New Findings for Multiple Myeloma

Joshua Richter, MD, provides an overview of new data from various trials presented at ASH 2020 regarding newly diagnosed patients with multiple myeloma.

Joshua Richter, MD: Selecting an induction regimen for newly diagnosed patients is a fairly complex thing, although in the United States many signs point to bortezomib, lenalidomide, dexamethasone [VRd] in some version. In general, when we think about any therapy, we consider 3 different categories: disease factors, host factors, and treatment factors. Disease factors; is it high-risk disease? Is it standard-risk disease? Is there extramedullary disease? Host factors; is the patient older, younger, fit, or frail? Do they have comorbidities? Treatment-related factors; does the patient have preexisting neuropathy from diabetes where we may want to avoid drugs like bortezomib? Do they have preexisting cardiac issues that may preclude drugs such carfilzomib? We use all 3 of these parameters to decide on the regimen.

Then of course, are they transplant eligible or ineligible? For those patients who are going to go on to transplant, there are only 2 rules you want to follow. One is to avoid melphalan or melphalan in their induction as this may preclude the ability to collect stem cells. We also recommend no more than 4 to 6 cycles of lenalidomide as this also may impact our ability to collect stem cells. Otherwise, the majority of patients tend to get something like VRd [bortezomib, lenalidomide, dexamethasone] in the United States, whether it’s full dose as a concentrated 21-day cycle, or a more VRd [bortezomib, lenalidomide, dexamethasone]-lite approach, with dose reductions and once weekly bortezomib instead of twice weekly bortezomib. The younger, fitter patients with high-risk disease may benefit from something like carfilzomib, lenalidomide, dexamethasone [KRd].

If patients are not going to go on to transplant, although regimens such as lenalidomide, dexamethasone and VRd [bortezomib, lenalidomide, dexamethasone]-lite are extremely appropriate, the recent data from the MAIA study [NCT02252172] with daratumumab, lenalidomide, and dexamethasone [DRd] show some of the longest progression-free survivals we’ve seen of any study in this space. There are a lot of options with how to choose and try to incorporate all 3 of those parameters into picking the drugs. In general, 3 drugs are better than 2, and in a handful of cases, 4 may be better than 3.

Outside of the United States, thalidomide is the immunomodulatory drug of choice in the upfront setting. Whereas in the United States we use a lot of VRd [bortezomib, lenalidomide, dexamethasone]; outside the United States and in many places in Europe, bortezomib, thalidomide, and dexamethasone [VTd] is the standard. The CASSIOPEIA trial [NCT02541383] tried to augment this and compare daratumumab plus VTd [bortezomib, thalidomide, dexamethasone] versus VTd [bortezomib, thalidomide, dexamethasone]. Although these data are extremely promising with very high response rates, one of the concerns of the study has ultimately been peripheral neuropathy because in this study we’re incorporating 2 drugs with overlapping toxicities. Both bortezomib and thalidomide cause peripheral sensory neuropathy, and what was found was that there was a significant amount of peripheral neuropathy in both the VTd [bortezomib, thalidomide, dexamethasone] and the daratumumab/VTd [bortezomib, thalidomide, dexamethasone] group.

Of note, there was actually less in the daratumumab/VTd [bortezomib, thalidomide, and dexamethasone] group, and some of this may come from some unknown ameliorating property of daratumumab in deference to the formation of peripheral neuropathy. The exact mechanisms of neuropathy are somewhat different between bortezomib and thalidomide, and some of this is not entirely known, although it may be related in some part to neurite shortening. We do know that there may be some degree of an inflammatory response. This is why some of the data from the Boston group have shown that giving steroids the day of and day after bortezomib reduced the incidence of peripheral neuropathy. By the same token, some of these properties of daratumumab may offset the development of sensory neuropathy in these patients, so again, the daratumumab/VTd [bortezomib, thalidomide, dexamethasone] group is not only better from an efficacy standpoint but from a tolerability standpoint as well.

The post-transplant setting in myeloma has clearly evolved over the last 10 to 15 years. It was clear for many years that transplant was great. What was unclear was what was the optimal strategy for post-transplant maintenance and was maintenance needed? The majority of studies across the years, ranging from the old interferon studies, to the MRC IX trial using thalidomide, to the HOVON/GMMG [NCT03617731] studies looking at bortezomib, to the CALGB-100104 [NCT00114101] data looking at lenalidomide, all of these studies have shown some improvement in progression-free survival. But it was only the more recent CALGB and the subsequent meta-analysis showing an overall survival advantage of lenalidomide post-autotransplant.

I think that in a day and age where long-term therapy such as interferon and bortezomib were more difficult, the majority of patients had trouble either tolerating maintenance therapy or even starting at all. Now with our ability to manage the toxicities and cytopenias of lenalidomide, especially in a maintenance setting, the ability to give long-term therapies becomes much more “user friendly,” and we’re able to keep people on long-term therapy without having to take them off because of toxicity. As such, the rates of maintenance therapy post-autograft have simply gone up and up over the years and are now the overwhelming majority, with different sources reporting between 80% and 90% of patients receiving some type of maintenance therapy post-autotransplant.

In my practice, we continue to provide maintenance therapy post-transplant for the overwhelming majority of people. It’s the rarity for someone who does not have some type of maintenance. For the standard patient, we follow the CALGB-100104 data, which is simply lenalidomide post-autotransplant. However, for patients with high-risk disease, we feel that something more is needed. A lot of great data are coming out of the Emory group looking at multiagent maintenance regimens, things such as VRd [bortezomib/lenalidomide/dexamethasone]; IRd [ixazomib, lenalidomide, dexamethasone]; daratumumab, lenalidomide, dexamethasone. A lot of this is ongoing in clinical trial as well with the AURIGA study [NCT03901963] randomizing patients between lenalidomide, dexamethasone and daratumumab, lenalidomide, dexamethasone as a maintenance strategy. For patients with higher-risk disease, the patients with 17p deletions, 1q gains, I discuss multiagent regimens for maintenance, such as Ninlaro [ixazomib] and lenalidomide, or daratumumab and lenalidomide, such as the AURIGA trial.

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