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US Food and Drug Administration and European Medicines Agency approvals sought for new combined drug regimens in multiple myeloma
During March 2019, several applications were filed with the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for potential new combined drug regimens in newly diagnosed multiple myeloma (NDMM). These are summarized below and the founding trial information is included in Tables 1 and 2.
Daratumumab, bortezomib, thalidomide and dexamethasone (dara-VTd) for transplant eligible NDMM
A type II variation application (having a significant effect on quality, safety or efficacy of a medicinal product) was submitted to the EMA for this 4-drug regimen in transplant eligible NDMM, alongside a supplemental biologics license (sBLA) to the FDA.1,2 These applications are based on the findings from part 1 of the CASSIOPEIA trial.
Table 1: Summary of CASSIOPEIA clinical trial part 11–3
|
ASCT, autologous stem cell transplant; dara, daratumumab; NDMM, newly diagnosed multiple myeloma; sCR, stringent complete response; VTd, bortezomib, thalidomide and dexamethasone |
|
|
Trial name |
CASSIOPEIA (MMY3006) |
|---|---|
|
NCT reference |
|
|
Drug combination |
Dara-VTd VTd |
|
Patient setting |
Transplant eligible NDMM |
|
Trial phase |
Phase III |
|
Trial design |
Dara-VTd versus VTd |
|
N |
1,085 |
|
Dosing schedule |
Four cycles of VTd induction +/- daratumumab (16 mg/kg), high-dose therapy and ASCT followed by two cycles of VTd consolidation +/- daratumumab (16 mg/kg) |
|
Primary endpoint |
sCR |
|
Efficacy
|
sCR (dara-VTd vs VTd): 28.9% vs 20.3% (odds ratio: 1.60, 95% CI, 1.21–2.12, P ≤ 0.001) |
|
Safety |
Safety profile of dara-VTd consistent with that of VTd and daratumumab alone. |
Daratumumab, lenalidomide and dexamethasone (DRd) for transplant ineligible NDMM
A type II variation application was submitted to the EMA for DRd in transplant ineligible NDMM, alongside a sBLA to the FDA.4 These applications are based on the findings from the MAIA trial.
Table 2: Summary of MAIA clinical trial4,5
|
CR, complete response; DRd, daratumumab, lenalidomide and dexamethasone; HR, hazard ratio; NDMM, newly dianosed multiple myeloma; ORR, overall response rate; PFS, progression free survival |
|
|
Trial name |
MAIA (MMY3008) |
|---|---|
|
NCT reference |
|
|
Drug combination |
DRd Rd |
|
Patient setting |
Transplant ineligible NDMM |
|
Trial phase |
Phase III |
|
Trial design |
DRd versus Rd |
|
N |
737 |
|
Dosing schedule |
Rd: oral lenalidomide (25 mg) on days 1–21 of a 28-day cycle with 40 mg dexamethasone once per week. DRd: As per Rd arm with the addition of intravenous daratumumab (16 mg/kg) once weekly for cycles 1–2, every 2 weeks for cycles 3–6 and every 4 weeks for cycle 7 onwards until disease progression, unacceptable toxicity or study end |
|
Primary endpoint |
PFS |
|
Efficacy (Given as DRd vs Rd) |
Median follow-up: 28 months Median PFS: not reached vs 31.9 months ≥ CR: 47.6% vs 24.7% ORR: 93% vs 81% Risk of reduction of disease progression or death with DRd vs Rd alone: 44% (HR 0.56, 95% CI, 0.43–0.73, P < 0.0001) |
|
Safety
|
In the DRd arm, there were higher rates (≥5% difference) of grade 3/4 pneumonia, neutropenia and leukopenia Safety profile is in line with previously reported daratumumab studies |
References