Early Use of Novel Therapies in Multiple Myeloma Could Target Bone Marrow Microenvironment

Using novel agents early on in the treatment of multiple myeloma (MM) may boost the drugs’ effectiveness by targeting the bone marrow microenvironment (BMME), giving patients an edge before they develop resistance to therapy, according to paper appearing July 10 in International Journal of Molecular Sciences.

Authors from the Medical University of Graz, Austria, explained how MM emerges from earlier clinical phases and the tumor’s microenvironment in the early course of the disease plays a critical role in the survival of myeloma cells.

Thus, they argue, “therapeutic interventions targeting the BMME are a novel and successful strategy for myeloma care.” However, the newest, most powerful drugs and combinations may not be given until later in the course of the disease, “when most patients are already pretreated.”

In later stages, they write, the patient’s immune system may already be too compromised for treatments to be fully effective. The proliferation of new treatment choices in MM, and multiple drug classes, adds to the current challenge.

“There is a lack of clear consensus on the use, combination, and sequence of these new therapies, and finally, most myeloma patients will experience relapse due to the development of resistance mechanisms because of continuous treatment with (novel) agents,” they write.

The authors outline the clinical stages before MM is diagnosed. MM, they note, “is consistently preceded by an asymptomatic monoclonal gammopathy of undetermined significance,” or MGUS, and about 15% of patients who exhibit MGUS will develop multiple myeloma over a 25-year period.

Whether full-blown MM emerges is the result of “complex interplay between myeloma cells and the cellular components of the BMME that is essential for MM development and progression.”

The authors spend considerable time outlining results from recent clinical trials involving multiple novel agents, including anti–CD38-based therapies, immunomodulatory drugs, CAR T-cell therapies, bispecific antibodies, and antibody-drug conjugates, which they note have significantly improved the long-term outcomes for patients with the disease.

As they note, however, there is some debate when to offer these agents, despite evidence that patients’ responses are more robust when the most powerful agents are offered early. This discussion is occurring in the context of the treatment of other blood cancers as well, such as diffuse large B-cell lymphoma. They also offer examples of the effects of well-known therapies.

For example, “Treatment with daratumumab can rapidly deplete CD38+ T_regs (regulatory T-cells), [myeloid-derived suppressor cells], and B_regs (regulatory B-cells) and is associated with clonal expansion of CD4+ and CD8+ T cells in myeloma patients,” they write. “Hence, CD38-directed antibody therapy—besides targeting CD38-positive myeloma cells—can also restore an immunologically functional BMME exerting appropriate anti-MM T-cell responses.”

“Understanding the pathophysiology of resistance to commonly used antimyeloma agents requires further research,” the authors conclude. “Furthermore, new targets in the myeloma cells or in the BMME have to be identified to develop therapeutical approaches with a novel mode of action, which might help to overcome this drug resistance.”

Reference

Neumeister P, Schulz E, Pansy K, Szmyra M, Deutsch A. Targeting the microenvironment for treating multiple myeloma. Int J Mol Sci. 2022:23(14):7627. doi:10.3390/ijms23147627