General MM,   Patients non-eligible for transplant,  Patients eligible for transplant

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

Trial name

CASSIOPEIA (MMY3006)

NCT reference

NCT02541383

Drug combination

Dara-VTd (daratumumab, bortezomib, thalidomide, dexamethasone)

VTd (bortezomib, thalidomide, dexamethasone)

Patient setting

Transplant eligible NDMM

Trial phase

Phase III

Trial design

Dara-VTd versus VTd

N

1085

Dosing schedule

Four cycles of VTd induction +/- daratumumab (16 mg/kg), high-dose therapy and autologous stem cell transplant (ASCT) followed by two cycles of VTd consolidation +/- daratumumab (16 mg/kg)

Primary endpoint

Stringent complete response (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

Trial name

MAIA (MMY3008)

NCT reference

NCT02252172

Drug combination

DRd (daratumumab, lenalidomide, dexamethasone)

Rd (lenalidomide, dexamethasone)

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

Progression-free survival (PFS)

Efficacy

(Given as DRd vs Rd)

Median follow-up: 28 months

Median PFS: not reached vs 31.9 months

≥Complete response (CR): 47.6% vs 24.7%

Overall response rate (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
  1. EU Application Filed for Daratumumab in Newly Diagnosed, Transplant-Eligible Myeloma. https://www.onclive.com/web-exclusives/eu-application-filed-for-daratumumab-in-newly-diagnosed-transplanteligible-myeloma [accessed 2019 March 28]
  2. FDA Approval Sought for Frontline Daratumumab Regimen in Transplant-Eligible Myeloma. https://www.onclive.com/web-exclusives/fda-approval-sought-for-frontline-daratumumab-regimen-in-transplant-eligible-myeloma [accessed 2019 March 28]
  3. Genmab. Genmab Announces Positive Topline Results in Phase III CASSIOPEIA Study of Daratumumab in Front Line Multiple Myeloma.https://ir.genmab.com/news-releases/news-release-details/genmab-announces-positive-topline-results-phase-iii-cassiopeia [accessed 2019 April 02]
  4. EU Approval Sought for Frontline Daratumumab/Rd in Transplant-Ineligible Myeloma. https://www.onclive.com/web-exclusives/eu-approval-sought-for-frontline-daratumumabrd-in-transplantineligible-myeloma [accessed 2019 March 28]
  5. Facon T. et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Abstract #LBA-2. 2018 Dec 1–4. ASH 60th Annual Meeting and Exposition, San Diego, CA.
Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Was this article informative? Thank you for your feedback!