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A four-drug regimen for newly diagnosed high-risk multiple myeloma induced high rates of sustained minimal residual disease (MRD) negativity regardless of transplant status, a German research group reported.

Two-thirds of transplant-eligible patients achieved MRD-negative status after induction and consolidation therapy consisting of isatuximab (Sarclisa), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Isa-KRd). Half of transplant-ineligible patients also achieved MRD-negative status.

MRD negativity was sustained for at least a year in 62.6% of patients, reported Katja C. Weisel, MD, of University Medical Center Hamburg-Eppendorf in Hamburg, Germany, and co-authors in the .

"Taken together [with previously reported studies], there is now a strong body of evidence for high-risk disease, supporting use of the most effective multidrug treatment options in induction, followed by high-dose therapy and autologous stem-cell transplantation in transplant-eligible patients, a prolonged consolidation, and a multidrug maintenance regimen," the authors concluded. "This approach, as shown in the trial with Isa-KRd, can lead to unprecedented rates of (sustained) MRD negativity and PFS [progression-free survival] duration in patients with high-risk newly diagnosed multiple myeloma."

Borrowing from German lore of the (four-leaf clover), the authors of an wondered whether the Isa-KRd regimen is "the answer we have been seeking" or if good fortune played a role in the study's outcome. They discussed four potentially lucky points from the study.

In the CONCEPT study, two-thirds of patients had one high-risk cytogenetic abnormality and a third of the patients had isolated 1q21 (>3 copies), higher than most other studies. As a result, "we can call this study a win" for those types of patients, wrote Sagar Lonial, MD, of Emory University and Winship Cancer Institute in Atlanta, and co-authors.

"The heterogeneity of the population may call for redefining our risk groups rather than broadening the definition of high risk, raising a question of patient selection affecting the reported outcomes," they continued.

The choice of MRD negativity as the primary endpoint (with PFS as a secondary outcome) raises questions about the optimal measure of success. The timing of the measurement varies and often represents best response.

"In high-risk disease, declaring victory early on the basis of the depth of response alone is a dangerous game," Lonial and colleagues noted.

A third point relates to the definition of acceptable toxicity and death rate. Myeloma specialists continue to struggle with carfilzomib dosing, dosing schedule, cardiac toxicities, and use in older patients. In CONCEPT, 20% of transplant-ineligible patients had grade ≥3 cardiac toxicity as compared with 2.1% of transplant-eligible patients. A smaller percentage of transplant-ineligible patients reached maintenance therapy.

"The concept of using a carfilzomib-containing quad among frail patients likely is not a sustainable option," the editorialists wrote.

Finally, defining transplant eligibility "remains the most ambiguous question in today's myeloma treatment paradigm," they noted. An optimal definition is especially important in high-risk patients if they are to get the full benefit of treatment.

"The median age in the current study for the transplant-ineligible patients was 74 years, and at our center and others, this would be potentially transplant eligible if fitness was not a major concern," the editorialists continued. "If fitness is a major concern, the quad regimen is not a suitable solution."

Caveats notwithstanding, "these results are outstanding and occur in the context of a more narrowly defined high-risk population, and one that has historically experienced short remission durations and early death."

"The road ahead for high-risk patients remains a challenge, but we have science and outstanding clinical trials like this one on our side," Lonial and co-authors concluded. "These results form the basis for a new direction in myeloma trials, and with Glücksklee as a start, we have a new direction to pursue going forward."

Reported by the German Multiple Myeloma Group, the results followed those of a previous study that showed a 50.1% rate of MRD negativity after induction therapy with isatuximab, bortezomib (Velcade), lenalidomide, and dexamethasone (Isa-VRd), compared with a rate of 35.6% in patients who received induction with VRd alone.

The phase II CONCEPT study involved 125 patients with newly diagnosed high-risk myeloma, defined as International Staging System stage II or III combined with one or more of the following: del17p, t(4;14), t(14;16), or more than three 1q21 copies (high-risk cytogenetic abnormalities). Patients received Isa-KRd as induction and consolidation therapy, followed by Isa-KR maintenance.

The primary endpoint was MRD negativity at the end of consolidation therapy, defined as <10^-5 by next-generation flow. Patients older than 70 and those ineligible for high-dose therapy were deemed transplant ineligible. The study population comprised 99 transplant-eligible patients and 26 who were transplant ineligible.

The results showed that 67.7% of transplant-eligible and 54.2% of ineligible patients met the primary endpoint of MRD negativity at the end of consolidation therapy. Additionally, 81.8% of transplant-eligible patients achieved MRD negativity at any time point. After a median follow-up of 44 months for transplant-eligible patients and 33 months for ineligible patients, median PFS had yet to be reached in either group.

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