On Friday Sept 14, the myeloma community assembled in NYC for the 5th in a series of yearly meetings held to assess progress toward approval of MRD as a surrogate endpoint in myeloma clinical trials. The meeting was a joint collaboration between the MMRF and Memorial Sloan Kettering Cancer Center, and was chaired by Drs. Ola Landgren (MSKCC) and Daniel Auclair (MMRF).
MRD, or Minimal Residual Disease, is the measurement of the number of cancer cells still remaining after treatment. Due to rapid progress in the field,here are now several very sensitive methods including VDJ sequencing and next generation flow cytometry,that can detect as few as 1 myeloma cell in 1 million cells in a bone marrow biopsy. Many cancer centers already routinely measure MRD in their myeloma patients using one of these two techniques. Once approved for clinical trials, the ability to assess MRD in patients at this level of sensitivity will move the myeloma field forward in a number of ways:
- It will be an accurate and definitive way to determine how well patients respond to treatment
- It will help detect when patients relapse earlier
- It could shorten, and therefore lower the costs of, clinical trials if a patients’ response can be determined earlier and more accurately
MRD testing is already approved and in use in other hematological cancers, including CML. Recent data in myeloma patients have confirmed that MRD negativity is a strong predictor for both longer progression free survival and overall survival in newly diagnosed MM patients treated with Revlimid/Velcade/dex, regardless of whether they received a transplant, their myeloma risk profile, or their ISS stage at diagnosis. This data suggests there is considerable value in measuring MRD status as a predictive biomarker in myeloma. However, a number of questions remain to be answered before MRD can become an accepted and useful clinical test for myeloma:
- What technique is the best one to use to measure MRD?
- How sensitive does the technique need to be?
- What does it mean to be MRD negative?
- How will treatment choices and timing change as a results of a MRD positive or negative measurement?
- When during the course of disease and treatment should MRD be measured?
- How often should MRD be measured?
The MMRF and MSKCC researchers are working closely with other researchers, pharmaceutical companies, patients in clinical trials, and the FDA in gathering the correct data to provide the answers to these and other remaining questions necessary to bring MRD forward as an approved clinical endpoint.
The meeting began with reports from several investigators using MRD in current clinical trials for newly diagnosed and relapsed refractory patients and how the information might be used to improve clinical trial designs and results measurements. The second session looked at MRD measurement in other clinical settings such as immunotherapy (CAR-T trials) and maintenance therapy.
Over a working lunch, the FDA’s Dr. Nicole Gormley discussed the progress that has occurred in this effort over the past few years, and the entire group discussed what next steps are necessary to move forward toward approval of this test by the FDA.
After lunch, MMRF SVP of Research, Dr. Daniel Auclair, was co-moderator of a session on new MRD measurement technologies, including blood-based testing vs. marrow-based testing, testing by genomic sequencing, and impacts of immune monitoring, proteomics, and imaging techniques on MRD measurement.
The meeting wrapped up with a session on the latest FDA perspectives on MRD testing in myeloma, and a wide-ranging panel discussion on whether MRD can be used for treatment decisions at this time. D Ola Landgren of MSKCC ended the meeting with a brief summary of the day’s findings, and what next steps are necessary to move closer to an approved MRD test in myeloma. It is clear that in order to standardize and approve MRD testing as a clinical trial endpoint, more trials utilizing MRD measurement must be designed, and their outcomes correlated with other approved endpoints such as progression free survival and overall survival. This effort will be led by Drs. Auclair and Landgren and will be facilitated by MMRF guidance and investment, to ensure that future clinical studies in myeloma, both within and outside the MMRC , include MRD measurement and its correlation with patient outcomes. Only by gathering this additional data, demonstrating the value of MRD data in clinical trials, can the approval of MRD testing as an endpoint in myeloma clinical trials become a reality.