Daratumumab Therapy Effective for Newly Diagnosed High-Risk Multiple Myeloma

A recent study published in Nature highlighted the efficacy of 2 unique four-drug therapies for newly diagnosed multiple myeloma anchored by daratumumab; of particular note, these combination therapies proved effective in managing multiple myeloma displaying high cytogenic risk.

Darzalex (daratumumab) is a monoclonal antibody drug currently approved for both refractory and new MM. It’s available in intravenous and subcutaneous formulations.

Multiple myeloma (MM) is a type of blood cancer affecting white blood cells. Several MM characteristics are used to assess disease severity and risk. Patients with MM whose myeloma cells harbor two or more mutations that are considered high risk (referred to as high risk cytogenetic abnormalities or HRCAs) do not fare as well as those with either no mutations in their cells or only one.

HRCAs are associated with more severe disease and an increased risk of progression. Approximately 25% of people with newly diagnosed MM experience these high-risk abnormalities, but it remains uncertain how they should impact the treatment decisions.

With this in mind, a group of researchers led by Natalie Callander M.D. of the University of Wisconsin sought to evaluate how daratumumab would perform as the cornerstone medication in a four-drug regimen for newly diagnosed MM in individuals at varying levels of risk based on present HRCAs.

“Our analysis focused on a subset of multiple myeloma (MM) patients who have high-risk myeloma,” Callander says in an email interview with MHE. “This is due to the presence in their abnormal plasma cells (the myeloma cells) of mutations in the genetic codes.”

The investigators analyzed data from two previously completed clinical trials of different regimens, including:

• D-KRd regimen, used in the MASTER trial, consisted of daratumumab + carfilzomib, lenalidomide and dexamethasone;
• D-RVd regimen, used in the GRIFFIN trial, consisted of daratumumab + lenalidomide, bortezomib and dexamethasone.

The researchers examined data from the MASTER and GRIFFIN trials. They conducted a post-hoc analysis to evaluate the effectiveness of each treatment based on the number of HRCAs: 0 (standard risk), 1 (high risk), or ≥ 2 (ultra-high risk). To determine relative efficacy of the treatment regimens across each of the different risk groups, the researchers compared rates of complete response and progression-free survival. Of note, all participants across both trials received autologous stem cell transplant, an important step of MM treatment.

The results of the analysis showed that 57% of participants in the MASTER trial possessed at least one HRCA, placing them at a higher cytogenic risk level; in the GRIFFIN study, only 39% fell into this category. Across both trials, those receiving either D-KRd and D-RVd with standard-to-high risk disease had significantly higher rates of complete response compared to those at ultra-high risk disease with 2 or more HRCAs.

While 80-90% of those with 0 or 1 HRCA had a complete response with the daratumumab-based therapy, only 60-70% of those with ≥ 2 HRCAs experienced the same outcome. There was also a difference in progression-free survival between standard or high risk individuals compared to ultra-high risk individuals. For those with 0 or 1 HRCA, 85-95% experienced progression-free survival up to 48 months, while only 55% of those at ultra-high risk did the same.

“Recently the use of a four-drug combination (from four different classes of drugs) at the time of initial treatment has emerged as a new standard of care and seems to be helpful for most myeloma patients,” Callender explains. “Our analysis showed that unfortunately those patients with the highest risk MM did not have their disease trajectory changed by those four drugs and still relapsed at a much higher rate.”

Ultimately, the findings of this study support the benefit of daratumumab-based therapy in treating MM with high cytogenic risk, while also highlighting the remaining need for advancements in treatments for those at ultra-high risk. Importantly, the daratumumab-anchored therapy shows efficacy at limiting progression following transplant, even in those at high cytogenic risk.

Regarding the cost implications of these findings, Callender states that this group of patients will likely need MORE therapy at the time of initial diagnosis. This likely includes “some of the newer treatments under development, such as cellular therapy. This will make treatment more expensive. At the same time, we are trying to identify those lower risk patients who can get LESS therapy and potentially stop therapy if they are in a very deep remission,” Callender says.