MRD testing in myeloma takes center stage
Last week’s 4th Annual ESLHO (European Scientific foundation of Laboratory Hemato Oncology) Symposium in Zurich, Switzerland was the first ever dedicated exclusively to examining “New Developments in MRD Diagnostics.” The two-day event provided a comprehensive review of the current status of MRD (minimal residual disease) testing and future options, and included comments from Dr. Gerald Marti (Medical Officer, Center for Devices and Radiological Health, US Food and Drug Administration) on possible FDA approval of both the MRD tests themselves and acceptance of MRD negativity as a new treatment endpoint.
A bit of background
The ESLHO consortia which organize these meetings (ably chaired this year by Prof. Jacques van Dongen, MD, Erasmus University, Rotterdam, The Netherlands) are scientific working groups of the European Hematology Association (EHA). This is very similar to the IMF’s Black Swan Research Initiative® (BSRI), which is a working group of the International Myeloma Working Group (IMWG). Both groups are very much focused on MRD, with the BSRI—as you might suspect—fully dedicated to the area of myeloma.
As regular readers may know, a key underpinning of the Black Swan Research Initiative approach to finding a cure for myeloma is the highly sensitive assessment of any remaining disease. Therefore, the ESLHO symposium—with attendees from around the world—was an ideal forum in which to highlight the progress made by our research collaborators.
Prof. Alberto Orfao (University of Salamanca, Spain) provided an overview of new developments in MRD detection in his introduction. He emphasized the importance of the joint collaboration between the EuroFlow Consortium and the IMF’s Black Swan Research Initiative in developing the Next Generation Flow (NGF) cytometry for MRD detection in myeloma. This has really spurred the development of MRD detection in myeloma ahead of the other hematologic malignancies, which were also discussed in detail at the meeting.
‘A completely new and innovative approach’
As Prof. Orfao noted, NGF “provides a completely new and innovative approach.” It is obviously disease (myeloma) -specific and provides rapid, accurate, sensitive, and reproducible results. New computer software and database tools give test results in 13 minutes! Greater sensitivity is achieved by several factors, including special sample preparation, routinely analyzing more cells, and using 8 antibodies (to give 8 colors) versus previous 4 or 6 antibody (color) approaches. There is also the potential to expand to 10 or 14 colors if needed. The fundamental point is that this approach to measuring MRD is standardized and standard operating procedures (SOPs) are available for global use.
Pros and cons of two MRD testing methods
The myeloma panel discussants in Zurich were Drs. Ola Landgren (Memorial Sloan Kettering Cancer Center, New York); Bruno Paiva (University of Pamplona, Spain), and Philippe Moreau (University Hospital, Nantes, France). Prof. Orfao and I co-chaired. I gave an overview of the IMF’s Black Swan Research program and evaluated the significance and importance of the new, sensitive MRD testing achievable using both NGF and Next Generation Sequencing (NGS), the alternate molecular approach. Both methods detect disease at the one-in-a-million level—meaning that if there are a million cells, the presence of just one myeloma cell can be detected.
The pros and cons of both methods were reviewed: NGF needs fresh samples; NGS can use stored samples. NGS does not give answers in 10-15% of cases; NGF gives results in all cases—and is more widely available and cheaper. Traditionally, the flow method has been less reliable. Thus, investigators have preferred NGS, which is tracking the myeloma clone. But now, with the very reliable NGF method, the picture has changed. In addition, we now understand that there are multiple myeloma subclones, and those can be detected and studied using flow (NGF). We are now really at a transition point during which the evidence demonstrates the clear advantages of using the new NGF method.
Is MRD monitoring feasible today?
Dr. Landgren discussed the feasibility of MRD monitoring at the present time. Obviously, the need for repeated bone marrow samples is a serious negative for patients. He emphasized the need for a blood test that would also avoid potential sampling problems in the bone marrow. (The IMF, through the BSRI project, is well on the way to identifying a blood test. This will really change the landscape for routine MRD monitoring.) Dr. Landgren also raised the question of whether the 1 in a million sensitivity is sensitive enough. I think only time will tell.
Deeper responses, longer remissions
Dr. Bruno Paiva reviewed all the data correlating MRD testing with the outcomes of the patients. These data came mostly from Spanish trials, but also from UK trials and other trials globally. The correlations are impressive! Deeper responses clearly lead to longer remissions.
The lingering question is: “At what point can we declare that a patient has achieved a functional cure—a likely very long or permanent remission?” Much more work is needed to assess this point. As BSRI moves into phase two, the “Cure Trials” will provide the framework to assess if early aggressive treatment can achieve a permanent MRD-negative status. Obviously, we need to be aware of some patients who have a permanent “MGUS status” or “signature”: the disease is not gone, but is in a benign state.
In addition, MRD-positive patients will need additional novel therapies. Dr. Moreau discussed the novel therapies potentially available in this MRD-positive setting. The most promising results have been seen in both daratumumab (as well as the SAR compound, both anti-CD38 agents) and elotuzumab (anti-SLAMF7).
By the end of the Zurich symposium it was clear that more work needs to be done to gain FDA approval of the MRD tests themselves and acceptance of MRD negativity as a new treatment endpoint. But there was broad optimism that the future is bright and that MRD testing will be a new standard in myeloma care very soon!
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.