Rafael Fonseca, MD: So at this [American Society of Hematology annual] meeting, we had an update from the ARROW study. For those not familiar with this, this is a weekly administration of carfilzomib. This is, of course, very important because of convenience; the classic carfilzomib schedule is more demanding on patients’ time. They did a randomization between the standard doses of carfilzomib, or an escalation to 20 or 70 mg once a week. The regimen was highly effective. There was no particular signal with toxicity, and in particular with regard to cardiac events.
I think many of us were a little bit worried when we had originally seen the data with the CHAMPION-1 study. But in the ARROW study, the results were reassuring. One has to, of course, be mindful in patients who have cardiac history and patients who may have hypertension that needs to be very well controlled. But it really provides a framework upon which we can use the weekly carfilzomib.
Now, it’s very important for the audience to remember the following. First of all, the 20 mg should only be used on the first day. Occasionally, we’ve seen the practice that you know we’re running, and it’s maybe in our computer, so patients may stay on 20 mg. That’s not proper. Number 2, it’s correct to use it on a weekly basis, but the doses will depend on whether it’s used alone or in combination.
In my opinion, without having the complete dataset to support this, what we’re doing is 70 mg if you are to use carfilzomib and dexamethasone only. And I use it at 56 mg if we use it in combination with an IMiD [immunomodulatory imide drug].
The OPTIMISMM study explores the efficacy of the combination of bortezomib with pomalidomide and dexamethasone. And what it really highlights is that pomalidomide will be the go-to backbone for the relapsed and refractory schedules in clinical trials. We have alluded to the combination of elotuzumab, pomalidomide, and dexamethasone. There’s a study from Moffitt [Cancer Center] that looked at pomalidomide, cyclophosphamide, and dexamethasone, and now there’s one that is bortezomib, pomalidomide, and dexamethasone.
I have had the opportunity to previously use this regimen in our clinical practice, and even in patients who have refractory disease to other agents, it has shown a significant level of activity. So if someone has a patient who would be eligible for such combination and would tolerate those 2 drugs, and in particular has no major issues with peripheral neuropathy with prior bortezomib exposure, a clinician should consider that.
The ELOQUENT-3 clinical trial reported on the combination of elotuzumab, pomalidomide, and dexamethasone versus pomalidomide and dexamethasone. And this has also led to the approval of this combination recently by the FDA. Both in levels of response as well as progression-free survival, pretty much there’s the doubling of the times and level of the response you see with a triplet versus the doublet combination. Now, this highlights once more that we may have to lean quite a bit on the potential aspect of elotuzumab for combinations in relapsed and refractory patients. When you look at combinations that have been reported by other groups, including daratumumab, you know they kind of fall into that ballpark. And elotuzumab is an agent that hasn’t had single agent activity but clearly works in combination. There’s clear proof of principle based on the previous ELOQUENT studies. So I’m very curious to see how this pans out. For me, the key question is whether we can have that efficacy in patients with prior exposure with daratumumab.
Newer agents have provided opportunities for the treatment of myeloma that obviously didn’t exist before, but have really shown the power of novel mechanism of actions and combinations.
For multiple myeloma, the ability to induce very deep responses was not existent before. And there are some versions of myeloma that will always respond to something. So there’s some biology behind how a person may have a complete response, how a person might get into an MRD [minimal residual disease]—negative status, even with a simple regimen like RD [lenalidomide/dexamethasone]. But there’s a much bigger layer of therapeutic efficacy, and it is only because of that layer that we have … high MRD negativity rates in patients with even relapsed and refractory disease with a regimen, for instance, that used in the POLLUX study, which was a combination of DARA [daratumumab], lenalidomide, and dexamethasone.
So they have dramatically changed how we think about this. And I think it’s fair to say that we already know, even with older agents, that there’s a small fraction of myeloma patients that can be cured. I think the fraction is growing. And the group from Emory University presented data with the not-so-new agents, so the bortezomib, LEN/DEX [lenalidomide/dexamethasone], followed by transplant. And at 10 years, they reported at this meeting in a poster of overall survival, 77%. For those with standard risk, it was I believe closer to 80%, with a curve that looks pretty flat out there.
Now maybe that’s an extremely positive result, but even if you were to find some changes in the data and how you would want to analyze them, it really speaks to the availability of a very long duration of disease control. And then from a payer perspective, hopefully we can do this with an abbreviated course—maybe transplant, maybe consolidation, limited maintenance—and off you go without a need for future care for multiple myeloma.
The unmet need for myeloma is the second relapse. And “unmet need” is a term that is used, of course, with regulatory purposes. But the reality is that patients that have experienced the benefit of some of those regimens that I alluded to with daratumumab-based combinations, so the carfilzomib-based combination, have very limited options. So, there are a number of drugs that will be coming to the forefront—drugs like Selinexor, drugs like venetoclax. But when you look at the real-world data, you very quickly realize that the duration of therapy for first line is long; second line, third line, fourth line becomes very short.
Now we’re hoping that’s going to be prolonged with things such as immunotherapy, and we’re just delighted to see there’s so much work on CAR [chimeric antigen receptor] T cells and bispecific antibodies. But I would say the second relapse is a problem, because the reality is still that the majority of patients go through various relapses. Hopefully, less so with what I’m saying about cure. But still, that’s a patient population that is very difficult to treat.