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Simple Summary: Multiple myeloma (MM) is a frequent hematological malignancy characterized by the uncontrolled growth of clonal plasma cells, primarily in the bone marrow. Over the past years, novel therapies have been discovered and introduced into clinical practice that have dramatically changed the treatment landscape of MM. Despite the tremendous advances, MM remains incurable, with poor outcomes particularly in patients with relapsed/refractory disease, emphasizing the need for new therapeutic approaches. In this review we discuss the current treatment paradigm of multiple myeloma and focus on promising future approaches. 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. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a heterogeneous group of clonal disorders characterized by abnormal proliferation of undifferentiated myeloid progenitors, impaired hematopoiesis, and variable response to therapy. To date, only about 30% of adult patients with AML become long-term survivors and relapse and/or disease refractoriness are the major cause of treatment failure. Thus, this is an urgent unmet clinical need and new drugs are envisaged in order to ameliorate disease survival outcomes. Here, we review the latest therapeutic approaches (investigational and approved agents) for AML treatment. A specific focus will be given to molecularly targeted therapies for AML as a representation of possible agents for precision medicine. We will discuss experimental and preclinical data for FLT3, IDH1, BCL-2, Hedgehog pathway inhibitors, and epitherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is a cancer of antibody-producing plasma cells that remains incurable. These cells heavily depend on protein disulfide isomerase, PDIA1, for folding and structural integrity of antibodies and other secretory proteins to avoid unresolvable stress caused if they remain unfolded. High PDIA1 expression confers resistance to proteasome inhibitors and other stressors due to the gain in endoplasmic reticulum (ER) function, while maintaining or increasing vulnerability to PDIA1 inhibition. Here we report the identification and characterization of an orally bioavailable novel PDIA1 inhibitor CCF642-34 that is effective against multiple myeloma in pre-clinical models. PDIA1, the ER resident enzyme essential for the folding of disulfide bond-containing proteins, is upregulated in relapse and refractory myeloma. This increase in PDIA1 confers its sensitivity to CCF642-34, a structurally optimized PDIA1 inhibitor that induces apoptosis in myeloma cells but not in normal bone-marrow-derived CD34+ hematopoietic stem and progenitor cells. Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34+ hematopoietic stem and progenitor cells. Bortezomib resistance leads to increased PDIA1 expression and thus CCF642-34 sensitivity, suggesting that proteasome inhibitor resistance leads to PDIA1 dependence for proteostasis and survival. CCF642-34 induces acute unresolvable UPR in myeloma cells, and oral treatment increased survival of mice in the syngeneic 5TGM1 model of myeloma. Results support development of CCF642-34 to selectively target the plasma cell program and overcome the treatment-refractory state in myeloma. [ABSTRACT FROM AUTHOR]