Three-Drug Combination Improves Progression-Free Survival in Patients with Multiple Myeloma

A new three-drug combination may offer improved progression-free survival and lower the risk of death due to multiple myeloma, according to study findings presented at the 2019 American Society of Hematology Annual Meeting.

By adding Darzalex (daratumumab) to a combination of Kyprolis (carfilzomib) and the steroid Decadron (dexamethasone), researchers saw a 37% reduction in the risk of disease progression or death in patients with relapsed or refractory (treatment-resistant) myeloma, compared with the two-drug treatment of Kyprolis and Decadron.

Both targeted drugs designed to home in on cancer cells, Darzalex is a monoclonal antibody that targets the protein CD38 and Kyprolis is a proteasome inhibitor.

While standard treatments like Revlimid (lenalidomide), an immunomodulatory drug, and Velcade (bortezomib), a proteasome inhibitor, have improved survival in patients with multiple myeloma, many will experience disease progression or unacceptable toxicity on these drugs. Because of this, researchers saw an opportunity to investigate new therapies such as the drug triplet.

“The majority of patients have disease progression on lenalidomide and, of the six treatment combinations that are currently approved in this setting, four have lenalidomide as part of their treatment combination. It makes little sense to re-challenge a patient with something they are progressing on just by adding other drugs,” lead study author Dr. Saad Z. Usmani said in a press release. “So, there is a need for novel therapeutic options for patients with multiple myeloma who have relapsed or are refractory to lenalidomide-based treatments.”

The open-label, phase 3 CANDOR trial compared the use of Kyprolis, Decadron and Darzalex (KdD) versus Kyprolis and Decadron (Kd) in 466 patients with relapsed or refractory multiple myeloma who had received up to three prior therapies. The median age was 64 years.

Patients were split using a ratio of two to one; the larger group received KdD and a second received Kd only. Of the 466 patients, 42.3% had previously received Revlimid while 90.3% had received a treatment that included Velcade.

At a median follow-up of 17 months, researchers noted that the median progression-free survival (time without disease progression) ) for the three-drug combination of KdD had not yet been reached, while that of the Kd group was 16 months.

While about one out of every three patients was Revlimid-refractory, this survival benefit was also seen regardless of prior resistance to Revlimid, the researchers noted.

In addition to progression-free survival, researchers also examined the overall response rate (ORR), minimal residual disease (MRD), overall survival (OS) and safety of the three-drug combination compared to the duo.

By adding the third drug, deeper responses were seen in all categories, with a 28.5% complete response rate (compared to 10.4% in the duo group), and the rate of MRD, meaning that patients had no remaining detectable disease, was nearly 10 times higher (12.5% in KdD versus 1.3% in Kd). Researchers noted that, although it is too early to calculate any differences in OS (length of life) or determine if they are meaningful, favorable trends were seen across subgroups of patients who took the three-drug therapy.

In general, side effects were tolerable with the triple-drug combination, the authors stated. Although KdD patients had higher rates of grade 3 (serious) or worse side effects, treatment discontinuations due to these events were similar in both arms. The most common side effects were thrombocythemia (low white blood counts), anemia, diarrhea and high blood pressure. Cardiac events occurred in 4% to 8% of patients, which was expected, but the rate of heart failure was lower in the KdD group.

Five treatment-related deaths, all in the KdD group, were reported; these deaths were caused by pneumonia, sepsis, septic shock infection and cardiac arrest.

“It seems adding daratumumab to carfilzomib and dexamethasone may be helpful in controlling their disease,” Dr. Usmani said. “Myeloma is a heterogeneous (variable) disease — even within a single patient we see many different clones, at an average of 10 to 15 clones at the time of diagnosis — so if you want optimal disease control, you have to target different mechanisms of action to control the disease more effectively.”