Multiple Myeloma Therapy: Emerging Trends and Challenges

Abstract

Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergence of genetically heterogeneous sub-clones are the major causes of the relapsed-refractory state of MM. Cytopenias from cumulative treatment toxicity and disease refractoriness limit therapeutic options, hence creating an urgent need for innovative approaches effective against highly heterogeneous myeloma cell populations. Here, we present a comprehensive overview of the current and future treatment paradigm of MM, and highlight the gaps in therapeutic translations of recent advances in targeted therapy and immunotherapy. We also discuss the therapeutic potential of emerging preclinical research in multiple myeloma.

Keywords: immunotherapy; multiple myeloma; targeted therapy.

Figure 1

Five-Year Relative Survival Percent, as reported at the Surveillance, Epidemiology, and End Results (SEER) Program(SEER Cancer Statistics Review, 1975–2018, National Cancer Institute. Bethesda, MD, USA, https://seer.cancer.gov/csr/1975_2018/ (accessed on 22 July 2022), based on November 2020 SEER data submission, posted to the SEER web site). The overall survival of MM dramatically improved after the development of novel proteasome inhibitors, immunomodulators and monoclonal antibodies. However, the survival advantage has plateaued over the past several years, emphasizing the need for discovery of new therapeutic modalities.

Figure 2

Clinical definitions, risk stratification, and available therapies for multiple myeloma and preexisting plasma cell disorders. End organ damage is defined as: Hypercalcemia (serum calcium > 1 mg/dL higher than the upper limit of normal or >11 mg/dL); renal insufficiency, creatinine clearance < 40 mL/minute or serum creatinine > 2 mg/dL; anemia with a hemoglobin value > 2 g/dL below the lowest limit of normal or a hemoglobin value < 10.0 g/dL; and Bone lesions, ≥1 osteolytic lesion on imaging. Abbreviations: M, monoclonal; BMPC, Bone Marrow Plasma Cells; FLC, Free Light Chain; B2M, Beta-2 Microglobulin; CA, Cytogenetics, IMiD, Immunomodulators; AHCT, Autologous Hematopoietic Cell Transplantation; CAR, Chimeric Antigen Receptor.

Figure 3

The basic principles of the immunotherapies in MM and their place in the current treatment landscape. CAR T cells are T cells genetically modified with the use of a viral vector to express a chimeric antigen receptor on their surface, which targets specific tumor antigens of malignant plasma cells. Similarly, bispecific antibodies are monoclonal antibodies targeting both an antigen on the malignant MM cells and simultaneously an antigen on the surface of physiologic T cells, creating an immunologic bridge. ADC are monoclonal antibodies against antigenic epitopes on the surface on MM cells, carrying a cytotoxic payload. The binding of the above agents to their antigenic targets on malignant MM cells leads to activation of the immune system, with subsequent destruction of the MM cells.

Figure 4

Underlying mechanism of action of selected targeted therapies used for MM in the clinical setting. Venetoclax works by primarily binding to the BCL-2 anti-apoptotic protein, allowing the activation of BAK and subsequently caspases leading to MM apoptosis. Selinexor blocks the transport of vital proteins and other molecules from the nucleus to the cytoplasm of the MM cells, leading to cell death. Histone deacetylation inhibitors act at an epigenetic level, blocking the deacetylation of the DNA in the nucleus of the malignant cell.

Figure 5

Heightened PDIA1 is critical to maintain ER homeostasis in MM Cells. Disruption of the ER causes dysregulation of the protein folding process, known as ER stress, secondary to the accumulation of unfolded or misfolded proteins. This leads to activation of the unfolded protein response (UPR), with subsequent activation of downstream pathways inducing apoptosis. Abbreviations: PDIA1, protein disulfide isomerase inhibitor A1; ER, endoplasmic reticulum; UPR, unfolded protein response.