“Now there are emerging data on BCMA [B cell maturation antigen] as a target in multiple myeloma,” Dr Lonial said.

But despite its promise in advanced myeloma, the use of CAR-T therapy is “currently limited by toxicities,” noted Dr Hutchins.

Another immunotherapeutic approach undergoing evaluation against multiple myeloma is the use of BiTEs, fusion proteins that show promise in acute lymphoblastic leukemia.

Ultimately, combinatorial regimens that tackle more than one facet of myeloma cell immune escape seem a more likely solution than a single-agent “silver bullet” treatment.

Immune checkpoint inhibitors like the PD-1-targeting agent, pembrolizumab, “alone don’t have a lot of activity with multiple myeloma,” Dr Lonial said. “But they certainly work well with immunomodulators [IMiDs] like lenalidomide,” a thalidomide analogue.

Despite “incredible progress” with checkpoint inhibitors, monotherapies “showed little impact in myeloma trials thus far,” agreed Clement Chung, PharmD, of the Lyndon B. Johnson General Hospital, Harris Health System in Houston, Texas. “But when added with other anti-myeloma agents, such as lenalidomide or mAbs such as elotuzumab or daratumumab, they have an increased response rate.”

“Myeloma has complex disease biology, with multiple clones even within a single patient,” Dr Chung noted. “It is possible that immune responses may vary from patient to patient.”

Moreover, several immune checkpoint systems “are in play at any given time,” Dr Chung added. “It is known that PD-1 was found on T cells, but PD-1 was also found on the surface of activated B cells and natural killer cells. The PD-1 pathway regulates immune-specific responses, not just general T cell activation, and also influences the bone marrow microenvironment.”

Other pathways may be involved in multiple myeloma’s immunosuppressive tumor microenvironment.

“Studies for combining checkpoint inhibitors with vaccines, CAR-T cell therapy, chemo, or radiation are likely to continue,” Dr Chung told Cancer Therapy Advisor.

Candidate peptide and dendritic-fusion cancer vaccines are also being studied for preventing progression of early-stage multiple myeloma and “smoldering” myeloma, including a phase 3 trial for patients who have undergone stem cell transplantation, Dr Lonial noted. “That’s just getting under way.”

Multiple myeloma is widely considered incurable for most patients, but as immunotherapy research matures, that might well change, Drs Lonial and Hutchins agreed.

“We are already curing 10% to 15% of patients with aggressive treatment,” Dr Lonial said. “But I suspect that with the appropriate application of immunotherapies, the fraction of patients we can cure should increase.” 

References

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  2. Hutchins IM, Schachter LG, Mahindra AK. Immunotherapy in multiple myeloma. Transl Cancer Res. 6(1):109-6. doi: 10.21037/tcr.2017.01.34
  3. Rasche L, Weinhold N, Morgan GJ, van Rhee F, Davies FE. Immunologic approaches for the treatment of multiple myeloma. Cancer Treat Rev. 2017;55:190-9. doi: 10.1016/j.ctrv.2017.03.010
  4. Chung C. Role of immunotherapy in targeting the bone marrow microenvironment in multiple myeloma: an evolving therapeutic strategy. Pharmacotherapy. 2017;37(1):129-43. doi: 10.1002/phar.1871
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