Quadruplet Tx in Myeloma May Reduce Need for Transplants

Nancy A. Melville

July 27, 2022

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” say Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the Myeloma Division, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.

They were commenting in an editorial in JAMA Oncology that was prompted by a paper describing new results with a novel quadruple combination of therapies that included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists comment.

“Novel immunotherapies are here to stay,” they add, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”

Study Details

The trial of the novel quadruplet regimen was a multicenter, single-arm phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, Chicago, Illinois, and colleagues.

These patients had a median age of 62; more than two thirds of patients were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle eight and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explain.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received six additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle eight was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle eight to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle eight. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 myocardial infarction. Three patients discontinued the treatment due to intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors write.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy vs treatment including stem cell transplantation, a phase 3 randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo vs anti-CD38 mAb based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors note.

Randomized Trial Anticipated to Clarify Benefit

In their editorial, Kazandjian and Landgren agree with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists point out that the recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed that the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also point out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone — on its own — was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex), instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasize.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high dose mephalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they add.

The study was sponsored in part by Amgen, Bristol Myers Squibb, and the Multiple Myeloma Research Consortium.

Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. The other authors’ disclosures are included in the published version of the study. Kazandjian declares receiving advisory board or consulting fees from Bristol Myers Squibb, Sanofi, and Arcellx outside the submitted work. Landgren has received grant support from the National Cancer Institute and theNational Institutes of Health, the US Food and Drug Administration, Leukemia & Lymphoma Society, Rising Tide Foundation, Memorial Sloan Kettering Cancer Center, Multiple Myeloma Research Foundation, International Myeloma Foundation, Paula and Rodger Riney Foundation, Perelman Family Foundation, Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm; has received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer; and served on Independent Data Monitoring Committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

JAMA Oncology. Published July 21, 2022. Abstract. Editorial.

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