Final analysis of phase III FIRST trial in transplant-ineligible patients

The FIRST clinical trial investigated the survival outcomes in transplant-ineligible Newly Diagnosed Multiple Myeloma (NDMM) patients (pts) treated with lenalidomide and low-dose dexamethasone (Rd) until disease progression (Rd continuous), Rd for a fixed duration of 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). An updated and final analysis of this trial with a median follow-up of 45.5 months was analyzed by Thierry Facon from Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France, and colleagues, and published in Blood in January 2018. To see details of the trial set-up, see previously published MM Hub article.

Key Findings:

• N = 1623 pts: Rd continuous (n = 535), Rd18 (n = 541) and MPT (n = 547)
• Final data cutoff: 21 January 2016
• Median duration of follow-up for surviving pts = 67 months (0–86.8)
• Study discontinuation mainly due to disease progression: Rd18 (67%), MPT (62%) arms and Rd continuous arm (51%)
• Significant increase in PFS with Rd continuous vs MPT: HR = 0.69 (95%CI, 0.59-0.79); P < 0.00001
• Rd continuous vs Rd18 vs MPT:
  • Median PFS = 26.0 vs 21.0 vs 21.9 months
  • 4-year PFS rate = 32.6% vs 14.3% vs 13.6%
• Prolonged PFS in Rd continuous in comparison to Rd18 and MPT in pts with non-high-risk cytogenetics
• Higher PFS benefit for pts who achieved CR or VGPR with Rd continuous vs Rd18 (HR = 0.52; 95% CI, 0.40–0.66) and Rd continuous vs MPT (HR = 0.47; 95% CI, 0.38–0.59)
• CR for Rd continuous vs Rd18 vs MPT: Median PFS = not reached vs 41.0 vs 37.6 months
• Good responders (VGPR or CR) benefited from Rd continuous treatment
• Rd continuous vs Rd18 vs MPT: ≥ VGPR = 79% vs 70% vs 53%
• No of deaths at a median follow-up of 5.6 years (yrs): Rd continuous =286 pts; Rd18 =283 pts; MPT =337 pts
• Rd continuous vs Rd18 vs MPT:
  • Median OS = 59.1 vs 62.3 vs 49.1 months
  • Median time to next antimyeloma treatment (TNTT) = 36.7 vs 28.5 vs 26.7 months
  • In pts who achieved ≥ VGPR, median TNTT = 69.5 vs 39.9 vs 37.7 months
• Rd continuous vs MPT:
  • Median OS for pts achieving ≥ VGPR = 79.5 vs 55.7 months; HR = 0.63; (95% CI, 0.48–0.83)
  • ORR (≥ PR) = 81% vs 67%
• Higher-quality responses observed in pts treated with Rd continuous in comparison to MPT, in both the intention-to-treat (ITT) population and pts with standard-risk cytogenetics
• In regards to the second line therapy, 557 pts were treated with bortezomib-based regimens: Rd continuous arm: 179 (60%) pts; Rd18 arm: 208 (55%) pts; MPT arm: 170 (45%) pts
• ≥ VGPR more frequent in pts who received bortezomib as second-line therapy in the Rd continuous and Rd18 arms than in MPT arm

 Table 1. Median OS (in months) based on second-line treatment for each arm

• ≥ VGPR achieved in the majority of pts receiving long-term treatment with Rd continuous
  • Treated for > 18 months: 77%
  • Treated for ≥ 3 years: 86%
  • At data cutoff: 92%
• No new safety concerns compared with earlier analyses, as discussed in previous MM Hub article
  • Grade 3 or 4 neutropenia: MPT (45%), Rd continuous (30%), Rd18 (26%)
  • Hematologic secondary primary malignancy (SPM): MPT (3%); Rd continuous (1%); Rd18 (1%)

This study found that overall survival is prolonged in patients who have been treated with Rd continuous in comparison to MPT treated patients. It was also found that patients who were treated with bortezomib-based therapy after Rd continuous or Rd18, displayed better-quality responses to second-line treatment than those who were given bortezomib-based therapy after MPT. This supports the use of continuous lenalidomide-dexamethasone as an upfront therapy in transplant ineligible patients.