Emerging options in multiple myeloma: targeted, immune, and epigenetic therapies

Abstract

Considerable progress has been made in the treatment of multiple myeloma in the past decade with median survival for the disease improving significantly. This has come through a combination of better understanding of the disease biology and coordinated research into new treatment approaches including better supportive care. However, patients eventually become refractory to available treatments and succumb to the disease, highlighting the need to develop new treatment approaches. The genetic heterogeneity in the disease and clonal evolution under treatment pressure underlie the development of resistance, underscoring the need to develop more effective therapies that can eradicate the disease at initial treatment as well as the need for new classes of drugs with varying mechanisms of action. To this end, there has been intense focus on exploring novel approaches to therapy including small-molecule inhibitors targeting specific abnormalities, immune therapies including monoclonal antibodies and adaptive T-cell therapy, as well as epigenetic approaches. Although many of these drugs are in the early stages of clinical development, the early data appear to be very promising. Many of these drugs can be safely and effectively combined with the current treatment classes such as proteasome inhibitors and immunomodulatory drugs, further enhancing the treatment options for myeloma.

The immunomodulatory drugs lenalidomide and pomalidomide enhance the potency of AMG 701 in multiple myeloma preclinical models

“…[2][3][4][5][6][7][8] However, relapse of disease is common and patients with relapsed or refractory MM (RRMM) have a poor prognosis. 9 An increased number of prior lines of anti-MM treatments is associated with increased evolution, survival, and proliferation of drug-resistant clones, ultimately leading to drugresistant minimal residual disease (MRD), clinical relapse, and treatment failure. [10][11][12] Thus, there remains an urgent need to develop novel immunotherapeutic strategies with different mechanisms of action and greater potency to overcome drug resistance and eliminate disease in patients with RRMM.…”

Bone Marrow Stromal Cells-Induced Drug Resistance in Multiple Myeloma

“…Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), without an improvement in patient survival, multiple myeloma (MM) remains a non-curable disease. [1][2][3][4][5][6] Moreover, change in the therapeutic approach moving toward a long-term treatment, with the goal of providing continuous disease suppression, improves responses and survival without effect on disease curability. [7,8] Relapsed patients remain not easy to treat, because the disease tends to become more aggressive, they develop drug resistance, and each relapse shortens their response duration [2][3][4][5].…”

Angiogenesis and Antiangiogenesis in Multiple Myeloma

“…The combination of biological drugs in the actual therapeutic strategies of MM have improved the outcome of MM patients because of their activity on microenvironment [17,[151][152][153].…”