Proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies were all initially evaluated in advanced multiple myeloma and relapsed and refractory disease, but have since moved into the frontline setting for newly diagnosed patients, states Kenneth Anderson, MD. In most cases, triplet therapy is commonly utilized in the frontline setting, which generally consists of a proteasome inhibitor (bortezomib or carfilzomib) in combination with dexamethasone and either lenalidomide or cyclophosphamide.

The oral agent ixazomib is a next-generation proteasome inhibitor currently under investigation, comments Anderson. The agent is given once weekly and is well tolerated. Ixazomib, lenalidomide, and dexamethasone comprise an all-oral regimen, which would be convenient for patients. In the relapsed/refractory setting, ixazomib, lenalidomide, and dexamethasone demonstrated an improvement in progression-free survival (PFS) compared with lenalidomide and dexamethasone alone.

Incorporating proteasome inhibitors into initial management helps achieve high extent and frequency of response, even in high-risk patients, such as in individuals with 17p deletion or p53 non-functioning multiple myeloma. In the older, non-transplant-eligible population, attenuated doses of these same triplets are used as initial treatment, as these individuals are more likely to have comorbid diseases and are more susceptible to adverse events from these medications.

In the FIRST trial, which was the largest randomized clinical trial in newly diagnosed, elderly non-transplant candidates, lenalidomide plus dexamethasone administered continuously until progression extended PFS and overall survival (OS), comments Anderson. Based on an extension in PFS versus MPT of 4.3 months in this trial, the combination of lenalidomide and dexamethasone was approved by the FDA for newly diagnosed patients in February 18, 2015. In the interim analysis, OS was improved by 10.4 months with the doublet versus MPT.