Should Monoclonal Antibodies Be Used in the Front-Line Setting for MM?

Ajai Chari, MD, Associate Professor of Medicine, Director of Clinical Research at the Multiple Myeloma Program, Icahn School of Medicine, Mount Sinai, New York, NY, explains whether anti-CS1, anti-CD38, and bispecifics, should be used in the frontline setting for multiple myeloma.

Transcript

Hello, my name is Ajai Chari. I'm an associate professor of medicine and the director of clinical research at the Multiple Myeloma Program, at the Icahn School of Medicine at Mount Sinai, in New York.

My task today is the presentation of monoclonal antibodies, in particular, the anti-CS1, anti-CD38, and bispecifics, whether they should be used in the frontline setting. I think it's important to start this discussion with the fact that, no myeloma study has shown a flat overall survival curve.

We are continually losing patients, including standard risk, low-risk patients, even those patients don't have a flat survival curve. The other important part is that we lose patients continually with each relapse. Not every patient who's diagnosed will get to first relapse, and subsequently second, and third.

We have diminishing returns with respect to response rate in PFS. I do think it's important to use highly efficacious regimens in the initial setting, although I would put a caveat that just because we start with those, doesn't mean that every patient must be maintained on every drug that we start with. We can taper off at maximal debulking.

When we start with the first antibody listed the anti-CS1, Dr. Laubach did present at ASCO 2017, the results of the Elo-RVD study, which showed very encouraging depth of response, including 55% greater VGPR or better after 4 cycles. Those outcomes are comparable, if not better, to the other previous studies with RVD triplets.

However, Elo's main strength really comes from progression-free survival benefit, and that data was not yet presented. The other concern with the Elo in that study, was the risk of infection. 18% of patients discontinued induction therapy, and there were significant infections, 1 death, 1 sepsis grade 4, and 3 grade 3 events.

I think it raises the question of potentially exacerbating infections, perhaps when given with proteasome inhibitors, because that was also seen with the Elo-VD versus VD study. Future studies are pending though. Elo-RD in transplant-ineligible, Elo-RVD from both the German Group and SWOG, so stay tuned.

Moving to anti-CD38, here we have a lot more data that's been published, and actually even led to approval. When you start with the transplant-ineligible setting, where we tend to have a little bit more follow up and more data there, we have Dara. Dara's the one that's been obviously approved.

Dara is approved in the MAIA setting DRD versus RD in transplanting ineligible, and also in Alcyone Dara-VMP versus VMP. Both of those showed significant improvement in response rate, depth of response, and PFS, and that led to the approval of these drugs.

To interpret this data, because the question is, "OK, now that we have these, how did these compare to historical studies?" I think the 2 studies that people think about would be the SWOG SO777 study, where RVD was compared to RD, and then the RVD-lite.

When you put these 4 studies together, I think one important distinction is the median age. SWOG was without the intent for transplant, but the median age was only 63, whereas all of these other studies are over 71. This is truly a transplant-ineligible patient population, where the SWOG study wasn't necessarily.

The other important part along with that was that SWOG gave twice-weekly bortezomib, which many of us feel would not be tolerable in the transplanting ineligible older population, and these other studies give a more practical bortezomib administration schedule.

The RD-lite once weekly bortezomib, with the VMP, dara-VMP, both the arms had primarily weekly Bortezomib. I think those are important considerations. The hazard ratios are also very encouraging, with the dara containing regimens 0.43, 0.5 for the Alcyone and MAIA Study, whereas the SWOG was 0.71.

I think the take-home message is really, can a regimen be delivered on label as per the study to your patient that's sitting in front of you in clinic, and is the toxicity manageable? I think the dara containing regimens are a great option.

Moving to the transplant eligible population, we have the 2studies that have been discussed and presented, the Dara-VTD versus VTD, which is known as CASSIOPEIA, and then also recently, Griffin was presented at the IMW, which is the American version of Dara-VRD versus VRD.

Both again showed improvement in response depth. CASSIOPEIA, interestingly, with only 19-month follow-up has already shown a PFS benefit. GRIFFIN, the data not mature, only median follow-up of approximately 13.5 months. I think the question is then, what do we do with dara in this population?

The comparator our arms historically. It would have been probably 2. Again, the IFM study which was RVD with early transplant versus delayed transplant, and then the other FORTE Study from the Italian group looking at KRD. When we compare these regiments to the dara containing regimens, it's hard to compare because first, the number of cycles of chemo varies tremendously.

For the RVD, from the IFM Study, there was only 3.5 months of chemo. Moving to FORTE, 8 months, including 12 months if they didn't get the transplant. It's hard to compare when you're having such heterogeneity in the number of cycles of chemo.

Also, other than GRIFFIN, all three other studies gave side mobilization, which could obviously contribute to depth of response. Of course, the question is the outcomes. If you look at the depth of response at day 100, post-induction, consolidation with transplant, and 2 cycles of consolidation, it seems like it's the same time point.

Really when you factor in the prior to transplant number of cycles, and the side mobilization, it's very heterogeneous. I think what we see…I think it's surprising that dara-VTD with only 18-month follow-up is already showing a PFS benefit, suggesting that there's probably this added value for adding the dara.

I think, of course, one of the questions will be in the future, if we're getting such high rates of response, what is the role of transplant if you're really attaining MRD negative status with induction therapy? Stay tuned. I think the last part of the discussion is the bispecific antibodies or BiTEs.

The problem with this segment is we have very little data. Obviously, all the data that we have is in heavily treated patients. These are novel agents. We don't yet have an approved drug in myeloma.

What I think is encouraging is the fact that the response rates in heavily treated patients, although not as heavily treated as some of the other relapse studies, the Amgen 420, for example, showed a response rate of 70%, although in small numbers: 10 patients.

It raises the possibility that these drugs may be even more potent than our other agents because our typical response rate in this relapse refractory setting is probably 30-40% as a single agent. If you're getting something like 70%, the question is how might that do earlier up, in particular newly diagnosed patients?

I think the area to probably study first would be high-risk patients. One of the things we've seen with the CD38 studies is that high-risk patients do benefit, but they do not overcome. They still do worse than standard risk. We need agents that are going to make high risk basically obsolete.

It would be nice if we had an era of drugs and treatments where it didn't matter if you were high risk or not because the novel agents would overcome that. I think we've improved but not overcome, opening the role for novel agents such as bispecific.

I think the final point in that would be, we know that T-cell exhaustion is an important issue in advanced myeloma patients. Since these BiTEs are engaging T-cells, one might wonder whether we're going to get more efficacy if used earlier, although clearly, safety and toxicity studies need to be done as well.

I think there's a lot of excitement of moving these antibodies into frontline setting, because of their safety, combine ability, encouraging clinical data. It'll be exciting to see newer studies result out as well.