MAIA study: second interim analysis results

The combination of lenalidomide and dexamethasone (Rd) is commonly utilized as induction therapy for patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for autologous stem cell transplant (ASCT). Daratumumab is an anti-CD38 monoclonal antibody which has proven efficacy both as monotherapy (GEN501¹ and SIRIUS²) and in combination with other established regimens in both the frontline setting (ALCYONE ³) and the relapsed/refractory setting (CASTOR⁴ and POLLUX⁵).

The phase III MAIA study (NCT02252172) is investigating whether the addition of daratumumab to Rd (dara-Rd) as frontline therapy reduces the risk of progression or death in patients with NDMM who are not eligible for ASCT, compared to Rd alone.⁶

During the 60^th American Society of Hematology (ASH) meeting, the second interim results from the MAIA study were presented by Professor Thierry Facon.⁷ Subsequently, an approval request was submitted to the United States (U.S.) Food & Drug Administration (FDA) for the triplet combination based on these results, which was shortly followed by a submission to the European Medicines Agency (EMA).^8,9 The results of the second interim analysis were subsequently published in the New England Journal of Medicine and are summarized here at a median follow-up of 28 months.⁶

Study design and patient characteristics⁶

• Randomized, open-label phase III trial

• Patients with NDMM (N= 737) who were ineligible for ASCT (due to age [≥ 65 years] or the presence of coexisting conditions) were randomized 1:1 to:

  • Dara-Rd, n= 368

  • Rd, n= 369

  • Patient stratification was by International Staging System (ISS) stage disease, geographic region and age (< 75 vs ≥ 75 years)

• Treatment schedule per each 28-day cycle:

  • Lenalidomide (orally): 25mg on days 1–21

    • Dose reductions were recommended as follows:

      • Creatinine clearance of 30–50ml per minute: 10mg daily

      • Neutropenia and thrombocytopenia: interruption of treatment followed by the administration at the next lower dose

    • Dexamethasone (orally): 40mg on days one, eight, 15 and 22

      • Dose reduction to 20mg once weekly was recommended for patients ≥ 75 years old and those with a body mass index < 18.5

  • Daratumumab (intravenous): 16mg/kg once weekly in cycles one and two, every two weeks in Cycles 3–6 and every four weeks after cycle six

• Patient characteristics:

  • Median age: 73 years (45–90)

  • High-risk cytogenetics: 14.3%

  • Median time since diagnosis: 0.9 months (0–14.5)

• Treatment continued until disease progression (PD) or unacceptable side effects

• Primary endpoint: progression-free survival (PFS)

• Secondary endpoints included:

  • Time to progression (TTP)

  • Percentage of patients with a complete response (CR)

  • Stringent CR plus a normal free light-chain ratio and absence of clonal plasma cells

  • Negative status for minimal residual disease (MRD) assessment

  • Overall response

  • Very good partial response (VGPR) or better

  • Overall survival (OS)

  • Time to response

  • Duration of response

  • Efficacy by cytogenetic subgroup

  • Safety

Adherence to treatment⁶

Given as dara-Rd versus Rd

• Median treatment duration: 25.3 (0.1–40.4) vs 21.3 (0.03–40.6) months

• The median number of treatment cycles: 27 (1–44) vs  22 (1–43)

• More patients in the dara-Rd group had dose modifications of lenalidomide due to adverse events (AEs)

• Lenalidomide discontinuations: 20.9% vs 17 %

• In the dara-Rd group, 35 patients discontinued Rd therapy but continued to receive daratumumab monotherapy for an average of 7.3 months (0.03–31.2)

Efficacy⁶

• Efficacy analysis was conducted in the intention-to-treat (ITT) population (all randomized patients) and is summarized in Table 1

• Hazard ratio (HR) for PD or death with dara-Rd= 0.56 (95% CI, 0.43–0.73), p< 0.001

• PFS benefit observed in all subgroups including age, ISS stage disease, cytogenetic profile, race and geographic region

• Exception: those with hepatic impairment at baseline (HR= 1.08)

• The rates of MRD-negativity were three times higher in the dara-Rd group compared to Rd (Table 1)

• MRD-negativity was associated with prolonged PFS regardless of treatment arm

• All patients who were MRD-negative had CR or better

• OS was not reached (NR) in either arm, with follow-up ongoing

• Of the responding patients, 80.3% in the dara-Rd arm and 65.7% in the Rd arm sustained the response for 30 months

• The median time to CR or better: 10.4 vs 11.2 months

Table 1. Efficacy analysis in the ITT population

	Dara-Rd (n= 368)	Rd (n= 369)	p value
ORR, %	92.9	81.3	< 0.001
Best overall response
≥ CR, %	47.6	24.9	< 0.001
≥ VGPR, %	79.3	53.1	< 0.001
MRD status
Undetectable MRD*, %	24.2	7.3	< 0.001
Survival probability
PD or death, %	26.4	38.8	-
Deaths, %	16.8	20.6	-
Median OS, months	NR	NR	-
PFS probability, 30 months, %95% CI	70.6 65–75.4	55.6 49.5–61.3	-
Median PFS, months95% CI	NR	31.9 28.9–NR	-
* MRD measured as one tumor cell per 105 white cells. ORR; overall response rate

 

Safety⁶

Given as dara-Rd versus Rd

• Safety analysis was conducted in all patients who received ≥ one dose of study treatment (dara-Rd: 364, Rd: 365)

• Most common grade III/IV AEs occurring in > 10% of patients:

  • Neutropenia: 50% vs  35.3%

  • Anemia: 11.8% vs 19.7%

  • Lymphopenia: 15.1% vs 10.7%

  • Pneumonia: 13.7% vs 7.9%

• Infection:

  • Any grade infection: 86.3% vs 73.4%

  • Grade III/IV infection: 32.1% vs 23.3%

  • Discontinuation due to infection: 0.5% vs 1.4%

• Serious AE (SAE): 62.9% vs 6 2.7%

  • Most common: pneumonia 13.2% vs  7.4 %

• AE leading to discontinuation: 7.1% vs 15.9%

• AE leading to death: 6.9% vs 6.3 %

  • Most common: pneumonia 0.5% vs 0.8%

• Invasive secondary primary cancers: 3.3% vs 3.6%

• Infusion-related reactions (IRRs) related to daratumumab: 40.9%

  • Of these, 2.7% were grade III or IV

  • No grade V events

  • IRR led to discontinuation in one patient

Conclusion⁶

Patients with NDMM who are ineligible for ASCT had a 44% reduced risk of PD or death when treated with dara-Rd compared to Rd alone. Patients receiving dara-Rd had a longer PFS, higher response rate, increased the depth of response and longer duration of response compared to Rd.

Notably, in this trial, 99% of patients were aged 65 or older, and the PFS benefit was maintained regardless of age. The HR for PD or death in patients aged over 75 treated with dara-Rd was 0.63 reflecting a 37% reduction compared to Rd alone. However, regimen selection should be carefully considered in patients with hepatic impairment given the benefit in PFS was not observed in this population.