Management of Multiple Myeloma - Episode 2

Case 1: Ineligibility for Transplant in Myeloma

September 25, 2018

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDAjai Chari, MD:When we look at a case like this, let’s look at the data that are available, in terms of guiding treatment and our approach to caring for a patient such as the one in this case. An important study, given that we have been using RVd [lenalidomide, bortezomib, and dexamethasone] for so long with the absence of phase III data, is the SWOG S0777 study, which compared RVd versus Rd [lenalidomide and dexamethasone] in newly diagnosed myeloma patients without an intent for immediate autologous transplant. This was published inLancetby Durie, et al.

This was a randomized, open-label, phase III trial of 525 patients with good performance status. The regimen was bortezomib. Importantly, it was given at a dose of 1.3 mg/m2intravenously, twice weekly—on days 1, 4, 8, and 11—along with lenalidomide, dosed at 25 mg, and dexamethasone, at a dose of 20 mg. That’s the triplet regimen compared to the doublet (Rd).

The primary endpoint here was progression-free survival. While the median age was 63, this was, again, studied without the intent for transplant. The number of patients who were older than age 65 was relatively low (43%), so it’s important that we don’t extrapolate it to all patients who might be over age 70, such as our patient here.

But looking at the results, we see that the progression-free survival, or the primary endpoint, was superior—43 months versus 30 months with a hazard ratio of 0.71. Interestingly, that also translated into a median overall survival benefit of 75 months versus 64 months; again, with a hazard ratio of 0.71. The response rate, as we might expect, was also superior—82% versus 72%. So, I think this confirms what we had been doing for a long time with triplet therapy versus doublet therapy, but really in the absence of phase III data.

It’s nice to see this study come out. We’ll talk about some of the limitations of it. The twice-weekly bortezomib regimen can be quite difficult for older patients to tolerate. And so, in theBritish Journal of Haematology, the Dana-Farber Cancer Institute group published their RVd-lite regimen, which is lenalidomide reduced to a dose of 15 mg for days 1 through 21. This is important. As we know, lenalidomide is cleared renally. Even though patients may have a “normal” creatinine, their clearance might be quite impaired because of their age and decreased muscle mass. Bortezomib was given subcutaneously here—once weekly at a 1.3 mg/m2dose. Dexamethasone was given at a dose of 20 mg on the day of, and after bortezomib. This was given for 9 cycles, followed by VR [lenalidomide and bortezomib] consolidation.

The median age was older here—ranging from age 65 to as high as age 91. The response rates were quite impressive. The overall response rate was 86%, and there was a very good partial response—66%. Complete response was actually achieved in 32% of patients, including a stringent complete response in 12% of patients. While this is a relatively small study, with just 50 patients, it shows us another way to use RVd in newly diagnosed patients, particularly those who may be older.

Most recently, we saw data from the long-anticipated study that looked at the impact of daratumumab in frontline myeloma. This was a phase III study. This looked at the quadruplet regimen of daratumumab with VMP [bortezomib, melphalan, and prednisone] versus VMP. This was published in theNew England Journal of Medicineby Dr Mateos and colleagues. This 706-patient trial is known as the ALCYONE trial.

Again, these were newly-diagnosed patients who were ineligible for transplant. As alluded to, daratumumab/VMP versus VMP was the study design. Again, this studied an older population. The median age at baseline was 71 years, and the range was from age 40 to as high as age 93.

In terms of the efficacy, the median follow-up was at 16.5 months. At 18 months, the progression-free survival was 71.6% with the quadruplet regimen versus 50.2 months with the triplet regimen. The hazard ratio was 0.5.

It’s important to note that the control arm does discontinue after 9 cycles. Daratumumab continues on beyond that. So, when we look at the curves, we do see a slight change in the shape of the curve when we move to single-agent daratumumab as maintenance therapy. When we look at the forest plot for comparisons of various prespecified subgroups, we see that across the board, including for renal clearance and ISS [International Staging System] stage, all of those favor the addition of daratumumab.

In terms of safety, we didn’t see much difference in safety signal. Interestingly, and we could discuss this further, there was no significant difference in the rates of grade 3/4 neutropenia. The adverse effect profiles are essentially comparable in both arms. The one slight difference was the rate of infection. For grade 3/4 infection, the rate was 23.1% in the daratumumab arm versus 14.7% in the control group. We’ll discuss some of the reasons for that, but it may be in part because of this patient population, which is clearly present in both arms, and the contribution of melphalan in conjunction with daratumumab.

Transcript edited for clarity.