Management of Multiple Myeloma - Episode 6

Case 2: The Role of Maintenance Therapy in Myeloma

September 25, 2018

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDNina Shah, MD:Now I’d like to move on to the second case. This is about a 68-year-old Caucasian man diagnosed with stage I multiple myeloma. At the time of diagnosis, genetic testing showed a t(4;14) translocation in 50% of the plasma cells by FISH [fluorescence in situ hybridization]. He was started on treatment with lenalidomide [Revlimid]/bortezomib [Velcade]/dexamethasone—RVd—followed by autologous transplant. At day 100, he has an unconfirmed complete remission with RVd and transplant.

So, we want to discuss the role of maintenance therapy after transplant for patients like the one, in this case. I think one of the most important manuscripts and presentations that we’ve seen, that is related to this, is a meta-analysis that was first presented at the 2016 ASCO [American Society of Clinical Oncology] Annual Meeting and was most recently published in theJournal of Clinical Oncologyin 2017, looking at lenalidomide maintenance after autologous transplant in newly diagnosed multiple myeloma.

This meta-analysis combined 3 different clinical trials and looked at lenalidomide maintenance versus placebo or observation. One of the 3 trials that was included was the CALGB 100104 trial. This trial was the American trial that was sort of the partner study to IFM 2005-02. In this study, patients underwent transplant and eventually were randomized to lenalidomide versus placebo.

In the GIMEMA RV myeloma transplant trial [GIMEMA RV-MM-PI-209], patients were actually randomized to tandem transplant versus not with a second randomization of maintenance versus not. The purpose of this meta-analysis was really to combine all of the data, because although the American trial had shown some increase in overall survival, it wasn’t clear that the other 2 trials did, as well, and so we really wanted to understand what the contribution of lenalidomide maintenance was in these patients.

These trials looked at 1208 patients, which is a really sizable number. The trials looked at lenalidomide maintenance versus placebo or observation. Here, you can see that the progression-free survival—PFS—was very impressive in the lenalidomide group: 52.8 months versus 23.5 months in the observation or placebo group. In addition, the median overall survival at the time of analysis was not reached versus 86 months, which was very significant, as well. The PFS2, their next PFS after having salvage treatment, was also noted at 73.3 months versus 56.7 months. At this time, the hazard ratio was also at 0.72, showing favorably for the lenalidomide maintenance group.

Just looking at the curve, you can see the blue representing lenalidomide maintenance versus the gold—not being lenalidomide maintenance. You can see that there’s a nice separation between the curves. Looking at the subgroup analysis in the forest plot, you can see that most of the groups benefited from lenalidomide maintenance, although there is some question regarding whether the higher-stage patients benefited, which may be related to the number of patients included in this group.

When we look at lenalidomide maintenance versus placebo or observation, based on previous therapy, you can see that almost every group of therapies in panel C demonstrated a benefit derived from lenalidomide maintenance versus not. And, if you look at the 3 separate trials, again, the CALGB 100104 trial had the most data for overall survival. Still, if you combine all of the data but then look individually, you can see that it trended, in each study, toward having a benefit from lenalidomide maintenance therapy.

I really applaud the investigators for doing this, because we really needed more solid data. We thought that lenalidomide was better. We knew that the progression-free survival had been proven in these studies. They’re really showing your patients a long-term overall survival outcome, which is important. And actually, when they presented the data, they showed that there was an actual increase of about 2.5 years for patients who got lenalidomide maintenance versus not. This is something we are able to look at in our practices, because we want to justify to the patients why they should be on further therapy or why we think it may be better in certain cases.

Secondary primary malignancies—SPMs—are a concern, and this has definitely been shown to be increased in the lenalidomide maintenance groups. Here, you can see that even before progressive disease, lenalidomide patients tend to have higher secondary primary malignancies, both hematologic and solid tumor. Theoretically, the risk of PD—progression of disease—was higher than the risk of SPM in both groups. For that reason, we tend to think that the risk of getting lenalidomide maintenance is outweighed by the benefit. I present these numbers because there’s a relative risk that’s increased, which is the sort of multiplying risk. But the absolute risk increase should also be discussed with patients, because it’s not as much as the known risk of progressive disease.

Transcript edited for clarity.