Integration of Novel Agents into the Care of Patients with Multiple Myeloma

Abstract

The pace of therapeutic drug development in multiple myeloma has reached unprecedented levels, with five regulatory approvals for relapsed and/or refractory disease of either new drugs or new drug regimens in 2015, one already in 2016, and still others anticipated. This has provided a wide array of options to be considered by patients and their health care providers in the event of relapse after or progression on front-line therapy. Most of these agents are currently being evaluated in earlier patient populations, including as parts of induction, consolidation, and maintenance therapy approaches, where their benefits may be even greater. Moreover, additional randomized studies have been completed with our previous stable of novel agents that inform their use in these settings as well. In the current contribution to this CCR Focus on multiple myeloma, we will present an overview of some of the key recent data that have supported the addition of these new therapeutics to our armamentarium against multiple myeloma. Also, we will provide some guidelines about possible best practices in applying these regimens and attempt to extrapolate how they will be used as parts of our future standards of care. Clin Cancer Res; 22(22); 5443-52. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "MULTIPLE MYELOMA MULTIPLYING THERAPIES".

Figure 1. Factors to be wighed in deciding on therapy for patients with multiple myeloma

Patient fitness, disease burden, International Staging System (ISS) and Revised-ISS stage, and molecular risk should be considered in making treatment decisions for myeloma patients in either the newly-diagnosed, relapsed, or refractory settings. However, randomized controlled trials (RCTs) trials addressing the use of these factors have largely not been performed. These suggestions are therefore grounded in the clinical experience of the authors, and are not as evidence-based as we would ideally like. Also, practitioners will need to keep in mind the settings for which these drugs have or have not been approved. In particular, many of the options, including some of the immunomodulatory drugs (IMiDs), pegylated liposomal doxorubicin (PLD), proteasome inhibitors (PIs), monoclonal antibodies (MAbs), and the deacetylase inhibitor (DACi) are not approved for front-line therapy. Finally, the options are presented alphabetically, and their order should not be construed as a suggestion of their appropriate sequencing, since such studies have not been performed. Additional abbreviation: dex, dexamethasone.

Figure 2. Evidence-based algorithm for treatment of patients with relapsed and/or refractory myeloma using our currently approved novel agents

This diagram provides an overview of just some of the considerations and options that are involved in management of patients with relapsed and/or refractory disease. Please consult the text for further details about the use of this approach, which will need to be individualized to the molecular characteristics of each patient’s disease (Figure 1). The patient’s prior exposure to, and tolerance of these drug classes needs consideration, as do their comorbidities. With regard to the latter, some suggestions are provided about appropriate options in the fit (pink background) and frail patient (gray background). Also, please note that this list includes only recently approved novel single agents and combination regimens, as well as some combinations that will likely be approved based on already available phase III data. For the sake of brevity, we have not incorporated other drug classes, such as conventional alkylating agents, which may be of substantial use in this setting either at standard doses, or in the context of high-dose therapy with autologous stem cell rescue. Moreover, other combinations that have been reported to show encouraging outcomes, such as carfilzomib with pomalidomide and dexamethasone, are not included due to the lack of phase III data. Thus, this algorithm should not be taken as a representation of the full array of available therapies in this setting. “Carfilzomib” refers to the use of this drug as a single-agent at the standard dose (20 mg/m² on days 1, 2, 8, 9, 15, and 15 in cycle 1, and then 27 mg/m² on the same days starting cycle 2), while “Carfilzomib/dex” refers to its use at a high dose, which is detailed in Table 1. As in Figure 1, the options are presented alphabetically, and their order should not be construed as a suggestion of their appropriate sequencing, since such studies have not been performed.