Usmani Discusses MRD and Other Myeloma Developments

Saad Z. Usmani, MD

Although the importance of achieving minimal residual disease (MRD) negativity in patients with multiple myeloma has been established, further application in practice is dependent on phase III findings from ongoing trials, explains Saad Z. Usmani, MD.

“The next step is utilizing MRD as a potential surrogate for survival to then stop therapy or determine if something more needs to be done to achieve MRD negativity in a given patient,” said Usmani, who is clinical professor of medicine, UNC-Chapel Hill School of Medicine, chief, Plasma Cell Disorders Program, director, clinical research in hematologic malignancies, Levine Cancer Institute, Carolinas HealthCare System.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Multiple Myeloma and Myeloproliferative Neoplasms, Usmani, who was chair of the program, discussed the clinical applications of MRD and managing patients with relapsed/refractory multiple myeloma.Usmani: I spoke about MRD, the importance of depth of response in myeloma, and where that data come from. Then, I segued into some clinical data with prospective clinical trials looking at MRD negativity with different methodologies. There [are many] unanswered questions. Ultimately, MRD status should not be used to change treatment.

[We should] be on the lookout for the clinical trials that are asking those kinds of questions. If a patient has been on lenalidomide (Revlimid) maintenance for 3 years and they're MRD negative, can we stop treatment in those patients, or do we continue lenalidomide maintenance forever?

Does your initial treatment approach differ in patients who have MRD-positive disease versus MRD-negative disease?

For high-risk patients, what does surveillance entail?

What does the timeline look like for trials examining MRD as an endpoint?

After a very robust induction treatment with the conventional 3 drugs we use—bortezomib (Velcade), cyclophosphamide, and dexamethasone (CyBorD); lenalidomide, bortezomib, and dexamethasone (RVD); or even carfilzomib (Kyprolis), lenalidomide, and dexamethasone (KRd)—[can we] combine them with a CD38-targeted monoclonal antibody or anti-SLAMF7 monoclonal antibody? If we're achieving MRD after induction in a sizable number of patients, do they really need an autologous stem cell transplant? These are the questions we need to ask in clinical trials; however, they don't influence our practice as of now. For standard-risk patients, my clinical practice does not change. For high-risk patients, you have to be on high alert because any level of residual disease means that those patients will be at a high risk of relapse. That's where surveillance becomes important. In those patients, an early change in treatment is likely when we would make those treatment decisions. As a clinician, that's where I feel I can use MRD data. Outside of that, we still need to wait for the clinical trials to read out and help us understand what MRD positivity or negativity means in the context of clinical practice. These patients should be getting monthly myeloma markers. If they're in the maintenance setting, they are usually on more intensive maintenance regimens than standard-risk patients. They might be on both a proteasome inhibitor as well as an immunomodulatory drug. If they were presenting with extramedullary disease, it may be reasonable to evaluate with PET-CT scans once or twice a year during the surveillance period. I wouldn't make that recommendation for someone who has standard-risk disease, but with high-risk patients you have to be a little bit more vigilant. One European clinical trial looked at a bortezomib-based triplet induction regimen with or without daratumumab (Darzalex) following transplant. That particular clinical trial had MRD endpoints built into it. The IFM 2009 trial also had MRD endpoints built into it, but maintenance was restricted in the IFM 2009 study. Within the IFM 2009 study, MRD was evaluated at different endpoints. We have learned about the postinduction and posttransplant data, but we are still waiting on some long-term follow-up data to see how MRD patterns evolved in each of those 2 arms.

Is there anything else you would like to emphasize with regard to MRD?

There was a presentation at the 2017 ASH Annual Meeting last year from the IFM 2009 study that covered the initial part of MRD assessments. This highlighted the fact that patients who get a transplant have a better depth of response and higher MRD-negativity rates, which translates into better progression-free survival (PFS). We are already getting some inkling about MRD negativity being better for survival outcomes, [but we don’t know] how that pattern will evolve. Is achieving MRD within the first 6 months of diagnosis important, or [will] patients who achieve MRD at the end of 2 years of treatment have the same outcomes as someone who reached that endpoint earlier? We don't know the dynamics of how this will evolve.The significance of MRD negativity in newly diagnosed patients, especially in the transplant-ineligible population, is different compared with patients who are in their first relapse. For newly diagnosed patients, there's hope that you can cure myeloma. We're expending all of our energy in trying to come up with the right “recipe” for the right patient to achieve that goal.

Even though relapse patients at this time are achieving MRD negativity, they've already demonstrated to us that the disease comes back. In those patients, long-term disease control is going to be key.

You also lectured on relapsed/refractory myeloma. How has the management of this disease evolved?

MRD negativity is important for transplant-ineligible patients in the newly diagnosed setting, as well. However, in their situation, we're aiming for long-term disease control, since defining curability for an older, frail, transplant-ineligible patient is going to be exceedingly difficult. There might be MRD negativity 6 years after they're diagnosed. If they have a heart attack and pass away, we won't be able to say that they were cured; they were just in remission. The management of relapsed/refractory multiple myeloma is becoming quite complex with the number of new agents and combinations that have been approved over the past 2 to 3 years. We have to consider that every patient with relapsed/refractory myeloma is different.

Myeloma is very heterogeneous at the time of diagnosis, and even within a given patient you have clonal heterogeneity. A biopsy from the pelvic bone may have different clonality compared with a focal lesion that is biopsied from a different skeletal area. This builds into the concept of using the right combination chemotherapies for each given patient. You also have to keep in mind what they got previously and what kind of adverse events patients had from previous treatments.

Bearing those issues in mind, we looked at the various phase III trials and subgroup analyses in more depth. One of the challenges as a clinician is utilizing the phase III data that was used to get a combination or drug approved in clinical practice because the drug exposures patients may have had are very different.

Can you elaborate on some of those newer agents?

How does the evolution of CAR T-cell therapy in myeloma compare with the approach in other hematologic malignancies?

What is the greatest unmet need in relapsed/refractory patients?

My presentation covered some of those nuances, how to tackle the different clinical scenarios, and what combinations to use. It also covered some newer mechanisms of action, such as antibody-drug conjugates and CAR T cells that are coming down the pike for relapsed/refractory and, hopefully, newly diagnosed patients. I spoke about some HDAC inhibitors, specifically ACY-241, which is a selective HDAC6 inhibitor. There are combination data with that. I discussed data with isatuximab combined with pomalidomide (Pomalyst) and dexamethasone. Isatuximab is another CD38-targeted monoclonal antibody, which is a little different than daratumumab in terms of the CD38 epitope it binds to. I also talked about the BCMA-targeted antibody-drug conjugate being developed by GlaxoSmithKline. There are some promising data with that. I spoke about the CAR T-cell technology in the context of myeloma by summarizing 4 different constructs that have been presented at international meetings and the data around the 2 that are farther ahead in clinical development.It's probably further behind in development compared with the leukemia and lymphoma world, but the data that we've seen with the BCMA-targeted CAR T cells in terms of efficacy appear to be pretty good in terms of safety. The cytokine release syndrome (CRS) rates that we are seeing appear to be quite manageable for the most part. There are differences between the different constructs and, of course, stimulatory molecules. There are also some differences in the BCMA epitope that the constructs bind to. There will likely be differences in CRS rates based on that. There may be some constructs that don’t require a lot of cell dose, and that will potentially lower the CRS rates, as well. When patients become refractory to proteasome inhibitors and immunomodulatory drugs, the overall survival is about 8 to 9 months. The PFS is about 4 to 5 months. We definitely need new mechanisms of action to help our patients. We also need to understand the mechanisms of resistance in patients relapsing off of these therapies. One thing we also need to appreciate is that there is a difference between a patient on their third relapse within their first year of diagnosis compared with someone who is relapsing for the third time, 8 years after their diagnosis. Disease biology is important in the context of relapsed/refractory disease, as well.