In newly diagnosed patients, RVd (lenalidomide-bortezomib-dexamethasone) is most commonly used because of its very high extent and frequency of response. In autologous stem cell transplantation candidates, RVd is used as induction therapy, followed by transplant and then lenalidomide maintenance. The IFM/DFCI 2009 Study has not shown a significant difference in overall survival between the transplantation group and the RVd-alone group. Thus, the combination of a PI, lenalidomide, and dexamethasone can be very effective. In nontransplant patients, we similarly use this combination, but consideration can be given to attenuated doses (ie, RVd-lite) so that patients who are elderly or frail can benefit as well.

How can you explain the remarkable activity of PIs in combination with IMiDs? Well, we have learned over the years that PIs and IMiDs have their own cell death induction mechanisms. The IMiDs have direct effects and they stimulate an immune response, so they are aptly named. Recent data show that the PIs also induce an immune response through immunogenic cell death. In other words, both lenalidomide and bortezomib not only have their unique separate activities but they are also both triggering an immune response against myeloma cells.

What about other PIs combined with lenalidomide? Carfilzomib, the more potent second-generation PI, is associated with less peripheral neuropathy and may be combined with lenalidomide in certain patients with neuropathy or high-risk multiple myeloma.  Another second-generation PI, ixazomib, is orally available, so ixazomib-lenalidomide-dexamethasone is a particularly useful option in nontransplant candidates who would prefer an all-oral regimen.

The idea of combining a PI with an IMiD is exciting for not only newly diagnosed patients but also for relapsed patients. We have the second-generation IMiD pomalidomide, which can be combined with second-generation PIs carfilzomib or ixazomib and can achieve responses even when first-generation agents lenalidomide and bortezomib are no longer effective.

Building on the successes of the RVd backbone, the future is now with the addition of monoclonal antibodies, in both the upfront and relapsed settings. Daratumumab is combined with RVd in the upfront setting to achieve very high rates of response, especially high rates of minimal residual disease negativity. Daratumumab-RVd is often used in transplant candidates; among nontransplant, newly diagnosed patients, the combination of daratumumab and Rd (lenalidomide-dexamethasone) resulted in a significantly lower risk of disease progression or death than Rd in the MAIA trial. We also have ongoing trials that are adding daratumumab to RVd-lite. In patients with relapsed multiple myeloma that is refractory to lenalidomide, daratumumab-bortezomib is approved by the US Food and Drug Administration (FDA); conversely, daratumumab-lenalidomide-dexamethasone is FDA approved to treat relapsed disease that is refractory to bortezomib. We now also have the ability to add second-generation agents (eg, carfilzomib and pomalidomide) to daratumumab. Moreover, we have other antibodies that are FDA approved. For example, isatuximab, an anti-CD38 antibody with unique biologic activities from daratumumab, is FDA approved in combination with pomalidomide. Elotuzumab, an anti-SLAMF7 monoclonal antibody, is approved in combination with lenalidomide or pomalidomide. Given these many options, we can usually choose an appropriate regimen that matches the patient, predicated on frailty status, disease morbidity, risk assessment, treatment history, and lifestyle.