I asked some of the world’s best myeloma specialists what they considered to be their favorite ASH 2017 myeloma abstracts. I am so pleased to provide the myeloma patient population the “Best of the Best ASH 2017 Myeloma Abstracts.”
Two of my firm beliefs have become 1) MRD (Minimal Residual Disease Testing) is integral to treatment success, and 2) Finding and treating myeloma in its earliest stages (MGUS or Smoldering) will prevent permanent organ damage and provide the best prognosis for CURE. As noted below, Dr. Landgren’s experience and focus hits both of these core beliefs.
Dr. C. Ola Landgren is the Chief of the Myeloma Service in the Division of Hematologic Oncology at Memorial Sloan Kettering Cancer Center and Professor of Medicine at Weill Cornell Medical College. Previously, Dr. Landgren was the Chief of the Multiple Myeloma Section at the National Cancer Institute (NCI) in the Center for Cancer Research. He is one of the pioneers in the development of MRD testing in myeloma, in collaboration with colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) and he implemented advanced MRD testing in clinical trials at MSKCC.
He is involved in the service’s rational treatment program (small molecule, monoclonal antibody, immune-based) for newly diagnosed, relapsed and refractory myeloma and amyloidosis patients. In addition, he studies the mechanism and markers of progression from MGUS/smoldering myeloma to symptomatic multiple myeloma, and the identification of high-risk precursor patients who may be candidates for early treatment. He has a strong interest in the development of early-treatment clinical trials targeting high-risk smoldering myeloma.
Dr. Landgren has chosen Abstract 435 as one of his favorites.
Abstract 435 – Minimal residual disease in multiple myeloma: Final analysis of the IFM 2009 trial.
Dr. Landgren states, “This large randomized study for newly diagnosed multiple myeloma confirms that sequencing-based MRD is more sensitive than flow cytometry (can rule out 1 tumor cell in 1 million cells versus 1 in 100,000), and that sequencing based MRD negativity has the same progression free survival independent of therapy (i.e. with versus without transplant). This study is clinically very important.”
Very significant improvements in survival have been observed in the past decade in multiple myeloma. This improvement is mainly due to the availability of new, effective drugs that have also improved response rates. With such combinations, the complete response rate increased from a few percent to up to 80%. Thus, the complete response rate cannot be anymore a realistic endpoint for trials, and more sensitive techniques are mandatory to try to monitor the real remaining disease burden. We used a very sensitive technique, immunoglobulin gene next generation sequencing, in a prospective trial to quantitate minimal residual disease (MRD), and to correlate with PFS (Progression Free Survival) and OS (Overall Survival).
The IFM2009 trial randomized 700 patients to received high-dose melphalan or not following a Revlimid/Velcade/dex induction. All the patients then received a 12-month lenalidomide maintenance. MRD was assessed before and after maintenance using the ClonoSeq kit by Adaptive. This kit enables to detect 1 tumor cell in 1,000,000 bone marrow cells. This MRD test is about 1000 times more sensitive than the method used to determine complete Response.
Minimal residual disease was evaluated in 269 patients who achieved at least very good partial remission (VGPR). Patients who did not achieve a very good partial remission were considered MRD positive. First, we found that sensitivity is very important. Patients with a MRD level below 10-6 presenting a significant better progression free survival than patients not achieving this level. We thus defined MRD negativity as patients with a MRD lower than 10-6. Using this cutoff, at a median follow-up of 55 months, the median PFS (see graph A) for patients achieving MRD negativity was not reached, versus 29 months for patients who did not reach MRD negativity (see figure). Second, we analyzed the results according to treatment arm. If more patients in the transplant arm achieved MRD negativity, we did not observe any difference in PFS in patients with MRD negativity, meaning that patients able to achieve MRD negativity without transplant present a similar outcome than those transplanted. Third, we looked at the role of high risk cytogenetics. High risk patients who achieved MRD negativity presented a significantly better outcome than standard risk patients who did not achieve MRD negativity, meaning that “high risk” is a dynamic concept that should be re-evaluated during treatment. Fourth, we did also observe a significantly longer overall survival in patients who achieve MRD negativity.
We showed that MRD could (should?) be considered as a novel surrogate biomarker for trial evaluation. This study showed that the best sensitivity is associated with the best discrimination in progression free survival and overall survival, and suggested that 10-6 should be the optimal cutoff.
Thank You, Dr. Landgren for such an outstanding favorite abstract and for all of your groundbreaking work on improved disease burden measurement and early treatment.