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Dara-KRd With MRD Response-Adapted Therapy Leads to High MRD Negativity for Newly Diagnosed MM

March 30, 2022

April 2022

Treatment with quadruplet therapy comprising daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd), in combination with autologous hematopoietic cell transplantation (AHCT) and measurable residual disease (MRD) response-adapted consolidation, resulted in high rates of MRD negativity in patients with newly diagnosed multiple myeloma (MM). This was according to findings from a single-arm, phase II trial published in the Journal of Clinical Oncology. The study suggests that the strategy may allow for MRD surveillance in lieu of indefinite maintenance in patients with zero or one high-risk cytogenetic abnormalities (HRCAs).

According to lead author Luciano J. Costa, MD, PhD, of the University of Alabama at Birmingham, the current treatment of newly diagnosed MM is based on a “one-size-fits-all” approach that follows an inflexible paradigm of induction therapy, AHCT with or without consolidation, and indefinite maintenance therapy.

“We don’t modify therapy unless there is objective progression,” he explained. “This paradigm is a legacy from the long-standing approach of doing clinical trials for newly diagnosed MM based on transplant eligibility exclusively and not accounting for the vast heterogeneity in disease biology and disease response.”

He added, “While the current ‘standard’ performs well in most patients and is a clear advance over what we had 10 or 20 years ago, it is clearly not enough for some patients and perhaps too much for others.”

The trial enrolled 123 patients with newly diagnosed MM and planned enrichment for HRCAs. Based on MRD status, participants received Dara-KRd induction, AHCT, and Dara-KRd consolidation.

The investigators used next-generation sequencing (NGS) at the end of induction, after AHCT, and every four cycles of consolidation to evaluate MRD. The primary endpoint was achievement of MRD negativity (<10-5). Patients who had two consecutive MRD-negative assessments were allowed to enter a treatment-free MRD surveillance period.

In the overall cohort, 43% had no HRCAs, 37% had one HRCA, and 20% had two or more HRCAs. The median age of the study population was 60 years (range = 36-79). Approximately 96% of patients had MRD that was “trackable” by NGS.

Over the median follow-up of 25.1 months, 80% of patients reached MRD negativity. In patients with zero, one, and two or more HRCAs, up to 78%, 82%, and 79% of patients, respectively, reached MRD negativity. Additionally, around 66% reached MRD <10-6, while 71% reached two consecutive MRD-negative assessments during treatment and subsequently entered treatment-free surveillance.

The overall two-year progression-free survival (PFS) was 87%. The two-year PFS was proportionally higher for patients with one HRCA (97%) versus patients with zero (91%) or two or more (58%) HRCAs. After 12 months of treatment cessation, the cumulative incidences of MRD resurgence or progression were 4% in patients with no HRCAs, 0% in patients with one HRCA, and 27% in patients with two or more HRCAs. The most common serious adverse events with the treatment regimen were pneumonia (6%) and venous thromboembolism (3%).

Dr. Costa noted that the normalization of triplets for induction and consolidation and the arrival of quadruplets significantly changes the risk of progression over time after induction-transplant-consolidation. He said this is cause to revisit maintenance therapy with lenalidomide.

“By omitting maintenance, we are sparing the patient from the short- and long-term toxicity of the maintenance agent, including the well-demonstrated increase in risk of second primary malignancy,” Dr. Costa added. “We are minimizing doctor visits and tests used to monitor toxicity of maintenance, and we are deflecting a cost that approaches $20,000 a month in the U.S.”

As an alternative, Dr. Costa said, clinicians can monitor patients using traditional parameters in addition to annual MRD assessment.

“That gives us the opportunity to respond to a rising, sub-clinical burden of disease in the few instances where that happens and reassure the patient that MM remains undetectable in the majority of cases,” he noted.

The study findings are preliminary, feature a relatively short follow-up period, and lack a comparator arm, according to the researchers. Despite these limitations, Dr. Costa noted that the findings represent “a small but important step toward personalized medicine” in newly diagnosed MM.

Any conflicts of interest declared by the authors can be found in the original article.

Reference

Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma [published online ahead of print, 2021 Dec 13]. J Clin Oncol. doi: 10.1200/JCO.21.01935.

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