Evolving Paradigms in the Management of Multiple Myeloma: Novel Agents and Targeted Therapies

Abstract

Multiple myeloma (MM) is a clonal plasma cell disorder defined by bone marrow infiltration and osteolytic bone lesions and is the second most common hematologic malignancy after non-Hodgkin lymphoma. The landscape of MM treatment was transformed at the dawn of the twenty-first century by the introduction of novel agents including proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide, lenalidomide), which have prolonged the survival of MM patients. The recently revised International Myeloma Working Group diagnostic criteria for MM added validated biomarkers (clonal bone marrow plasma cell ≥60%, involved:uninvolved serum free light chain ratio ≥100, or >1 focal lesion on magnetic resonance imaging) to identify near inevitable progression to symptomatic MM requiring therapy. In addition, the definition of myeloma-defining CRAB features (hypercalcemia, renal failure, anemia, and bone lesions) has been refined based on advances in imaging and laboratory techniques since the 2003 IMWG consensus. Despite expanded treatment options, MM remains an incurable disease. Drug resistance and clonal evolution remain problematic, and novel therapeutic agents are needed. New approaches to myeloma treatment include anti-CD38 antibodies, next generation proteasome inhibitors, epigenetic modulation with histone deacetylase inhibitors, and targeting the tumor microenvironment. In this article, the diagnosis, staging, and prognostic stratification of newly diagnosed MM will be reviewed. Clinical data pertaining to the emerging targeted agents will be discussed, and a suggested framework for integration of these new therapeutic options will be provided.

Characteristics and outcomes of patients with multiple myeloma : Data from a developing country

“…Paradigm of MM management evolved by introducing novel drugs including proteasome inhibitors and immunomodulatory drugs. These agents have increased the response rates before and after autologous hematopoietic stem cell transplantation (ASCT) ( 18 ).…”

IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies

“…11 The pleiotropic consequences of proteasome inhibition result in synergistic or additive activity with other therapeutic protocols, including autologous stem cell transplantation, glucocorticoids, alkylating agents and anthracyclines, immunomodulatory drugs, histone deacetylase inhibitors, and monoclonal antibodies. 10,12 Despite these enormous advances, relapses and disease progressions are common among MM patients, suggesting a prominent role for either innate or acquired drug resistance. 13,14 Moreover, although the toxicity of PI is quite well controlled in clinical settings, they display distinct adverse profiles, imposing limits to their doses.…”

Navigating the treatment landscape in multiple myeloma: which combinations to use and when?

“…Recent years have also seen the development and approval of numerous new treatments for patients with MM, including the second-generation proteasome inhibitors carfilzomib and ixazomib, of which carfilzomib demonstrated improved survival in a head-to-head study of carfilzomib plus dexamethasone versus bortezomib plus dexamethasone [4]. Other therapies with different mechanisms of action have emerged, including the immunomodulatory agent pomalidomide, the alkylating agent bendamustine, the histone deacetylase (HDAC) inhibitor panobinostat, and the monoclonal antibodies elotuzumab and daratumumab [5, 6]. Results from clinical trials suggest that the use of these agents may help to improve outcomes further [7–16].…”

“…Clonal heterogeneity is often observed in patients with MM, and it has been suggested that suboptimal treatment may lead to eradication of sensitive subclones while allowing resistant clones to expand [19]. As a result, combination therapy using agents from different drug classes with distinct and synergistic mechanisms of action is increasingly being utilized in an attempt to remove more subclonal groups, to reduce the risk of developing drug resistance and to induce a deeper response [5, 19]. For example, preclinical and clinical data suggest that a synergistic effect is observed when immunomodulatory drugs and proteasome inhibitors or monoclonal antibodies are used in combination [7, 10, 16, 20–22].…”

“…In addition, monoclonal antibodies induce cell death via a number of mechanisms including antibody-dependent cell-mediated cytotoxicity (ADCC) and immunomodulatory drugs may enhance this anti-myeloma activity by activating the effector cells of ADCC [22]. However, when making treatment decisions, it is important to consider patient-related factors (i.e., age, comorbidities, and eligibility for autologous stem cell transplantation (ASCT)), disease-related factors (i.e., cytogenetics, disease burden, and aggressiveness of relapse in the relapsed/refractory disease setting) and previous therapies (i.e., number of previous therapy lines, response to previous therapies, and tolerability to previous therapies) [5, 17, 23]. Physicians also need to consider the balance between increasing the depth of response from a drug regimen and exposing patients to increased toxicity [24].…”