ASH 2019: Triple drug combination delays disease progression in people with stubborn multiple myeloma

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Adding daratumumab to carfilzomib and dexamethasone to treat patients with relapsed or refractory multiple myeloma led to a significant survival benefit, with a 37% reduction in the risk of disease progression or death compared with patients taking daratumumab and carfilzomib alone, according to a study presented today during the 61st American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando.

Researchers say the results support this three-drug combination as an effective new regimen for this patient population, including patients previously treated with lenalidomide.

Although the life expectancy of people diagnosed with myeloma has greatly improved, it remains an incurable disease and the majority of patients eventually relapse.

In particular, while the use of lenalidomide and bortezomib in patients with newly diagnosed multiple myeloma has improved survival outcomes, researchers say many patients will experience disease progression while on these agents or stop them due to toxicity.

“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,” said lead study author Saad Z. Usmani, MD, of Atrium Health.

“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 impetus of this trial, he said, was to see if progression free survival (PFS, defined as the time from randomisation to disease progression or death from any cause) could be improved by adding daratumumab to the current standard of care that uses carfilzomib plus dexamethasone.

The proteasome inhibitor carfilzomib and the anti-CD38 monoclonal antibody daratumumab are both approved by the U.S. Food and Drug Administration (FDA) as single agents or as components of combination regimens for the treatment of relapsed and refractory multiple myeloma.

The combination of carfilzomib, dexamethasone, and daratumumab has been shown to be efficacious and safe in a previous study of multiple myeloma.

A total of 466 patients with relapsed or refractory multiple myeloma who have received one to three prior therapies at 102 sites worldwide were enrolled in CANDOR, an open-label, phase III trial. Patients (median age of 64 years) were randomized 2:1 to receive carfilzomib, dexamethasone, and daratumumab or carfilzomib and dexamethasone.

Of those in the trial, 42.3% and 90.3% had previously received lenalidomide- or bortezomib-containing regimens, respectively.

Roughly one out of three patients were lenalidomide refractory.

After a median follow-up of 17 months, the median PFS for the three-drug combination had not yet been reached, compared to 16 months for the carfilzomib-dexamethasone group.

This PFS benefit was seen across patient groups, including lenalidomide-exposed and refractory patients.

Researchers also evaluated overall response rate, minimal residual disease, overall survival, and safety.

The addition of daratumumab resulted in deeper responses compared with carfilzomib and dexamethasone alone, including superior overall response rates (84.3% vs. 74.7%); the rate of complete response or better was 28.5% vs. 10.4%, respectively.

Moreover, the rate of undetectable minimal residual disease at 12 months was nearly 10-times higher in the three-drug treatment group, 12.5% vs. 1.3%, respectively.

Patients on the three-drug regimen were in treatment for longer (70.1 vs. 40.3 weeks).

Dr. Usmani said that it is too early to be able to see any differences in overall survival.

Importantly, favourable benefits of the three-drug therapy were seen across subgroups of patients.

Adverse events were generally manageable and the incidence of treatment discontinuation due to these events was similar in both groups (22-25% of patients).

The types of observed adverse events were reported to be consistent with known safety profiles of the individual agents. The most common adverse events were thrombocytopenia (low white blood counts), anaemia, diarrhoea, hypertension, upper respiratory tract infection, fatigue, and shortness of breath.

There was a high incidence of cardiac events, occurring in 5-8% of patients, which has been reported in prior studies; heart failure was lower in the three-drug combination group.

There were five treatment-related deaths reported, all in the three-drug treatment group; the cause of these deaths were pneumonia, sepsis, septic shock infection, and cardiac arrest.

“Having a therapeutic option without lenalidomide for patients who have been exposed to it or don’t respond to it is a real clinical need,” said Dr. Usmani. “It seems adding daratumumab to carfilzomib and dexamethasone may be helpful in controlling their disease. Myeloma is a heterogeneous disease – even within a single patient we see many different clones, at an average of 10-15 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.”


Source: American Society of Hematology

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