FDA Approvals and Prize-Winning Research Are Welcome Good News for Myeloma Patients
October 04, 2018
FDA Approvals and Prize-Winning Research Are Welcome Good News for Myeloma PatientsWRITTEN BY: Brian GM Durie MD
On September 28, the US FDA permitted marketing of ClonoSEQ assay, a next-generation sequencing (NGS) test used for assessing minimal residual disease (MRD) in multiple myeloma. This is excellent news and strongly supports the validity of MRD testing as a major predictive indicator. In parallel with this announcement, the MRD testing results in the IFM 2009 trial (evaluating VRd ± ASCT) were published in Blood.
“The IFM 2009 analysis demonstrates that MRD is the most important prognostic indicator in myeloma clinical trials when it is measured by a highly sensitive NGS MRD test,” said Hervé Avet-Loiseau, MD, PhD, Head of the Laboratory for Genomics in Myeloma, University Cancer Center Toulouse, and co-corresponding author. “In the study, patients who achieved MRD negativity with NGS MRD testing, which is able to detect a single myeloma cell among 1 million healthy cells, had better outcomes regardless of treatment, risk factors or disease stage. Given that MRD-negative patients can still relapse, these results demonstrate the importance of evaluating patients at diagnosis and monitoring them throughout treatment and remission, and it suggests this approach could be used to adapt treatment strategies in future clinical trials.”
Key Next Step
The key next step is the approval by the Food and Drug Administration of MRD testing as an endpoint in clinical trials (a goal set out by the Black Swan Research Initiative upon its launch in 2012). This step requires the submission of results from multiple clinical trials that have included MRD testing to validate MRD testing as a “surrogate endpoint” superior to traditional endpoints, such as CR (complete remission) or even sCR (stringent complete response). A special team called the i2TEAMM has been created to achieve this objective. Led by Drs. Nikhil Munshi, Jesús San Miguel, and myself, the team will incorporate data from both NGS and NGF (next-generation flow) testing in both frontline and relapse trials for submission to the FDA. A meeting with the agency is scheduled for December 11, 2018.
If te FDA submission is successful, new myeloma therapies will be available much faster, and the costs of large clinical trials will be drastically reduced. Why? Well, if one therapy produces more MRD negativity (especially at the deep response level of ≥ 10-5 , such as 10-6 [0/million bone marrow cells]) than another therapy, the higher level of MRD negativity can be considered to indicate better therapy. This will make a huge difference in the conduct of clinical trials. MRD negativity at between 9 and 12 months from the start of therapy can indicate superiority over having to wait several (maybe many, many) years to compare ultimate outcomes in a trial.
Bottom Line on MRD
The good news is that MRD testing is moving forward. By next year at this time, it is hoped that FDA surrogacy for approval will also be in place. But in the meantime, MRD testing is recommended only in a clinical trial setting until we have a better understanding of what MRD negativity or positivity means in terms of further therapy for patients who are not in clinical trials.
In Other News
On October 1, the US FDA approved a supplemental New Drug Application (sNDA) to expand the prescribing information for Kyprolis® (carfilzomib) to include once-weekly dosing (once-weekly KD 70 [carfilzomib 70 mg/m2]) for patients with relapsed or refractory multiple myeloma. This is definitely good news for patients! The once-weekly schedule, which in the [previously reported] ARROW trial achieved both excellent PFS (progression-free survival) and ORR (overall response rate), and comparable safety versus the twice-weekly schedule, is a much more convenient option. The approval took a relatively short amount of time—just over one month—thanks to a new FDA mechanism with a relatively long name: Oncology Center of Excellence Real-Time Oncology Review and Assessment Aid Pilot Program.
2018 Nobel Prizes
This year’s prizes remind us how much we depend upon basic research to understand disease and develop new therapies. The prize in physiology or medicine went to James P. Allison of MD Anderson Cancer Center and Tasuku Honjo of Kyoto University in Japan. The award was for breakthrough research of the immune system.
Around Christmas in 1994, Allison saw the results of a key mouse experiment, in which blocking antibodies to CTLA-4 (an important receptor between T cells and other cells) unleashed the T cells to attack and kill cancer cells. The mice were cured in these experiments! This led to the development of ipilimumab, a monoclonal antibody used to treat melanoma and approved in 2011 by the FDA. A truly amazing chain of events.
In 1992, Dr. Honjo had discovered something similar—a protein called PD-1, which also operates as a brake on T cells. You may have heard of the PD-1 monoclonal antibody inhibitors pembrolizumab (Keytruda®) and nivolumab (Opdivo®), both of which were initially approved in 2014 for the treatment of melanoma. These anti PD-1 checkpoint inhibitors are very effective and have been tested in myeloma. Unfortunately, as I have reported, IMiD/PD-1 inhibitor combinations produced unexpected toxicities and new studies are currently under review.
The breakthrough understanding of how these T cells can attack cancer cells has prompted an explosion in immunotherapy research and treatment development, including the use of CAR T cells and bispecific monoclonal antibodies linking T cells to myeloma cells, as described in the journal Cell.
So, basic research is leading to amazing new therapies.
The 2018 Nobel Prizes in both chemistry and physics also have important applications for the study of the immune system and have led to better understanding and the introduction of new treatment strategies. As reflected in the mission of the International Myeloma Working Group, collaboration among researchers is vital for translating more fundamental research into practical applications. And while the Nobel Prizes went to the scientists, the real winners are the patients who experience better outcomes as a result.
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