FDA Asked to Approve Darzalex Triple Combo for Relapsed or Refractory Multiple Myeloma

Janssen has asked the U.S. Food and Drug Administration (FDA) to allow Darzalex (daratumumab) to also be used in combination with Kyprolis (carfilzomib) and dexamethasone to treat people with relapsed or refractory multiple myeloma who received one to three prior lines of therapy.

The supplemental biologics license application (sBLA), asking for an extended label, is based on positive data from the Phase 3 CANDOR study (NCT03158688). It findings showed that adding Darzalex to Kyprolis (by Amgen) and dexamethasone prolongs life without disease progression in people with multiple myeloma who responded poorly to previous treatments.

“While we continue to make important strides in the treatment of multiple myeloma, unfortunately most patients will relapse at some point, so it is important that physicians have multiple treatment options and regimens for patients,” Craig Tendler, MD, vice president of Late Development and Global Medical Affairs at Janssen Research & Development, said in a press release.

“The results from the CANDOR study support the potential benefit of this Darzalex-based combination regimen for patients with multiple myeloma who have relapsed from prior treatment,” Tendler added.

CANDOR, co-sponsored by Amgen and Janssen (the pharmaceutical arm of Johnson & Johnson), compared the safety and effectiveness of the Darzalex triple combo versus Kyprolis and dexamethasone alone (control group) in 466 people with relapsed or refractory multiple myeloma and one to three previous lines of therapy.

All were given Kyprolis through injections into the bloodstream (intravenous infusions) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle, plus oral or infused dexamethasone weekly. In the group randomized to the triple combination, infusions of Darzalex were also given on days one and two of the first cycle, and once weekly for the remaining doses of the first two cycles. Then Darzalex was infused every two weeks in cycle three to six, and every four weeks thereafter.

Latest results from the study were shared at a late-breaking session at the 2019 American Society of Hematology (ASH) annual meeting, held in December in Orlando.

With a median follow-up of 17 months, the study met its primary efficacy goal: patients treated with the Darzalex combo had a 37% reduction in the risk of disease progression or death compared to those in the control group.

At the time of the analysis, the median progression-free survival for the control group was 15.8 months, but this median had not yet been reached for the Darzalex group. This means that most patients in the Darzalex group were still alive and progression-free at the time of the data cut-off.

More patients responded favorably to Darzalex combo, meaning more people on the triple combination experienced a partial or full reduction of disease signs and symptoms compared to patients in the control group.

The overall response rate was 84.3% for patients on the Darzalex combo versus 74.7% for patients taking Kyprolis and dexamethasone. Patients who had a complete response or better were 28.5% (Darzalex combo) versus 10.4% (controls).

At 12 months, nearly 10 times more patients also taking Darzalex were free of any detectable disease — a status called minimal residual disease negativity — compared with the control group, corresponding to a proportion of 12.5% vs. 1.3%.

The triple combo’s safety was consistent with the known safety profiles of each individual therapy. The most frequent treatment-related side effects were low platelet counts (thrombocytopenia), low red blood cell counts (anemia), diarrhea, high blood pressure, upper respiratory tract infection, fatigue, and shortness of breath.

Serious, life-threatening and fatal events were more common in the Darzalex group compared with the control group — 82.1% vs. 73.9% — but the rate of treatment discontinuation due to adverse events was similar between the two groups (22.4% vs. 24.8%).

All five deaths related to treatment happened in the Darzalex group. Causes were pneumonia, sepsis, septic shock, acinetobacter infection, and cardio-respiratory arrest.

Darzalex and Krypolis are two targeted therapies with distinct mechanisms of action. 

Darzalex is a lab-made antibody therapy that binds to a molecule called CD38, which is abundant on the surface of myeloma cells and other immune cells. By recognizing this molecule, Darzalex binds to and induces the death of malignant myeloma cells. It also suppresses regulatory immune cells and allows the immune system to grow robustly, to better identify and kill myeloma cells.

Kyprolis is a proteasome inhibitor that induces a toxic buildup of defective or worn-out proteins within cancer cells, halting their growth and promoting their death. The medicine preferentially affects fast-growing cancer cells, which are more prone to accumulating high amounts of proteins.