MRD Could Prove to Be a Valuable Tool in Multiple Myeloma

Marc J. Braunstein, MD, PhD

The addition of daratumumab (Darzalex) to up-front triplet and quadruplet regimens in multiple myeloma has contributed to increased depth and durability of response, and although minimal residual disease (MRD) assessment has proven to be a sensitive and specific means of assessing the likelihood and length of remission in a research setting, it should not yet be used to direct treatment decisions, said Marc J. Braunstein, MD, PhD, who instead highlighted patient fitness as one of the primary measures upon which to base initial interventions.

“What we aim to do in the field is figure out how to best tailor combinations of these therapies in order to produce the longest duration of remission and the longest overall survival. Many trials are using MRD as an end point in order to look at the deepest possible remissions that we can achieve using various combinations of these novel agents,” said Braunstein.

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on multiple myeloma, Braunstein, assistant professor in the Department of Medicine at NYU Long Island School of Medicine; course co-director of the Hematology-Oncology System and co-director of the Autologous Stem Cell Transplant Program, NYU Winthrop Hospital of NYU Langone Health’s Perlmutter Cancer Center, discussed the current landscape of newly diagnosed multiple myeloma and the utility of MRD in the research sphere.

OncLive: How is MRD being used to differentiate between the novel agents and regimens in multiple myeloma?

Braunstein: We’re seeing a tremendous expansion of the armamentarium of agents we have to treat newly diagnosed and relapsed/refractory multiple myeloma. In the past 4 or 5 years, we’ve seen an increase in the use of monoclonal antibodies targeting various antigens on the surface of malignant plasma cells in newly diagnosed and relapsed/refractory myeloma. We’re also seeing an increase in the use of additional agents targeting various mechanisms of neoplastic myeloma cells, including inhibitors of nuclear export, as well as inhibitors of BCMA.

What we aim to do in the field is figure out how to best tailor combinations of these therapies in order to produce the longest duration of remission and the longest overall survival. Many trials are using MRD as an end point in order to look at the deepest possible remissions that we can achieve using various combinations of these novel agents.

How is MRD typically evaluated, and how would you define its uptake in the field?

MRD is used in many other hematologic malignancies but is now becoming more standard in terms of regulatory approval for novel agents, and in clinical trials as a primary end point. MRD is a measure of how deep a remission you can achieve in a patient with multiple myeloma. There are 2 primary assays that are used to assess this: one is flow cytometry, where you’re looking with various markers on plasma cells to see how many residual cells there are at the end of treatment, and the other assay is an FDA-approved assay that uses next-generation sequencing to compare the initial clone when the patient was first diagnosed to see if there are any residual clones compared with their diagnosis at the end of treatment. Therefore, you need a comparator sample for that assay. They each have pros and cons. Both are able to look at the depth of MRD at a level between 10-5 and 10-6 remaining cells. They definitely are useful in terms of being very sensitive, and even specific.

The question we have yet to answer is how to make certain treatment decisions depending on whether a patient has MRD, despite having a deep remission by standard assessment criteria. [For example], if the patient has a complete or stringent complete remission [CR] but is still MRD positive, we still have unanswered questions about what to do with those patients after induction. Nevertheless, it’s clear that patients who do achieve MRD negativity have much better overall outcomes, including better survival than those who remain MRD positive. This can be a very valuable end point for clinical trials, because it can be assessed relatively easy without waiting for the duration of PFS that is historically used as the primary end point.

In terms of community uptake of MRD assays, it still varies. There’s no one standard assay that’s used from office to office. We’re going to be seeing more use of MRD, both in clinical trials and in practice. As time goes on, we’ll have answers to more important questions, such as what to do when you have a patient who is persistently MRD positive or goes from being MRD negative to MRD positive, despite absence of other indices of progressive or relapsed disease.

What goes into a comprehensive assessment of patient fitness?

There is an art to managing patients with multiple myeloma. Patients are best served by seeing clinicians who manage a larger cohort of myeloma patients in order to help them navigate through all the different options as well as assess the patient’s fitness. In oncology, we’re accustomed to assessing how fit a patient is in terms of their performance status. But even more so in multiple myeloma, we now have data supporting the use of frailty scores that take into account a more comprehensive assessment of the patient’s fitness for more or less intensive therapies.

Determining how fit a patient is has to be the first assessment that is made [to understand their eligibility for] the various lines of therapies as well as the trajectory for consolidation with autologous stem cell transplant [ASCT]. A lot of new data and updates of studies have compared the role of up-front ASCT versus standard of care agents, and we’ve seen better outcomes when we consolidate the disease with ASCT in those who are eligible.

How would you characterize the additive benefit of daratumumab to frontline triplet and quadruplet regimens?

When it comes to assessing and treating newly diagnosed patients with multiple myeloma, we have several combination regimens, including 2-, 3-, and 4-drug combinations. That’s why we really have to tailor and individualize our treatment decisions for these patients. We’ve seen a lot of new data in the past few years as well as updates at the recent 2020 ASH Annual Meeting and Exposition for the inclusion of daratumumab, which targets CD38 on myeloma plasma cells, as part of triplet and quadruplet regimens. The combination of daratumumab, lenalidomide [Revlimid] and dexamethasone was studied in the phase 3 MAIA study, and showed impressive outcomes at a 48-month median follow-up. The [48-month] progression-free survival [PFS] rate was 60%, and the median PFS hadn’t been reached in the triplet arm.

In transplant-eligible patients, we saw impressive data from the phase 2 GRIFFIN study, which was presented by Jonathan Kaufman, MD, of Winship Cancer Institute, and colleagues as an update at the 2020 ASH Annual Meeting and Exposition, showing that at 12 months of follow-up, at every step from induction through transplant, consolidation, and maintenance, patients who got the quadruplet regimen of daratumumab, lenalidomide, bortezomib [Velcade], and dexamethasone [D-RVd] had better overall outcomes compared with patients who received lenalidomide, bortezomib, and dexamethasone alone; this included depth of response and MRD negativity. At our institution, we have adopted this regimen of D-RVd for fit patients who are transplant eligible.

How has the utility of monoclonal antibodies evolved?

The initial randomized data we saw for the use of monoclonal antibodies in multiple myeloma was demonstrated in the relapsed/refractory setting after at least one line of therapy. In those studies, we saw impressive results in terms of the PFS when daratumumab was combined with 2 other agents, either bortezomib and dexamethasone, or lenalidomide and dexamethasone in the POLLUX and CASTOR studies, respectively. Those pivotal phase 3 studies showed a PFS [benefit] in the triplet arm versus the control arm, even in high-risk patients.

Now, when we when we look at the data for the up-front use of daratumumab for patients [with newly] diagnosed multiple myeloma, we do see impressive results in quadruplet or triplet regimens compared with controls that do not contain a monoclonal antibody when it comes to PFS and MRD negativity. However, we have not yet seen a benefit for high-risk patients. A meta-analysis showed a possible signal of benefit in those patients, but in the individual studies, either MAIA, ALCYONE, CASSIOPEIA, or GRIFFIN, we didn’t exactly see a benefit in the subgroup analysis for high-risk patients, although the numbers of those patients were relatively small. We’re going to be seeing increasing use of monoclonal antibodies up front for multiple myeloma.

In the relapsed/refractory setting, we’re not only going to be seeing an increased use of these immunotherapies, but also an increased array of options that target different antigens on myeloma cells. The most recently approved antibody we have for relapsed/refractory disease is belantamab mafodotin [Blenrep], which is the first-in-class antibody that targets BCMA. It’s also an antibody-drug conjugate that delivers cytotoxin directly to the plasma cells. This was studied in the relapsed/refractory setting and updated data were presented at the 2020 ASH Annual Meeting and Exposition. In combination with other conventional agents, we see between a 60% to 70% overall response rate in very refractory patients. We’re going to have a lot more options in terms of monoclonal antibodies, including ones that target novel agents that are in preclinical or early phase studies, such as BAFF, RASi, and other surface antigens that are in the pipeline that are being targeted.

One of the one of the advantages of treating multiple myeloma is there’s so much progress being made. One of the detriments is that it can be challenging to determine how we’re going to sequence these agents. However, that’s a good problem to have, and we’re going to have many more options for patients who progress.