MRD-Guided Treatment Approaches Under Study Across Hematologic Malignancies

Shaji K. Kumar, MD,

The step toward quadruplet regimens in multiple myeloma, although effective, has prompted questions over the necessity of treatment intensification in all-comers, which investigators hope to define with minimal residual disease (MRD)–guided clinical trials, explained Shaji K. Kumar, MD, who added that other research avenues in hematologic malignancies include the evaluation of therapeutic classes, including CAR T-cell therapy, antibody-drug conjugates, and JAK2 inhibitors.

“A lot of progress has been made across hematologic malignancies. Understanding the mechanism of action, the drugs, especially the newer drugs, and the toxicities that can come with them needs to be kept in mind when you start new therapies in the clinic,” Kumar said in an interview with OncLive® following an Institutional Perspectives in Cancer webinar on hematologic malignancies.

In the interview, Kumar, chair of the event and consultant and professor of medicine in the Division of Hematology, Department of Internal Medicine at Mayo Clinic, discussed key takeaways from each presentation on chronic lymphocytic leukemia (CLL), myelofibrosis, relapsed/refractory diffuse large B-cell lymphoma (DLBCL), CAR T-cell therapy, and multiple myeloma.

OncLive^®: What has been the biggest shift in multiple myeloma management over the past year?

Kumar: There have been a lot of changes in the treatment of patients with multiple myeloma overall, and the focus [of my presentation] was on some of the newer therapies that are going through clinical trials and updates that were presented at the 2021 ASH Annual Meeting and Exposition. In terms of newly diagnosed multiple myeloma, there’s increasing amounts of data with the use of 4-drug combinations, which appear to be more effective in terms of inducing responses compared with the 3-drug regimens. We don’t have a lot of mature data in terms of the progression-free survival [PFS] and overall survival for all these quadruplets yet, but those data are eagerly awaited. While we wait for those data, patients with high-risk multiple myeloma seem to be a subgroup where using these more effective regimens that are more likely to induce MRD negativity appears to be helpful.

In terms of the role of stem cell transplant, some of the more recent updates from the phase 3 trials continue to demonstrate a value for doing autologous stem cell transplant in the transplant-eligible patient population. Post-transplant maintenance routinely [consists of] lenalidomide [Revlimid]. In patients with high-risk disease, we tend to use more of the proteasome inhibitor and immunomodulatory drug [IMiD] combinations for maintenance as well.

In relapsed disease, we have seen a lot of immunotherapeutic approaches that appear to be quite effective. We have 2 CAR T-cell products that are currently approved, and there was updated data with ciltacabtagene autoleucel [cilta-cel; Carvykti] at the 2021 ASH meeting, showing nearly a 100% response rate with a median PFS of close to 2 years, which is quite encouraging in this late stage of disease.

We also saw a wide array of bispecific agents targeting 3 different antigens: BCMA, GPRC5D, and FcRH5, all of which appear to be quite effective with response rates between 60% and 70% and have manageable toxicity. We also saw some data with targeted agents like iberdomide, which appear to be effective in patients who are refractory to the current IMiDs, as well as updated data with venetoclax [Venclexta] demonstrating activity in patients with translocation 11;14 or high expression of BCL-2.

Across the board, we are seeing improved therapies, particularly new drug classes, and combinations that can induce very deep responses, and often lasting responses.

What questions and research avenues would you like to see explored?

A relevant question for the myeloma field is: What is the role of daratumumab [Darzalex] in maintenance therapy? The CASSIOPEIA trial [NCT02541383] showed that daratumumab is better than placebo, but we don’t have data to say whether daratumumab is comparable to lenalidomide or whether adding daratumumab to lenalidomide is better than lenalidomide alone for maintenance therapy.

We also have a wide array of studies looking at the clinical utility of MRD testing in terms of changing therapy. Ongoing phase 3 trials are looking at whether we can discontinue therapy based on MRD negativity, or whether we need to intensify therapy based on MRD positivity. With all these new therapies, especially the immunotherapies, one of the big questions is: Can we use different types of immunotherapies eventually, and can we combine immunotherapies with some of the other standard-of-care agents?

Veronika Bachanova, MD, PhD, of Masonic Cancer Center, and Yi Lin, MD, PhD, of Mayo Clinic, spoke about CAR T-cell therapy options in myeloma and lymphoma. What is exciting about these agents? What should be known about their use?

The CAR T-cell therapy approaches appear to be particularly effective in lymphoma and myeloma, and we have plenty of data [in that arena] right now. In the setting of lymphoma, there have been phase 3 trials now, 3 of which were presented at the 2021 ASH meeting, comparing the approach with autologous stem cell transplant [and] in the relapsed setting too, showing improved outcomes and one, not quite. Those are some of the more mature data that we have for the utility of CAR T-cell therapy in lymphoma. In myeloma, both idecabtagene vicleucel [Abecma] and cilta-cel seem to have shown significant activity in patients with late-stage disease who have become refractory to other therapies. This data show [that CAR T-cell therapy] is a very attractive platform.

CAR T cells are associated with some toxicities, and careful patient selection is important. Both speakers went over how we can select patients better and how best we can manage the toxicities we see after CAR T therapy, particularly the neurotoxicity as well as the cytokine release syndrome that is seen commonly in these patients.

They also alluded to the management of prolonged cytopenias that can be seen in some patients, as well as increased risk of infections and [spoke about] infection prophylaxis, particularly with respect to COVID-19, which was also discussed at great length.

How do you approach patient selection for CAR T-cell therapy?

Patient selection with CAR T-cell therapy right now is often limited by the label that these products have. In the myeloma setting, we are always looking at patients who have had at least 4 lines of therapy, which does limit the patient population to [those with] late-stage disease. Then, patient-specific characteristics need to be considered, such as reasonable cardiac and pulmonary function, renal function, and now significant central nervous system issues.

Those all have to be taken into consideration when we select patients for CAR T-cell therapy. This is even more important given the fact that we have limited availability for CAR T-cell therapy, particularly for patients with myeloma. We want to make sure we select the patients who are going to get the maximum benefit with the least amount of toxicity.

What was stressed in the presentation Ayalew Tefferi, MD, of Mayo Clinic, gave on myelofibrosis?

Dr Tefferi touched upon the variety of aspects of myeloproliferative disorders, including the current disease classification and the prognostic criteria that are used for myelofibrosis as well as other related myeloproliferative neoplasms, like essential thrombocythemia and polycythemia vera. He highlighted the importance of prognostication in patients with the current systems. He also highlighted the curative potential of allogeneic stem cell transplant and where we might end up using that approach compared with more palliative options, which are more directed toward symptom management.

He highlighted the use of a variety of drugs in the setting of myelofibrosis for managing anemia, such as hydroxyurea, as well as the use of JAK2 inhibitors for managing symptomatic splenomegaly and spoke about the role of JAK2 inhibitors for treatment of constitution symptoms. He went over the pros and cons of currently approved drugs, particularly ruxolitinib [Jakafi] and gave some initial data [supporting] the role of fedratinib [Inrebic], which is one of the newer JAK2 inhibitors for treatment. He went over the pros and cons of many of these newer drugs from the same class as well.

He also highlighted the differences in terms of toxicity that we see with the JAK2 inhibitors, and he talked about how when we stop therapy, we have to be very careful to try and avoid some of the inflammatory response, which can happen after the drug withdrawal.

Stephen Ansell, MD, PhD, of Mayo Clinic, discussed advances in relapsed/refractory DLBCL. What has been the most notable advance over the past year? What other approaches are being explored as potential treatment avenues? 

He highlighted several recent advances in the management of DLBCL, including the data from the POLARIX study [NCT03274492], which compared polatuzumab vedotin-piiq [Polivy]/R-CHP [rituximab (Rituxan), cyclophosphamide, doxorubicin, and prednisone] with the current standard-of-care R-CHOP [R-CHP plus vincristine] in untreated patients with DLBCL. The data showed some benefit with the new regimen, particularly in terms of PFS.

He also talked about 2 phase 3 studies that have looked at adding lenalidomide to R-CHOP, both of which have been published, and how the differences [in outcomes] might be related to some of the underlying abnormalities in terms of the germinal center of these subtypes of lymphomas. He also talked about phase 2 data with polatuzumab vedotin and bendamustine/rituximab in patients with relapsed lymphoma. He briefly touched upon some of the data with bispecific antibodies for the management of relapsed disease as well, which is another class of immunotherapy that seems to have activity across all hematological malignancies, particularly the lymphoid malignancies and plasma cell disorders.

In the presentation Sameer Parikh, MBBS, of Mayo Clinic, gave on treatment in CLL, he spoke about the use of BTK inhibitors. How are these agents being incorporated into more time-limited treatment strategies?

Dr Parikh comprehensively covered the current approach to the treatment of patients of CLL. He highlighted the fact that we have moved away from traditional chemoimmunotherapy and toward BTK inhibitors. He specifically talked about the BTK inhibitors that are available, some of which are approved and some not yet, highlighting the differences in terms of efficacy and toxicity between them.

He also highlighted the data that he has been presented with the use of the BCL-2 inhibitor venetoclax [Venclexta] and the combination trials with venetoclax plus the BTK inhibitors and talked about the increasing trend to move towards more limited-duration therapy rather than indefinite therapy. He briefly touched upon some ongoing clinical trials, looking at MRD-guided approaches to define the duration of therapy for these patients.

For patients with relapsed CLL, he highlighted the role of other agents outside of the BTK inhibitors and venetoclax that can be employed.