DETERMINATION trial subgroup analysis suggests potential strategies for individualization of myeloma treatment

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A subgroup analysis of data from the DETERMINATION study, co-led by researchers at Dana-Farber Cancer Institute, has found that there may be important subgroups of patients who benefit from less intensive treatment versus more intensive therapy for multiple myeloma. These hypothesis-generating findings warrant further prospective studies that may be valuable in individualizing treatment approaches for patients with newly diagnosed multiple myeloma and improving outcomes.

The findings were presented by Jeffrey Zonder, MD, of the Karmanos Cancer Institute, in a poster session at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, CA, on Monday, December 11, 2023.

In younger, transplant-eligible patients with newly diagnosed multiple myeloma who have been treated with a three-drug combination therapy have a growing number of choices for subsequent treatments, including the option of keeping high dose melphalan with autologous stem cell transplantation (HDM/ASCT) in reserve, versus using this intensive therapy early in their treatment course. The DETERMINATION study clarified the benefits and risks of using the RVd triplet regimen and early HDM/ASCT with prolonged maintenance versus keeping HDM/ASCT in reserve, with outcome of the two treatment options reported in a readout in 2022. The findings showed that patients had significant progression free survival benefit for early HDM/ASCT yet did equally well over the long term in terms of overall survival, suggesting there may be differences in benefit amongst subgroups with keeping HDM/ASCT in reserve, and this is especially important given the greater short- and longer-term toxicity seen with early use of HDM/ASCT as well as the effects on quality of life.

The DETERMINATION trial enrolled 722 patients under the age of 65 with multiple myeloma. Eighteen percent of participants in the DETERMINATION trial were African American, giving the trial the largest enrollment of African Americans of any similar myeloma treatment study to date. For African Americans, the risk of developing myeloma is twice that of whites.

In this subgroup analysis, the researchers compared the benefits and risks of the two treatment options in African American and white patients enrolled in the trial. They found that African American patients in general did not derive significant progression free survival benefit with early HDM/ASCT, and patients who had a high body-mass-index and were female derived more benefit from taking RVd alone.

"Our analysis led by Dr. Zonder sheds light on the complexity of best treatment choices for our patients and the importance of better understanding disease pathobiology, where a strategic and tailored approach to care balancing efficacy and toxicity is key to improving long term outcomes, and especially for our African American patients," said Paul Richardson, MD, principal investigator of DETERMINATION and clinical program leader and director of Clinical Research of the Jerome Lipper Multiple Myeloma Center.

Fifty-six cancer centers across the U.S. were involved in the study. Dana-Farber’s Kenneth C. Anderson, MD, program director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, and Nikhil Munshi, MD, director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center, are co-senior authors of the study with Dr. Richardson.

All participants received the RVd combination therapy, which includes the drugs lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone. Afterward, all received lenalidomide as “maintenance” therapy to keep myeloma from coming back until progression. Half were randomly assigned to undergo an autologous stem cell transplant (which uses their own stem cells) shortly after completing initial treatment with RVd, and half had their stem cells collected and stored for a possible future transplant.

In the overall trial population, patients in each arm of the trial responded to treatment at roughly the same rate both for partial and complete response. Patients who did not undergo an early transplant had a median PFS of 48 months; conversely, those who did receive an early transplant had a median PFS of 68 months – or more than five years. However, the overall survival rate was virtually the same – about 85% – for both groups with a median follow-up time of 76 months. Greater toxicity, higher rates of secondary blood cancer and a transient but meaningful impact on quality of life were also noted in the early HDM/ASCT arm of the study.

Importantly, the favorable PFS difference seen in the overall population was not seen in African American patients. Rather, PFS in African American patients was longer with RVd-alone compared to white patients and similar to white patients among those who received an early transplant. Rates of severe adverse events were similar across the two groups.

The African American patient group tended to be younger, more commonly female, and had a higher average body mass index. The group also had higher rates of other measures, including low hemoglobin. Approximately two-thirds of African American patients were DUFFY-null, an indication of a genetic variant in white blood cells called neutrophils that is common in people of African descent and may protect against malaria, but also has effects on cytokine homeostasis which may be important in myeloma pathobiology.

These findings have far-reaching implications for the treatment landscape, with the potential to reshape standard protocols for multiple myeloma, particularly in the context of racial disparities. More research is needed to determine if the characteristics observed in the African American patient group influence the potential to benefit from RVd alone, and especially with the advent of powerful quadruplets incorporating monoclonal antibodies, such as RVd combined with daratumumab, which may further allow HDM/ASCT to be deferred. Researchers will further explore DUFFY status in DETERMINATION patients and its impact on outcomes, through correlative studies of disease biology and treatment effects.

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Multiple Myeloma
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Paul Richardson, MD