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FDA Approval Sought for Frontline Daratumumab Regimen in Transplant-Eligible Myeloma

Gina Columbus @ginacolumbusonc
Published: Tuesday, Mar 26, 2019

Yusri Elsayed, MD, MHSc, PhD

Yusri Elsayed, MD, MHSc, PhD

A supplemental biologics license application (sBLA) has been submitted to the FDA for daratumumab (Darzalex) in combination with bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTd) for the treatment of patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).1

The application is based on findings from part 1 of the phase III CASSIOPEIA (MMY3006) trial, in which the stringent complete response (sCR) rate was 28.9% in patients who received the daratumumab regimen compared with 20.3% in those who received VTd alone following induction and consolidation therapy (odds ratio, 1.60; 95% CI, 1.21-2.12; P ≤.001).

"This submission marks an important step in the pursuit of potential treatments for newly diagnosed patients living with multiple myeloma, as Darzalex has the potential to improve clinical outcomes in combination with a standard regimen," said Yusri Elsayed, MD, MHSc, PhD, vice president, Hematologic Malignancies Disease Area Leader, Janssen Research and Development, LLC, the manufacturer of daratumumab. "We look forward to working closely with the FDA during review of the submission with the goal of bringing a new treatment option to newly diagnosed patients who are transplant eligible."

In the open-label, multicenter, phase III CASSIOPEIA trial (NCT02541383), 1085 patients with newly diagnosed, previously untreated symptomatic multiple myeloma who were eligible for high-dose chemotherapy and ASCT were enrolled. Patients were first randomized to receive 4 cycles of induction therapy with VTd alone or in combination with daratumumab at 16 mg/kg, high-dose therapy, and ASCT, and then consolidation therapy with VTd alone for 2 cycles or combined with daratumumab at 16 mg/kg.

To be eligible for enrollment, patients must have had previously untreated myeloma that is eligible for high-dose chemotherapy and ASCT, as well as an ECOG performance status of 0 to 2. Those who had primary amyloidosis, plasma cell leukemia, or smoldering multiple myeloma; prior or concurrent exposure to systemic therapy or stem cell transplant; 10-year history of cancer; known chronic obstructive pulmonary disease or moderate to severe asthma; or other interfering comorbidities were excluded.

The primary endpoint of part 1 of this trial was proportion of patients who achieved sCR. Part 1 results also showed that the safety profile of daratumumab in combination with VTd is consistent with the known profiles of VTd, which is used in patients receiving ASCT, as well as the known tolerability of daratumumab.

In the second part of CASSIOPEIA, which is ongoing, patients who achieved a partial response or better in part 1 of the trial will then undergo a second randomization to either receive maintenance daratumumab at 16 mg/kg every 8 weeks for up to 2 years or observation. The primary endpoint of this phase is progression-free survival (PFS).

Secondary endpoints include time to progression, proportion of post-ASCT/consolidation CR rate, proportion of post-ASCT/consolidation minimal residual disease negativity, proportion of post-induction sCR, PFS2, and overall survival.

Full findings of CASSIOPEIA are slated to be presented at an upcoming medical meeting and published in a peer-reviewed journal. The trial was sponsored by the French Intergroupe Francophone du Myeloma in collaboration with the Dutch-Belgian Cooperative Trial Group for Hematology Oncology.

Earlier this month, Janssen submitted an sBLA for the approval of daratumumab in combination with lenalidomide (Revlimid) and dexamethasone (DRd) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for ASCT. The application is based on findings from the phase III MAIA (MMY3008) trial, in which DRd led to a 44% reduction in the risk of disease progression or death in patients with newly diagnosed multiple myeloma who are transplant ineligible compared with Rd alone, at a median follow-up of 28 months (HR, 0.56; 95 CI, 0.43-0.73; P <.0001).3


  1. Janssen Submits Application for DARZALEX (daratumumab) Combination Therapy to U.S. FDA for Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma. Janssen. Published March 26, 2019. Accessed March 26, 2019.
  2. Genmab Announces Positive Topline Results in Phase III CASSIOPEIA Study of Daratumumab in Front Line Multiple Myeloma. Genmab. Published October 21, 2018. Accessed March 26, 2019.
  3. Facon T, Kumar SK, Plesner 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). Presented at: 2018 ASH Annual Meeting; December 4-8, 2018; San Diego, CA. Abstract LBA-2.

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