Novel Targeted Therapies in the Treatment of Multiple Myeloma

Jatin Shah, MD: In myeloma it’s very exciting. We’re really entering a new phase in myeloma therapy, new paradigms, and it’s really using targeted therapy. That’s a niche word or a buzzword that we use commonly in cancer now, but I think it’s important to really identify what targeted therapy is. The targeted, or truly targeted therapy is identifying one specific target that’s unique to the cancer or to the plasma cells or the myeloma cells that’s not expressed anywhere else. So, how do you directly target that cancer cell without affecting the rest of the patient, without causing any other damage to the heart or the kidneys, to the lung, causing hair loss or nausea, vomiting, etc?

That really is the definition of truly targeted therapy. And, it’s exciting finally, now in myeloma, that we have two different targeted therapies. And, importantly, when you look at CD38, for example, that really is targeted therapy because that is really expressed on myeloma cells and heavily expressed on myeloma cells, and that’s the way we identified plasma cells when we looked at the bone marrow to look for CD38-positive cells. So CD38 becomes really an important target that we see in myeloma that’s expressed on plasma cells and minimally expressed everywhere else.

So it becomes an important target now; and now, daratumumab, that really is truly targeted therapy in the sense that you have a specific drug that targets a very specific target with minimal or no other reactions that we see. That really is the definition of targeted therapy, and that’s the definition of immunotherapy where you’re using the immune system to kill the plasma cells as well. So I think that, in this era, lots of things are lumped in this immuno-oncology or immunotherapy space, or targeted therapy. But the definition of targeted therapy is one specific target with minimal expression anywhere else, and one drug that really goes after that one target; and that’s what we see with daratumumab and that’s what’s really exciting about daratumumab is you can specifically target CD38, lead to direct cell death of CD38 expressing plasma cells. So it’s very active in that setting, also minimal side effects other than infusion reactions that we may see initially. Beyond that there’s really no other off-target side effects that we see or adverse events, which makes it a very safe, as well as a very active drug, and that’s what really the definition of targeted therapy is.

Daratumumab was approved based on the pivotal trial called SIRIUS. This was a phase II single-arm study where they treated approximately 106 patients with relapse/refractory myeloma. In the study, patients all had prior IMIDs and proteasome inhibitors, so they had all of our known therapeutics in terms of both a proteasome inhibitor and an IMID. Importantly, they’re also refractory to a last line of therapy as well. So these are very heavily treated patients who’d seen a median of 5 lines of prior therapy. A very aggressive disease that’s very difficult to treat.

It’s important when you think about clinically, that almost all these patients were refractory to the last line of therapy, and what does that mean as opposed to relapsed? If you have relapsed disease, that means you had some sort of therapy, you came off therapy, I’ve been watching you closely, and now 3 months, 6 months, and 9 months later, your disease slowly starts coming back. That’s very different than somebody who’s refractory to their last line of therapy.

That means you’re getting chemotherapy, you’re getting an active combination, and your disease is growing through that. That’s a much more aggressive disease. That’s growing in the face of an active chemotherapy, or growing within stopping the therapy within 30 days. So that’s very different than relapsed myeloma. And, if you look at the SIRIUS Study, almost all the patients were refractory to their last line of therapy. So these are patients who were very aggressively treated, had lots of lines of prior therapy, and were growing on therapy, and those are very difficult-to-treat patients. You need to make immediate intervention and start therapy and get disease control.

So, in that setting, where there’s really an unmet need, the use of single-agent daratumumab led to a response rate of 30% in these patients. That’s a very impressive response rate. Now I think if we step back and say, 30% really is not that high, why are you getting excited about 30% if you just look at that number, but when you look at it in the setting of saying these patients had 5 lines of prior therapy, I have no other options for these patients, here’s a new drug that’s truly targeted that works in 30% of patients, I think that is very exciting data that we see in that heavily relapsed/refractory setting. And so, I think for an outsider, if you’re looking at only a 30% chance of working, it does not do it justice when you think about these patients who are really very aggressive and very heavily pretreated. And for us and the treating physicians, that’s a very impressive response rate I would say in that refractory setting when there’s no other options for these patients.

And, importantly, when you look at this, it’s not just the response rates that we see, but also the duration of response, and these are durable responses. And so remember, we talked about these patients and the aggressive disease and that they’re going through the last line of therapy. And, here, not only can you get these patients to respond to therapy, but they also have a durable response as well. So the duration of response was 7 months in these patients; so that’s a very durable response that we see in these patients that not only they’re getting an early response, but they’re maintaining that clinical benefit, as well, for a prolonged period of time. Now there’s some very interesting data that even after they come off that, there’s still some long-term benefits that we see with daratumumab as well, but we’ll see.

It’s exciting with daratumumab that we’ve seen this 30% response rate in as heavily pretreated late-line therapy. It’s really proof of concept saying this is a very active drug, very well tolerated. So now the next step is moving into earlier lines of therapy, like we do with all of our cancer therapeutics, that we use our best therapies up front. So we try and move these into earlier lines of therapy.

So we’ve seen now this with elotuzumab, now in a phase III in the 1 to 3 lines of therapy showing clinical benefit in that 1 to 3 lines of therapy. It’s very exciting now, at ASCO that we’ll see the addition of daratumumab to bortezomib and dexamethasone really leading in a phase III trial to a significant benefit in both in response rates, as well as progression-free survival and a hazard ratio of .37.

Excitingly, we’ll see at ECOG soon, the addition of daratumumab to lenalidomide and dexamethasone, again moving into earlier lines of therapy with 1 to 3 lines of therapy getting very high response rates that we’ll see as well as a very high CR rate in these patients. So not only getting them to respond, but now you’re getting a depth of response as well; so now 40% of these patients are going to complete remission, which if you look at lenalidomide and dexamethasone, it’s going to be much lower than that. And, importantly, they have a long progression-free survival as well. So very exciting that we have proven that this is a very active drug and a safe drug, and now we’re moving into earlier lines of therapy. And so the paradigm is shifting again. Keeping with our oncologic principles to use your best therapies earlier in the disease course, and I think that’s exactly what we’re doing with drugs like daratumumab.