Progress and Paradigms in Multiple Myeloma

Abstract

Remarkable progress has been achieved in multiple myeloma, and patient median survival has been extended 3- to 4-fold. Specifically, there have been 18 newly approved treatments for multiple myeloma in the past 12 years, including seven in 2015, and the treatment paradigm and patient outcome have been transformed. The definition of patients benefitting from these therapies has been broadened. Response criteria now include minimal residual disease (MRD), assessed in bone marrow by multicolor flow cytometry or sequencing, and by imaging for extramedullary disease. Initial therapy for transplant candidates is a triplet incorporating novel therapies-that is, lenalidomide, bortezomib, and dexamethasone or cyclophosphamide, bortezomib, and dexamethasone. Lenalidomide maintenance until progression can prolong progression-free and overall survival in standard-risk multiple myeloma, with incorporation of proteasome inhibitor for high-risk disease. Studies are evaluating the value of early versus late transplant and MRD as a therapeutic goal to inform therapy. In nontransplant patients, triplet therapies are also preferred, with doublet therapy reserved for frail patients, and maintenance as described above. The availability of second-generation proteasome inhibitors (carfilzomib and ixazomib), immunomodulatory drugs (pomalidomide), histone deacetylase inhibitors (panobinostat), and monoclonal antibodies (elotuzumab and daratumumab) allows for effective combination therapies of relapsed disease as well. Finally, novel therapies targeting protein degradation, restoring autologous memory anti-multiple myeloma immunity, and exploiting genetic vulnerabilities show promise to improve patient outcome even further. Clin Cancer Res; 22(22); 5419-27. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "MULTIPLE MYELOMA MULTIPLYING THERAPIES".

Figure 1. Bench to Bedside Translation of Novel Agents in Myeloma

Early advances in myeloma therapy included melphalan and prednisone, followed by combination chemotherapy and then high dose melphalan, rescued first by bone marrow and more recently by peripheral blood stem cell transplantation. Importantly, remarkable progress has been made in the last twelve years due to the FDA approval of proteasome inhibitors bortezomib, carfilzomib, and ixazomib; immunomodulatory drugs thalidomide, lenalidomide, and pomalidomide; histone deacetylase inhibitor panobinostat; as well as monoclonal antibodies elotuzumab and daratumumab (left). All these recent therapies have been initially evaluated and achieved responses in relapsed refractory MM, and then moved into clinical trials earlier in the disease course where their efficacy improves. Moreover, their use in combination, ie lenalidomide, bortezomib, and dexamethasone, can achieve unprecedented frequency and extent of response when used as initial therapy. They have been integrated into the treatment paradigm of transplant candidates and non-transplant candidates as initial and as maintenance therapies. As a consequence of these advances, overall survival has been extended from a median of 3 to 8–10 years (4), and the benefit of most recently approved drugs will further improve outcome (right).

Figure 2. Restoring Apoptotic Signaling By Serine Threonine Kinase Inhibiton in YAP1-Deficient Multiple Myeloma

A subset of patients with myeloma, lymphoma, and leukemia have decreased copy number and expression of YAP1 (37). As a result, these tumor cells with ongoing DNA damage do not undergo apoptosis (left). Serine threonine kinase (STK) 4 inhibits expression of YAP1; conversely, genetic or pharmacologic inhibition of STK4 allows re-expression of YAP1 and downstream p73-mediated apoptosis of these tumor cells with ongoing DNA damage to occur (right). Adapted from ref. 37.

Figure 3. Targeting Ubiquitin Proteasome System

Multiple proteasome inhibitors including bortezomib, carfilzomib, ixazomib, and opromazib primarily inhibit the chymotryptic-like proteasome activity, whereas marizomib inhibits chymotryptic-, tryptic-, and caspase-like activities. In the ubiquitin-proteasome cascade of protein degradation, ubiquitin proteasome receptors and deubiquitylating enzymes are upstream of the proteasome and required for recruiting and deubiquitylating ubiquitylated misfolded proteins, respectively, so that they can bind to the 20S core of the proteasome and be degraded. Blockade of either ubiquitin proteasome receptors and deubiquitylating enzymes upstream of the proteasome therefore has the potential to overcome proteasome inhibitor resistance.

Figure 4. Monoclonal Antibody-Based Therapies for Multiple Myeloma

Monoclonal antibodies used therapeutically in MM can trigger antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, block signaling pathways mediating MM cell growth, survival, and drug resistance, or trigger apoptotic signaling cascades. Clinically FDA approved monoclonal antibodies daratumumab and elotuzumab target CD38 and SLAMF-7, respectively. Adapted from ref. 93. © 2011 Yu-Tzu Tai and Kenneth C. Anderson. Published by Hindawi. This is an open access article distributed under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/us/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The article in which the original figure appeared is published with open access at http://dx.doi.org/10.1155/2011/924058.