Dara-Rd for patients with NDMM ineligible for transplant: 5-year follow-up of the MAIA trial

Current frontline treatment with lenalidomide and dexamethasone is unable to produce durable responses in patients with newly diagnosed multiple myeloma (NDMM). There is a need for more effective agents at the time of diagnosis for patients who are ineligible for autologous stem cell transplant or high-dose chemotherapy, who have limited treatment options if relapse occurs.  

The primary analysis of the phase III MAIA trial (NCT02252172) demonstrated improved survival outcomes when daratumumab, an anti-CD38 monoclonal antibody, was combined with lenalidomide and dexamethasone (Dara-Rd) as a frontline therapy compared with Rd alone. However, longer follow-up was needed to see if the advantage in progression-free survival (PFS) also translated into a prolonged overall survival (OS).^1,2 At the 26th Congress of the European Hematology Association (EHA), Thierry Falcon presented updated efficacy and safety results from this comparative study after almost 5 years of median follow-up.¹ We summarize the key findings below.

Study design

• This was a phase III, multicenter, randomized, open-label study, which enrolled patients with NDMM who were ineligible for autologous stem cell transplant or high-dose chemotherapy, due to an age of ≥65 years or comorbidities.
• Primary objective: To compare 5-year PFS between patients treated with Dara-Rd and Rd alone.
• Key secondary objectives: OS, overall response rate, minimal residual disease, and safety.
• Treatment cycle (28 days):
  • Dara-Rd:
    • Oral lenalidomide (25 mg on Days 1–21) and oral dexamethasone (40 mg on Days 1, 8, 15, and 22) until disease progression.
    • Intravenous daratumumab (16 mg/kg once weekly during Cycles 1 and 2, then every 2 weeks during Cycles 3–6, and every 4 weeks thereafter.
  • Rd:
    • Oral lenalidomide (25 mg on Days 1–21) and oral dexamethasone (40 mg on Days 1, 8, 15, and 22)

Results

Patient characteristics

Patient characteristics (n = 732) are summarized in Table 1.

Table 1. Patient characteristics*

Dara-Rd, daratumumab + lenalidomide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; Rd, lenalidomide + dexamethasone. *Data from Facon et al.2
Characteristic	Dara-Rd (n = 368)	Rd (n = 369)
Median age, years (range)	73 (50–90)	74 (45–89)
Female, n (%)	179 (49.3)	174 (47.2)
ECOG performance status, n (%)
0	127 (34.5)	123 (33.3)
1	178 (48.4)	187 (50.7)
≥2	63 (17.1)	59 (16.0)
ISS disease stage, n (%)
I	98 (26.6)	103 (27.9)
II	163 (44.3)	156 (42.3)
III	107 (29.1)	110 (29.8)
Cytogenetic risk, %
Standard risk	85.0	86.4
High risk	15.0	13.6

Primary endpoint

• After a median follow-up of 56.2 months, median PFS was still not reached for Dara-Rd vs 34.4 months for Rd alone.
• The 5-year PFS was 52.5% with Dara-Rd and 28.7% with Rd, with 47% reduction in the risk of progression or death (HR, 0.53; 95% CI, 0.43–0.66; p < 0.0001).

Secondary endpoints

• The 5-year OS rate was 66.3% with Dara-Rd vs 53.1% with Rd alone, representing a significant 32% reduction in the risk of death (HR, 0.68; 95% CI, 0.53–0.86; p = 0.0013).
  • Subgroup analysis, summarized in Table 2, shows a consistent OS benefit with Dara-Rd across patient subgroups.

Table 2. Subgroup analysis comparing survival outcomes between Dara-Rd and Rd treatment*

CI, confidence interval; Dara-Rd, daratumumab + lenalidomide + dexamethasone; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; ISS, International Staging System; Rd, lenalidomide + dexamethasone. *Data from Facon et al.1
	Number of deaths
	Dara-Rd	Rd	HR (95% CI)
Sex, n/total n
Male	71/189	88/195	0.78 (0.57–1.06)
Female	46/179	68/174	0.58 (0.40–0.84)
ECOG performance status, n/total n
0	24/127	36/123	0.61 (0.36–1.02)
1	64/178	82/187	0.74 (0.53–1.03)
≥2	29/63	38/59	0.57 (0.35–0.94)
ISS disease stage, n/total n
I	19/98	24/103	0.79 (0.43–1.44)
II	50/163	69/156	0.61 (0.42–0.88)
III	48/107	63/110	0.72 (0.49–1.04)
Cytogenetic risk, n/total n
Standard risk	25/48	26/44	0.64 (0.48–0.85)
High risk	80/271	116/279	0.80 (0.46–1.39)

• The updated overall response rate was 92.9% with Dara-Rd vs 81.3% with Rd (p < 0.001).² Read our previous article for more detailed information on patients achieving and maintaining a negative minimal residual disease with daratumumab.
• In terms of safety, there were a lower number of Grade 3/4 adverse events (AEs) observed following 24 months for both treatment cohorts.
  • The most common hematological Grade 3/4 AE was neutropenia, found in 54% of patients treated with Dara-Rd and 37% of patients treated with Rd alone.
  • The most common non-hematological Grade 3/4 AEs were pneumonia, (19% of patients in the Dara-Rd arm; 11% of patients in the Rd arm), hypokalemia (13% of patients in the Dara-Rd arm; 10% of patients in the Rd arm), and cataract (11% of patients in both treatment arms).

Conclusion

Overall, these data provide strong support for the use of daratumumab as part of frontline therapy for NDMM in elderly patients or those with comorbidities who are ineligible for transplant or high-dose chemotherapy. Importantly, Falcon highlighted a clinically significant improvement in 5-year OS with Dara-Rd versus Rd alone, with a 32% reduction in the risk of death. The primary endpoint was also met, with a significant benefit for PFS with the addition of daratumumab maintained from the primary analysis. Finally, a favorable safety profile with similar, lower rates of AEs between both treatments was observed after longer follow-up.