What the Approval of Isatuximab Plus VRd Adds to Multiple Myeloma Care

The recent FDA approval of isatuximab (Sarclisa; Sanofi-Aventis) in combination with the triplet therapy bortezomib, lenalidomide, and dexamethasone (VRd) adds another option for patients with transplant-ineligible multiple myeloma.

In a previous interview with The American Journal of Managed Care^®, Surbhi Sidana, MD, MBBS, vice chair of the American Society of Hematology’s Committee on Communications and associate professor of medicine and director of the Myeloma Disease Focused Group at Stanford University, explained the importance of this approval and how it addresses treatment gaps for transplant-ineligible multiple myeloma.

Here, she dives deeper into the treatment’s the progression-free survival data, how clinicians can incorporate isatuximab plus Vrd into treatment for older patients, and how the standard of care for multiple myeloma care has changed in the past few years.

This transcript has been lightly edited for clarity.

Transcript

Can you elaborate on the clinical significance of the progression-free survival data from the IMROZ trial?

I think that is the critical time point. Progression-free survival is time until progression or death from any cause, and that is a very valid surrogate end point that has been accepted in the field. And what we saw was the progression-free survival was significantly higher with a quadruplet, with a hazard ratio of 0.6 compared to the triplet. This tells us that, yes, addition of an anti-CD38 antibody to the VRd backbone significantly improves progression-free survival.

Now, at current follow-up, we did not see any difference in overall survival. The data is still immature, but you could see the curve starting to separate, so hopefully in the future we will see that as well. Again, [this is] telling me that an anti-CD38 antibody is important to improve outcomes of patients. Two things came out, though, in the IMROZ trial.

Is bortezomib needed? Bortezomib was used twice weekly in these patients. Twice weekly in transplant-ineligible patients is a significant amount of bortezomib. We saw high rates of peripheral neuropathy. Of course, when we use this in the real world, even if we are using a triplet, we never use twice-a-week bortezomib. We always use once-a-week bortezomib, and we'll never use it in transplant-ineligible patients. So, that is where the trial design does not translate into the real world.

As I mentioned, there's another trial called the BENEFIT trial, which is truly looking at regimens that can be used in frail and elderly patients. That [trial] randomized patients to getting Isa [isatuximab]/VRd to Isa/Rd [lenalidomide-dexamethasone], so everybody gets an anti-CD38 but you add bortezomib on top of it. There, bortezomib was used once a week subcutaneously for 18 months and then stopped. So, I think that trial will tell us what the addition of once-a-week bortezomib does to these patients. But taking all of this together, yes, add an anti-CD38 to your transplant-ineligible patients—and your transplant-eligible patients, looking at other data.

Vrd is the current standard of care for transplant-ineligible multiple myeloma, but has been quoted as not often doing so well. What hope does the approval of isatuximab plus VRd add for patients?

Just to provide some context, in the original trial, the SWOG S0777 trial that Dr Facon [Thierry Facon, MD, Lille University Hospital] was referring to, the median PFS with VRd was 43 months. Here in the IMROZ trial, it's about 54 months—almost a year better. I think this is where the challenge of comparing 2 clinical trials that are done more than a decade apart comes in.

A lot of things have changed. The way we define active myeloma that needs treatment has changed. That was in the era of just defining myeloma with CRAB criteria. Now we have additional criteria, so some people we would not have treated as [having] active myeloma then, we treat them now with the SLiM CRAB criteria. Our supportive care is better. So, I think we have to be very cautious of comparing trials done almost 15 years apart, 10 to 15 years apart.

One of them is just that things have changed in how we treat myeloma, both with supportive care and who we treat. So, I think that is the difference why the VRd arm almost did 1 year better in this clinical trial than the other clinical trial. But, as I said, most of us are not using VRd as our standard of care anymore for transplant-ineligible [myeloma]. We are using Dara [daratumumab]/Rd. This doesn't answer that question exactly, but all of this emerging evidence taken together points us to the right direction.

How should clinicians balance the benefits of isatuximab plus VRd with the potential risks of adverse events, particularly for older or more vulnerable patients with multiple myeloma?

Seventy percent of patients in this clinical trial were above the age of 70. We don't exactly know the frailty of that population yet, I'm sure it'll come out in subsequent publications, but this was an older patient population. And just like with all of the other clinical trials of an anti-CD38 antibody, be it isatuximab or daratumumab, 2 things stood out in the safety profile. One is more grade 3 and 4 neutropenia, which is an absolute neutrophil count of less than 1000, and more infections that were grade 3 and 4. Those 2 things we have to keep in mind. That is always going to be there with the addition of an anti-CD38 antibody.

With the addition of bortezomib, we know that there is going to be—this was there in both arms, but just generalizing—more neuropathy. These are the nuances we have to take into account when looking at the patients in front of us to counsel them to use aggressive prophylaxis for supportive care, like [herpes] zoster prophylaxis, if someone has an infection, treating it aggressively, and so on.