Secondary endpoints: ORR, rates of ≥ very good partial response (VGPR) and ≥ complete response (CR), minimal residual disease (MRD), time to response, duration of response (DoR), and overall survival (OS)
  • Exploratory endpoint: PFS on subsequent line of therapy (PFS2)
  • Subgroup analysis was conducted by prior lines of therapy (1 and 1–3), prior lenalidomide treatment, refractoriness to bortezomib, and achievement of ≥ CR

Results²

Efficacy

• The median follow-up time was 44.3 (0–50.9) months
• DRd led to improved median PFS rates compared to Rd in the intention to treat (ITT) population and in subgroup analysis, as shown in Table 1
• Median ORR in the response evaluable population (n: 281 vs 276): 92.9% vs 76.4% (p < 0.0001)
  • ≥ VGPR: 80.4% vs 49.3% (p < 0.0001)
  • ≥ CR: 56.6% vs 23.2% (p < 0.0001)
• Median DoR: not reached (NR) vs 25.2 (95% CI, 19.3–29.7) months
• Median time to next therapy: 50.6 months vs 23.1 months (hazard ratio [HR] = 0.39; 95% CI, 0.31–0.50; p < 0.0001)
• Median PFS2: NR vs 31.7 months (HR = 0.53; 95% CI, 0.42–0.68; p< 0.0001)
• Deaths (n): 104 vs 121
• Median OS: NR in either arm
  • Forty-two-month OS rates: 65% vs 57%
• Patients in the ITT population who were MRD negative at a threshold of 10^-5 (p < 0.0001): 30.4% vs 5.3%

Table 1. Median PFS by subgroup²

HR, hazard ratio; ITT, intention to treat; MRD, minimal residual disease; NE, not estimable; NR, not reached; PFS, progression-free survival
Median PFS, months	DRd	Rd	HR (95% CI)	p value
ITT population n: 286 vs 283	44.5	17.5	0.44 (0.35–0.55)	< 0.0001
One prior therapy n: 149 vs 146	NR	19.6	0.42 (0.30–0.58)	< 0.0001
One–three prior therapies n: 272 vs 264	44.5	17.5	0.43 (0.34–0.54)	< 0.0001
Prior lenalidomide therapy n: 50 vs 50	38.8	18.6	0.38 (0.21–0.66)	0.0004
Refractory to bortezomib n: 59 vs 58	34.3	11.3	0.40 (0.24–0.67)	0.0003
MRD negative	NR	42.0	0.46 (0.19–1.08)	0.0667
MRD positive	29.4	16.0	0.60 (0.48–0.76)	< 0.0001

• Subgroup analysis:
  • Forty-two-month PFS rates in patients that had received one prior line of therapy: 57.3% vs 27.8%
  • PFS was prolonged in 159 vs 64 patients who achieved ≥ CR
    • Forty-two-month PFS rates: 73.6% vs 59.6%
  • Among patients receiving prior lenalidomide therapy, ORR: 84.0% vs 64.0% (p = 0.0233)
    • ≥ VGPR: 80.0% vs 36.0% (p < 0.0001)
    • ≥ CR: 54.0% vs 12.0% (p < 0.0001)

Safety²

• No new safety concerns were reported at this long-term follow-up
• Neutropenia was the most frequent treatment-emergent adverse event (TEAE) and was more common in the DRd arm: 63.3% vs 48.0%
• Patients who experienced TEAEs leading to treatment discontinuation: 14.8% vs 14.5%.
• Second primary malignancies occurred in 8.5% vs 8.9% of patients

Conclusion²

DRd significantly prolonged PFS compared to Rd in all patient subgroups, while demonstrating a 56% reduction in the risk of disease progression or death at the 3.5-year follow-up. The greatest clinical benefit of DRd was observed in patients that had received one prior line of therapy, supporting the use of DRd in patients with RRMM after first relapse. The safety profile of DRd remains as described in the 2018 analysis with no additional concerns, and DRd continues to produce favorable clinical outcomes in patients with RRMM.

Whilst the POLLUX study is comparing the Rd regimen to DRd, the phase III CASTOR study is comparing bortezomib and dexamethasone (Vd) to daratumumab and Vd (DVd). The MM Hub recently covered an age subgroup analysis from both trials, which is available here.