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Multiple myeloma (MM) is the second most common hematological cancer[1] and results from a series of mutations that lead to malignant plasma cells in the bone marrow.[2] The survival of MM ranges from 5 to 7 years on average, although patients with high-risk MM, defined as inactive TP53 or 1q21 activation, have reduced survival of 2 years.[3, 4] Due to the complexity of this disease, MM remains incurable, however, the emergence of CAR-T (chimeric antigen receptor T-cell) therapy has provided hope for MM patients.
Pathogenesis
Under normal conditions, plasma cells secrete polyclonal protein or immunoglobulins comprised of one heavy chain and one light chain.[5] MM is derived from a series of mutations in plasma cells and clonal plasmacytes that instead produce monoclonal proteins (M-proteins) within the bone marrow (BM).[6] This disease typically progresses from monoclonal gammopathy of undetermined significance (MGUS) that later develops into smoldering multiple myeloma (SMM) – both of which are asymptomatic plasma cell disorders with no end-organ damage.[7] MGUS is defined as a lower percentage of M-protein (<3g/dl) while SMM is defined as M-protein concentration exceeding 3g/dl.[8] It is thought that initial mutation events seen in MGUS, and ultimately in MM, that lead to M-protein secretion occur during somatic hypermutation or class-switch recombination events, namely translocations involving IgH locus and IgL locus.[7] The results of these mutations form an abundance of dysfunctional plasma cells within the bone marrow leading to reduced immune system responses and organ damage.
Therapeutics
Standard of care treatment for newly diagnosed MM includes a cocktail of high-dose chemotherapy agents: bortezomib, lenalidomide, and dexamethasone.[9] These chemotherapeutic agents are effective at damaging tumor cell DNA as well as tumor microenvironment. Following this aggressive combination therapy, patients undergo allogeneic stem cell transplantation (ASCT) to restore blood cell production.[10, 11] Despite the success of these treatments, many MM patients experience graft-versus-host disease (GVHD) and/or relapse,[12] making it essential for new and innovative treatments to emerge.
One treatment that has shown promise is chimeric antigen receptor T cell (CAR-T) therapy. CAR-T therapy is a type of immunotherapy that genetically modifies the patient's own T cells to target and kill cancer cells. [12, 13] In MM patients specifically, B cell maturation antigen (BCMA) targeted CAR-T therapy has been highly successful in newly diagnosed and relapsed MM patients. [13] Furthermore, clinical studies have found that CAR-T therapy has a 76% remission rate and conclude better 5-year patient outcomes.[14] Today there are two FDA-approved CART-T therapies for MM, Carvykti and Abecma, with others in development.[15] Despite successes, there are notable challenges with CAR-T therapy including cytokine release syndrome (CRS) and neurotoxicity, which may be managed with appropriate and timely interventions. [13] CAR-T therapy is also costly and requires specialized manufacturing facilities, limiting its availability to patients.
Importantly, new treatments outside of CAR-T therapy are also in development with novel targets, namely Selinexor. Selinexor targets Chromosome Region Maintenance 1 (XP01), a transporter of nuclear proteins with a key role in cell cycle regulation and proliferation.[16] XP01 has been implicated in several solid tumors, such as lung cancer, and is overly expressed in MM. Overexpression of XP01 allows tumor suppressor proteins, such as Rb, p53, and p21, to be exported into the cytoplasm rendering them inactive and therefore increasing anti-apoptotic cell signaling.[16, 17] Selinexor covalently binds to the “cargo-binding” groove of XP01 which prevents the displacement of tumor suppressor proteins mentioned above.[17, 18] As a result of its pre-clinical and clinical trial success, the FDA approved Selinexor as a combination therapy with dexamethasone for patients with more than one prior therapy and at least 4 prior dexamethasone therapies.[19, 20]
While MM continues to be a challenging cancer to treat, therapies such as CAR-T therapy and Selinexor provide MM patients with new hope for lasting remission. New clinical trials, such as NCT05177536 to test iberdomide maintenance therapy, are underway to explore the efficacy of new therapies and interventions to improve MM outcomes.
