KRd Maintenance Trial Safely Deescalates Nearly Half of Patients With Myeloma

Andrzej Jakubowiak, MD, PhD, director of the multiple myeloma program at the University of Chicago, discusses the innovative maintenance strategy utilized in the ATLAS trial (NCT02659293), which compared carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) against lenalidomide alone in patients with multiple myeloma following autologous stem cell transplant. A central feature of the KRd arm was the use of minimal residual disease (MRD) status and cytogenetic risk to direct therapy. By using the clonoSEQ assay to evaluate MRD at the 6-month mark, the study sought to identify patients who could safely reduce their treatment intensity, thereby limiting unnecessary exposure to the 3-drug combination.

The trial adopted a risk-stratified approach to deescalation. Patients in the KRd arm who did not possess high-risk cytogenetic features and who achieved MRD negativity after 6 cycles were given the option to transition to lenalidomide monotherapy. In practice, nearly 50% of the patients in the KRd group met these criteria and were deescalated to lenalidomide alone after 8 months of posttransplant KRd. In contrast, patients who either had high-risk cytogenetics, remained MRD positive, or both, continued receiving the full KRd regimen for up to 36 months, provided the treatment was well-tolerated.

Despite the reduction in treatment intensity for roughly half of the KRd cohort, the overall KRd group demonstrated superior outcomes compared to the group receiving standard lenalidomide maintenance and the subset of patients who underwent deescalation exhibited some of the best outcomes in the trial. Jakubowiak suggests that this is likely because these patients possessed disease that was highly sensitive to the KRd combination, so 8 cycles of KRd followed by lenalidomide maintenance provided sufficient therapeutic pressure to maintain long-term disease control.

These findings suggest that a one-size-fits-all approach to maintenance may not be necessary. By integrating MRD testing into clinical decision-making, oncologists can effectively tailor the duration and intensity of therapy. This risk-adapted model allows for the preservation of high efficacy while potentially reducing the long-term toxicity and logistical burden associated with prolonged triplet therapy in patients with highly responsive multiple myeloma.