Questions on Quadruplets and CAR T Set to be Answered As Myeloma Paradigm Parses Out the Clinical Value of MRD

Andrzej J. Jakubowiak, MD, PhD

The armamentarium of multiple myeloma has expanded with the introduction of combination regimens in the up-front setting and novel targeted agents, including CAR T-cell therapy, in the relapsed/refractory setting, according to a panel of experts from the University of Chicago (UChicago) Medicine that presented during an OncLive® Institutional Perspectives in Cancer webinar on multiple myeloma.

The panel added that as the field continues to add novel therapies into the paradigm, the emergence of minimal residual disease (MRD) may provide a potential tool to inform treatment decisions and answer open-ended questions.

Notably, the chair of the event, Andrzej J. Jakubowiak, MD, PhD, a professor of medicine and director of the Myeloma Program at UChicago Medicine, discussed differences in treatment regimens for patients with newly diagnosed, transplant-eligible and transplant-ineligible multiple myeloma, as well as the optimization of maintenance therapy.

Jakubowiak was joined by fellow faculty from UChicago Medicine:

• Benjamin Derman, MD, assistant professor of medicine, UChicago Medicine
• Michael R. Bishop, MD, professor of medicine, director, Hematopoietic Stem Cell Transplantation Program, UChicago Medicine

During the meeting, the panelists spoke to remaining questions regarding frontline treatment for transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma, considerations to inform treatment selection in the relapsed/refractory setting, the emergence of CAR T-cell therapy, and the evolving role of MRD negativity in multiple myeloma.

Frontline Treatment Considerations in Transplant-Eligible and Transplant-Ineligible Myeloma

Jakubowiak: In the transplant-eligible setting, quadruplet regimens that include daratumumab [Darzalex] added to standard backbone regimens have been shown to be better than triplet regimens. However, additional data are needed to determine whether daratumumab/lenalidomide [Revlimid]/bortezomib [Velcade]/dexamethasone [D-RVd] is preferred to daratumumab/carfilzomib [Kyprolis]/lenalidomide/dexamethasone [D-KRd]. Moreover, in the context of triplet regimens like RVd, KRd, and daratumumab/lenalidomide/dexamethasone [DRd], the role for pre–autologous stem cell transplantation is not fully realized, nor is the optimal duration of treatment.

Outside of a clinical trial, deferred transplant may be an option for patients with MRD-negative disease or high-risk patients with newly diagnosed multiple myeloma.

Additionally, the role of maintenance therapy remains in need of additional information to determine whether it should be given to patients following triplet-based induction therapy and/or quadruplet-based induction therapy, as well as for patients with high-risk disease.

In the transplant-ineligible setting, data confirm that triplet regimens are better compared with doublet regimens and the addition of daratumumab to backbone regimens has significantly improved outcomes for patients. However, additional studies are needed to determine whether RVd, D-Rd, or KRd is preferred. Moreover, it is unknown whether quadruplets will replace triplets for patients with transplant-ineligible disease.

Additionally, questions regarding the treatment of frail patients, as well as optimizing duration of treatment, remain unanswered and in need of further study.

Factors to Inform Treatment Decisions in Relapsed/Refractory Multiple Myeloma

Derman: At first relapse, the preferred treatment of patients with multiple myeloma includes a CD38-directed monoclonal antibody–based triplet. Selection of the partner drug, which consists of either a proteasome inhibitor or an immunomodulatory drug, is based on comorbidities, patient fitness, patient priorities, and number of visits.

For patients with triple-class refractory disease, it is critical to tailor therapy based on patient characteristics and to consider a clinical trial when possible. Patients with 11;14 translocations should receive venetoclax [Venclexta]-based therapy, whereas patients with p53 deletions should receive selinexor [Xpovio]-based therapy. For other patients without these alterations, BCMA-directed strategies, such as belantamab mafodotin-blmf [Blenrep] or idecabtagene vicleucel [Abecma], or cyclophosphamide-based therapies may be considered.

In the relapsed/refractory space, remaining questions include whether quadruplet regimens have utility in the second-line setting, how the frontline incorporation of CD38-directed monoclonal antibodies will affect sequencing, and whether BCMA-directed therapies can be sequenced back to back.

CAR T-Cell Therapy Offers a New Option in Relapsed/Refractory Disease

Bishop: BCMA is a successful target in multiple myeloma as it is expressed specifically on plasma and myeloma cells, with a higher expression on myeloma cells. Notably, BCMA is not expressed on other tissues, which has made it a rational target for therapies. Moreover, it promotes myeloma cell growth, chemotherapy resistance, and immunosuppression in the bone marrow microenvironment.

Ide-cel became the first BCMA-directed CAR T-cell therapy approved for use in patients with relapsed/refractory multiple myeloma. The agent demonstrated high response rates in this patient population in the KarMMA trial [NCT03361748].

Another BCMA-directed CAR T-cell therapy, ciltacabtagene autoleucel, is being developed for patients with multiple myeloma and has also demonstrated high response rates in this patient population.

The Potential for Early Utilization of MRD to Guide Treatment Decisions

Derman: Data suggest that the greatest benefit of maintenance therapy may be with early utilization. Sustained MRD negativity is necessary before consideration of treatment discontinuation, but who can safely stop therapy remains a difficult question to answer.

Notably, MRD negativity has applications to guide therapeutic de-escalation without complete treatment discontinuation.