Journal of Clinical Pathways is pleased to present a new section called “CME Corner,” which will highlight, when available, relevant continuing medical education (CME) opportunities deemed to be of use to readers. Articles will include an overview of a specific area where key opinion leaders have determined there to be an educational need, and a link to the available CME program will be provided.
The CME program titled "Looking for One in a Million: Is MRD the New Primary Goal for Multiple Myeloma Treatment?" is currently available on this topic until October 31, 2019.
Minimal residual disease (MRD) negativity has been found to be perhaps the strongest prognostic factor associated with a long progression-free survival (PFS) in patients with multiple myeloma (MM). Both meta-analysis and individual studies have supported this finding.1,2 There is emerging evidence that MRD negativity is stronger than both clinical staging as well as fluorescence in situ hybridization and cytogenetics that can be tested on baseline samples.3 Therefore, it is important to consider MRD as a clinically significant prognostic factor in MM.
Data to support the significance of MRD in this setting was initially observed in the clinic; patients with MM who received newer, more efficacious therapies were more likely to have a longer progression-free survival than those receiving conventional therapy.4
It was observed that more patients were reaching a complete response. It was also observed in clinical practice among patients with complete response to therapy that the outcomes were not the same for every patient.4 These findings triggered the search for more sophisticated tests to determine if there was detectable disease in some patients in that complete response category. Perhaps, these efforts would be able to explain the difference in clinical outcomes. The resulting answer was a resounding “yes.” Researchers found that despite novel therapies delivering better complete responses, residual disease was still being observed in some patients and therefore complete response could not be counted on as a very good outcome measure for novel therapies.4
The other effort to validate MRD negativity as a strong prognostic marker in MM was a meta-analysis published in 2016.1 I helped lead this study in collaboration with the National Library of Medicine. There was a second meta-analysis that was initiated and designed by Celgene and written-up in collaboration with Celgene and Dana-Farber as well as others; that study examined the same studies as the first study and they included some older studies as well.2 Both meta-analysis showed similar results. The large takeaway is that there are meta-analyses showing that MRD negativity is a very strong predictor of PFS.
Published research stemming from many countries are now considering MRD negativity.5 In the newly-diagnosed setting, many of the clinical trials being opened in recent months include MRD negativity as a secondary endpoint. There are clinical trials close to opening for enrollment in which MRD will be the primary endpoint.6 This is the direction the field is going in because results can be obtained rapidly, which makes sense on the drug development side. Industry can develop drugs without having to wait for 5 or 10 years to see if there is a discernable difference between the experimental and control arms. Results can be obtained in close to 1 year, which also bodes well for patients.
On this same note, if a drug is toxic and proving to be not efficacious, we do not want patients to be exposed to it for a long time. It is better to stop those studies that are not delivering. When viewing the situation this way, it is a win-win: early approval for the efficacious and less toxic drugs, and early termination for those that are not successful.
As for the current state of technology for measuring and defining MRD negativity status, efforts to improve flow cytometry assays have been ongoing for years.7 However, flow cytometry machines are not the same across the board. Many centers in other countries still have only 4, 6, or 8 colors at the same time. Multiple studies in myeloma have found that there should be at least 10 antibodies in the assay to reliably rule out residual disease.8,9 Beyond the technical limitations and the instruments, there are many details that go into the exact handling and the preparation of the sample, as well as the choice of which antibodies to go into an assay. One laboratory may look at the same markers as another laboratory, but the antibodies could differ, and the preparation of the sample could differ. If the same patient attends these 2 laboratories, in one laboratory the patient could test MRD-positive and could test MRD-negative in the other.
There needs to be a standardized, validated test that is done the same way in every sample. In 2018, the first next-generation sequencing-based assay was cleared by the US Food and Drug Administration: the Adaptive assay.3,10 This assay is currently only available as a service from Adaptive Biotechnologies. It is a monumental step forward in terms of standardization. The technology has a higher sensitivity for detecting residual disease. There is data showing that in a sample that has high yield, the flow cytometry assay can rule out at least one tumor cell in 100,000 bone marrow cells.8,9 With the next-generation sequencing-based assay, this number raises to almost one cell in 1 million, which increases sensitivity by a factor of ten.3
We are now at a point where next-generation sequencing assays will gradually become available at multiple sites—both centralized laboratories and also academic institutions. As a result of the inevitable and continued emergence of MRD negativity, patients with MM will be treated faster with better therapies and spared from toxicities, and clinical recurrences will be avoided to a high degree. All of these results will surely impact survival.
The CME program titled "Looking for One in a Million: Is MRD the New Primary Goal for Multiple Myeloma Treatment?" is currently available on this topic until October 31, 2019.
References
1. Landgren O, Devlin S, Boulad M, Mailankody S. Role of MRD status in relation to clinical outcomes in newly diagnosed multiple myeloma patients: a meta-analysis. Bone Marrow Transplant. 2016;51(12):1565-1568. doi:10.1038/bmt.2016.222
2. Munshi NC, Avet-Loiseau H, Rawstron AC, et al. Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma: a meta-analysis. JAMA Oncol. 2017;3(1):28-35. doi:10.1001/jamaoncol.2016.3160
3. Perrot A, Lauwers-Cances V, Corre J, et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018;132(23):2456-2464. doi:10.1182/blood-2018-06-858613
4. Landgren O, Iskander K. Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomes. J Intern Med. 2017;281(4):365-382. doi:10.1111/joim.12590
5. Rossi G, Falcone AP, Minervini MM, et al. Minimal residual disease and log-reduction of plasma cells are associated with superior response after double autologous stem cell transplant in younger patients with multiple myeloma [published online December 13, 2018]. Cyometry B Clin Cytom. doi:10.1002/cyto.b.21755
6. Landgren O, Lu SX, Hultcrantz M. MRD testing in multiple myeloma: the main future driver for modern tailored treatment. Semin Hematol. 2018;55(1):44-50. doi:10.1053/j.seminhematol.2018.03.001
7. Mailanjody S, Korde N, Lesokhin AM, et al. Minimal residual disease in multiple myeloma: bringing the bench to the bedside. Nat Rev Clin Oncol. 2015;12(5):286-295. doi:10.1038/nrclinonc.2014.239
8. Roshal M. Minimal residual disease detection by flow cytometry in multiple myeloma: why and how? Semin Hematol. 2018;55(1):4-12. doi:10.1053/j.seminhematol.2018.02.011
9. Roshal M, Flores-Montero JA, Gao Q, et al. MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods. Blood Adv. 2017;1(12):728-732. doi:10.1182/bloodadvances.2016003715
10. FDA authorizes first next generation sequencing-based test to detect very low levels of remaining cancer cells in patients with acute lymphoblastic leukemia or multiple myeloma [news release]. Silver Spring, MD: US Food and Drug Administration; September 28, 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm622004.htm. Accessed February 27, 2019.
