Treatment Strategy for Multiple Myeloma to Improve Immunological Environment and Maintain MRD Negativity

Abstract

Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve the immunological microenvironment. ASCT, MoAbs, and proteasome inhibitors (PIs) may be important for the achievement of MRD negativity. An improved immunological environment may be useful for maintaining MRD negativity, although the specific treatment for persistent MRD negativity is unknown. However, whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies, including IMiDs, PIs, MoAbs, and ASCT, and expected immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, via improvement of the immunological environment and maintenance of MRD negativity.

Measurable Residual Disease Testing in Multiple Myeloma Routine Clinical Practice: A Modified Delphi Study

“…MRD testing is not widespread in routine clinical practice for reasons such as insufficient MRD‐testing guidelines, availability, and budget. Therefore, there are multiple ongoing trials examining the use of MRD testing in MM and MRD‐directed treatments to enhance utilization as an intervention‐directing biomarker 2 , 26 . To bridge the knowledge gap, we invited 50 other experts from Europe to participate in our modified Delphi study to understand the use of MRD in clinical practice for patients with MM.…”

“…Higher MRD‐negativity rates were associated with prolonged OS and PFS in transplant‐ineligible patients regardless of age 43 , 44 . Sustained MRD negativity is one of the treatment goals pursued by cooperative groups as a biomarker during maintenance and for considering treatment discontinuation for myeloma patients regardless of transplantation status 19 , 26 . Because bone marrow aspiration is required to confirm CR status, simultaneous MRD assessment of the marrow would provide meaningful clinical information if the MRD‐testing technology is available to the clinician. MRD testing is recommended if a patient exhibits high‐risk disease features (expert agreement: 92%).…”

Reshaping the tumor microenvironment: The versatility of immunomodulatory drugs in B-cell neoplasms

“…Currently, induction treatments for MM have traditionally relied on a backbone of a combinations of IMiDs (thalidomide, lenalidomide and pomalidomide), proteasome inhibitors, alkylators (or anthracyclines), and/or steroids ( 274 ). In this scenario, IMiDs are believed to improve the immune environment beyond direct anti-tumor activity, which ensures persistent minimal residual disease (MRD) negativity through enhanced immunological surveillance against myeloma cells ( 305 ). In addition, the recently approved anti-CD38 antibodies have also shown to reshape the MM immune environment via activation of T and NK cells and suppression of Tregs ( 305 ).…”

“…In this scenario, IMiDs are believed to improve the immune environment beyond direct anti-tumor activity, which ensures persistent minimal residual disease (MRD) negativity through enhanced immunological surveillance against myeloma cells ( 305 ). In addition, the recently approved anti-CD38 antibodies have also shown to reshape the MM immune environment via activation of T and NK cells and suppression of Tregs ( 305 ). These combined immunogenic chemotherapies are paving a promising way to “cure MM”.…”

Detection of Measurable Residual Disease Biomarkers in Extracellular Vesicles from Liquid Biopsies of Multiple Myeloma Patients—A Proof of Concept

“…MRD evaluation is most important to determine when the myeloma clone is disappearing during treatment (remission) and when the myeloma burden, even low, is reappearing after treatment (relapse) [ 5 , 6 ]. Thus, its routine monitoring has the potential to guide therapeutic decisions [ 4 , 7 , 8 ].…”