A Q&A with MSK Experts
MSK played a central role in the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC)’s landmark decision in April 2024 to accept measurable residual disease (MRD) as an intermediate clinical endpoint for accelerated approval of new drugs and new indications in multiple myeloma clinical trials.
“The ODAC’s unanimous vote was a historic turning point that will allow patients to benefit from earlier access to new therapies and move the field rapidly towards improved outcomes and a potential cure,” said myeloma specialist and cellular therapist Dr. Saad Usmani, Chief of the Myeloma Service at MSK. “MRD negativity is a higher bar to clear than the previous overall response rate (ORR) for accelerated approval. Robust evidence shows it is highly correlated with progression-free survival (PFS) and overall survival (OS).”
For this Q&A, we spoke with two MSK experts who presented at the ODAC hearing: associate attending biostatistician Dr. Sean Devlin, senior author and lead statistician of the EVIDENCE meta-analysis, and Dr. Usmani, who spoke at the hearing in his capacity as Chair of the Alliance Myeloma Committee of the Alliance for Clinical Trials in Oncology.
Their responses provide essential insights into this milestone decision and what it means for patients and advancing multiple myeloma research.
How did the initiative to define a new endpoint for multiple myeloma clinical trials come about?
Dr. Devlin: I started working on this project at MSK about 10 years ago together with Dr. Ola Landgren, who was the former Chief of the Myeloma Service at MSK before he became Chief of the Myeloma Service at the Sylvester Comprehensive Cancer Center at the University of Miami. We collaborated with pharmaceutical companies and academic institutions to obtain datasets from clinical trials worldwide that used MRD as an exploratory or secondary endpoint to assess therapeutic response. We also met several times with the FDA, including the most recent ODAC hearing in April 2024, where I shared the findings from our EVIDENCE meta-analysis.
Why was a new endpoint needed for accelerated approval in multiple myeloma?
Dr. Usmani: With traditional OS, it takes more than 10 years to show a significant benefit for newly diagnosed patients. Despite improved survival from about 3.5 years in the late 1990s to more than 10 years today, in large part due to the approval of 13 new drugs in the last decade, multiple myeloma remains an incurable disease with a five-year survival rate of about 60%.
Also, as tools for assessing myeloma have improved significantly, we have learned that even among patients with a traditionally-evaluated “complete response” quote-unquote, those with MRD positivity have worse outcomes than those with MRD negativity.
The FDA previously established MRD as a prognostic indicator for several leukemia types. How is the MRD-negativity defined in multiple myeloma?
Dr. Usmani: MRD-negativity in multiple myeloma is determined by a validated bone marrow assay with a sensitivity of 10-5, meaning it can rule out at least one myeloma cell in 100,000 cells tested. This definition is supported as a response category and as early evidence of clinical activity by the International Myeloma Working Group and the National Comprehensive Cancer Network guidelines. (1) (2)
Presently, there are two validated assays for detecting MRD negativity — multiparameter flow cytometry and next-generation sequencing. They are broadly available and used by major cancer centers and community cancer treatment sites. We already use MRD test results to provide patients with evidence-based guidance on their prognoses, even patients with no detectable monoclonal immunoglobulin spike or free light chain abnormalities in their blood.
How does MRD negativity at the 10-5 threshold compare to previous endpoints in multiple myeloma clinical trials?
Dr. Devlin: MRD negativity 10-5 is a much deeper response at orders of magnitude below conventional endpoints. ORR is defined as a 50% response, and complete response (CR), is defined as 100% response on immunofixation. Over the past decade, numerous meta-analyses have shown that MRD negativity has a strong predictive value for clinical benefit measured by PFS and OS. (3) (4) (5) (6) (7)
What datasets did you include in the EVIDENCE meta-analysis, and what were the main findings you shared at the ODAC hearing?
Dr. Devlin: We examined whether MRD negativity as an intermediate endpoint could reasonably predict long-term clinical benefit in patients with multiple myeloma.
We invited sponsors of published, randomized phase 2 and phase 3 clinical trials that reported MRD negativity using an assay with 10-5 or better sensititivity to participate. Eligible clinical trials had a median follow-up of at least six months following an a priori defined time point of 12 months ± 3 months after randomization for assessing MRD negativity.
Our analysis included data from 8 high-quality datasets representing 4,907 patients with newly diagnosed multiple myeloma. MRD negativity was significantly correlated with PFS and OS, particularly among 1,686 transplant-ineligible patients, who represented about two-thirds of all patients.
Using a copula model, the global odds ratios for the association between MRD-negativity CR and PFS and OS among all 4,907 patients were 4.72 and 4.02, respectively, and among 1,686 transplant-ineligible patients were 6.15 and 4.08, respectively.
We published the EVIDENCE meta-analysis in Blood in May 2024. In that paper, we also analyzed data from four clinical trials of patients with relapsed/refractory multiple myeloma. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67. (8)
The i2TEAMM (International Independent Team for Endpoint Approval of Myeloma MRD), a group from the International Myeloma Foundation and their research collaborators, presented results from their separate meta-analysis. How did their results compare with your findings?
Dr. Devlin: Their results largely agreed with ours. In the newly diagnosed setting, we included eight randomized studies in our primary analysis of MRD at 12 months, which included nine separate treatment comparisons, due to one trial having multiple treatment arms. The i2TEAMM included six randomized studies in their analysis, which provided eight overall treatment comparisons. However, only four studies were included in both the EVIDENCE meta-analysis and the i2TEAMM analysis. In addition, the two teams had different approaches to how the 12-month MRD endpoint was evaluated.
Despite these differences, the i2TEAMM found a consistently high individual-level correlation between MRD negativity and survival. The i2TEAMM had additional randomized trials for newly relapsed/refractory MM (RRMM) patients, and in this setting, they found a similarly high global odds ratios.
What about patient safety concerns?
Dr. Usmani: Clinical trial sponsors using MRD as an intermediate endpoint for accelerated approval must collect and report early monitoring and longer-term safety and outcome data to the FDA before applying for regular approval.
Could MRD-negativity become a future primary endpoint in multiple myeloma clinical trials?
Dr. Usmani: We are committed to generating the next cadre of data to advance MRD as a primary endpoint. However, MRD negativity must first prove its benefit in later treatment settings before becoming a primary endpoint in earlier treatment settings.
Moving forward, we will encourage our industry colleagues to design clinical trials that include collecting sustained MRD negativity data. If we prove sustained MRD negativity results in better survival outcomes, we will be able to define the duration of treatment and feel more comfortable advising patients on when they can stop treatment.
Are there other advances on the horizon for improving multiple myeloma clinical trials?
Dr. Usmani: Our group has started evaluating MRD negativity as measured by peripheral blood assays to see how the results compare with bone marrow testing. Blood assays are much more agreeable for patients.
Learn more about MSK’s multiple myeloma clinical trials.