By Gayathri Ravi, MD
What can induction quadruplet therapy do for patients with Newly Diagnosed Multiple Myeloma (NDMM) and does that include next-generation sequencing? So we adopted a institutional strategy to start do quadruplet induction therapy with a 4 drug-based induction for multiple myeloma from the March of 2020. And since UAB is the only transplant center in the state of Alabama, we have entire state of population who are transplant eligible and are nearly diagnosed with multiple myeloma referred to UAB for transplant. So we have an established communication pathway with our community oncology partners. And so we made it a standard of care for all of the patients who are transplant eligible in cooperation with our community partners to start with quadruplet induction therapy and then once they finish 4 cycles of induction we would do an MRD (minimal residual disease) testing with ClonoSEQ at that time. And then again post-transplant between day 60 and day 80, we would do another MRD assessment with the ClonoSEQ from the bone marrow. And if patients were able to get to 2 MRD negative results, then they were given an option of discontinuation of therapy or if they did not achieve that MRD sure phase then they would proceed with additional cycles of consolidation and maintenance until they were able to get to that phase of MRD sure.
And if they did not achieve at any time point the MRD (minimal residual disease) sure. Then they would proceed with maintenance therapy, which is ongoing without any interruption, which is per the standard of care. And then the important highlights of our study that we noted was that 60% of our patients were induced in the community, which is reflective of the real world practice.
And we also were able to track MRD (minimal residual disease) sequences in about 88% of our study population. Which is again very Impressive for a real world data that we were able to establish this pathway and we were able to get results in a meaningful way for almost all patients, like 88% significant number to get results on.
So what we did find was that was very, the real world data of the ability to achieve MRD (minimal residual disease) negativity was very reflective of what happened in clinical trial setting, like GRIFFIN's, where the rates of MRD negativity, post induction and post transplant was very similar to what we got in the clinical trial setting and which is again reiterating the fact that this is doable in the real world.
I think the questions that I was asked regarding the study was mainly the feasibility of how were we able to establish this in the real world setting? And I think it's by establishing a good academic community pathway where we all, we work in collaboration with our community partners so that irrespective of where the patients get induced or for their, my new diagnosis of myeloma, the treatment will be the same.
So the data that we get or comparable, and that was one question. Then the next one was the testing of MRD (minimal residual disease), the technique that we used and why we picked it. So the technique that we used was ClonoSEQ which has a very high sensitivity of one in a million cell being a cancer cell that can be detected by identifying clonal sequences. And this has been very well validated across multiple clinical trials. So we know the results are reliable and that's why we chose to go with ClonoSEQ testing for the MRD and I think those were the major questions. And what was also the patient response in terms of when we tell them what is their, like how do we make the patients understand the significance of MRD?
And I think when we tell the patients from the time that we meet them, at the time in the beginning for evaluation of transplant we tell them that, we would like them to get their bone marrow done here because we could send it for the additional layer of testing with ClonoSEQ.
We were able to detect to a level of one in a million cell from the bone marrow if it's a cancer cell. Patients actually do not mind driving that extra 2 hours to come here to get the bone marrow testing done. And what I also noticed was that, even when they come for follow up, they remember that and are able to ask specifically, you told me this testing was going to look at this one in a million cell level of debt. Can you tell me what my number was? So I think it creates an awareness both in the patients as well as the practice and community partners, the significance of doing MRD testing in the real world practice.
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"Complete remission" is one of the most desirable phrases a patient might hear after completing a course of treatment. On the basis of scans and lab tests, there is no trace of cancer, indicating that the therapy has been successful.
However, there is another term that can be rather perplexing to patients: minimal residual disease (MRD). Physicians frequently employ this word when treating patients with blood malignancies such as leukemia, lymphoma, and multiple myeloma.
In order to assess MRD (minimal residual disease), we now have access to significantly more sensitive assays. These may include next-generation sequencing (genomic sequencing), which enables us to study bone marrow samples for genetic alterations. Even if nothing is visible under a microscope, the presence of mutations indicates the presence of limited illness residuals.
Flow cytometry permits us to examine for aberrant proteins on the cell surface in the same samples. By calculating the number of cells containing aberrant proteins, we can have a clearer understanding of the number of cancer cells that remain. Using these novel assays, we frequently attempt to quantify whether a patient has MRD (minimal residual disease) after receiving normal treatment.
There is much to be gained. These malignancies can adapt to therapy, which means that the cancer we have before treatment is not the same as the cancer we have after treatment. By examining the minimal residual disease (MRD), we can learn more about what remains following treatment.
This facilitates several tasks. First, it enables us to change our treatment by adding drugs that target specific vulnerabilities in the cancer cells, including those that are very effective at killing even residual cells, or by performing a stem cell transplant, which is capable of eliminating residual cells.
I think MRD (minimal residual disease) is a very well established prognostic marker. And like I have mentioned that most of the minimal residual disease (MRD) applicability so far has been done within the clinical trial setting. So looking at how we are going to move that into a real world, practice setting is going to be critical. And also there was a recent just for in this ash the Spanish group did present data comparing the IMWG (International Myeloma Working Group) response, even if you achieved a CR (complete response).
But if the patient was not able to achieve MRD negativity, then their progression-free survival (PFS) was very similar to a patient achieving a less than CR response. So that again stresses the importance of MRD, monitoring MRD status in a patient getting treated for multiple myeloma. So we make timely and timely decisions in the, in an appropriate setting.
The introduction of new medications and subsequent novel combinations for the treatment of newly diagnosed multiple myeloma (NDMM) has led to an abundance of treatment alternatives that might make the selection of initial induction therapy difficult. A better understanding of both patient- and disease-specific characteristics can facilitate the development of a customised treatment plan. Historically, the selection of an induction regimen has been based on a patient's initial transplant eligibility assessment at the time of diagnosis. As more successful and well-tolerated induction regimens have emerged, there has been a growing overlap in the induction techniques employed for all patients with newly diagnosed multiple myeloma (NDMM), which increasingly provide the ultimate aim of profound and long-lasting remissions. Using the best available data, the current therapeutic options and methods for the management of newly diagnosed multiple myeloma (NDMM) are examined to provide justification for these decisions.
What we are actually planning to look at is especially for patients whom we have discontinued and are being monitored in the minimal residual disease (MRD) sure phase. What is the durability of response? It's important to know, and also we have to know more about how frequently do we need to monitor MRD. Those are questions that are still unanswered.
In terms of how frequently we should monitor the testing and what additional parameters should be used in addition to MRD to predict earlier relapse or earlier progression.
I think the main takeaway is MRD monitoring can be done in real world practice. So it, there has to be an awareness created that MRD applicability in the real world setting outside of a clinical trial. Needs to be a part of regular monitoring of a patient getting treated for multiple myeloma.
The main thing is that again, the clinical trials setting, there is a lot of resource support and there is a lot of monitoring that happens. So extrapolating a data from a clinical trials setting to a real world practice needs to have a very clear, established pathway. And I think coordinating with our community partners is critical. The care is standardized for all our patients, irrespective of where they get their treatment. The monitoring becomes more uniform, the treatment is more standardized. And that is very important for all our patients.
Gayathri Ravi, MD - About The Author, Credentials, and Affiliations
Gayathri Ravi, MD, is a hematologist who practices in Rochester, Minnesota. She is linked with a number of hospitals in the surrounding area, including the Mayo Clinic and the University of Alabama at Birmingham Hospital, amongst others. She attended PSG Institute of Medical Sciences and graduated with a medical degree there. Dr. Ravi is an expert in treating problems related to the blood, spleen, and lymph glands, including anemia, coagulation disorders, sickle cell disease, hemophilia, leukemia, and lymphoma. His specialty is in the field of hematology.
MD Anderson Cancer Center - What is minimal residual disease (MRD)? MD Anderson Cancer Center, July 15, 2020
ASH Publications - Newly diagnosed multiple myeloma: making sense of the menu. ASH Publications, December 9, 2022