Josh Epworth, ARNP:
We are in a wonderful situation right now of fantastic treatments. I've been treating this disease now long enough to see a number of these new medications coming on board, and it's forcing us to ask a lot of different questions, and the biggest question is sequencing. How are we going to get the most impact against disease without getting in the way of treatments down the road? When I started, we were using Revlimid, Velcade, dexamethasone (Decadron) transplant, and then, usually, maintenance lenalidomide.
And I once was fortunate enough to talk to one of the great thinkers in multiple myeloma from the Mayo Clinic, about a guy named Dr. Vincent Rajkumar, who is just brilliant. And he was taking some time after a talk to really help educate me on a lot of things in myeloma because I was brand-new then. I asked him about an algorithm, and he said, “Well, right now,” – and this was five, 10 years ago – he said, “I know we have RVd plus transplant.”
After that, the algorithm goes out the window because it depends on a number of things. One, access to treatment. If they are near a facility that has the capacity to utilize multiple trials or has a provider who has a specific interest in myeloma and is very much up-to-date on these things or has a patient who is willing to come in or has access to infusions, RVd plus transplant is still the gold standard. Now, we can argue that daratumumab (Darzalex) added to that is a very useful approach. After that though, Dr. Lonial, from Emory was discussing recently about how, in their facility, their decision on second-line therapy comes from progression-free survival or the duration of the suppression of disease post-initial transplant. And his take on it was if the patient, a standard risk, had progression-free survival of greater than 18 months, typically, they'll introduce a daratumumab, plus pomalidomide (Pomalyst), plus dexamethasone. If it was under 18 months, they replaced the pomalidomide with carfilzomib (Kyprolis). And the thinking is, that if it's under 18 months, it has a greater aggressiveness which needs to be addressed aggressively in turn.
Now, we've talked about these high-risk cytogenetics. I think we're going to find, in the next five to 10 years, those are not the only factors that are driving the disease. So when we talk about how do we start, the first question is, how willing are they to be on a study? Because that's how we move this whole treatment landscape forward. An important thing about studies is, with cancer studies, we don't do one drug versus placebo. That is unethical. So it's usually standard of care versus standard-of-care-plus-something, to see if, one, it's safe, two, if it's more effective, and three, if it's equally well-tolerated, so that's the first place to begin.
The second place is, is how willing are they to engage in a transplant. How much support do they have from family members to get through that transplant period? Three, that we look at, is going, okay. How much access do they have to an infusion center? And this is where we come into a very interesting topic about financial toxicity. Medicare typically pays for nearly 100% of all infused medications and 90% of all oral medications. And that's great unless you're looking at a $15,000-a-month drug, or lenalidomide, or ixazomib (Ninlaro), with a $1,500 copay. So there are structures around that. We have terrific resources, like the Leukemia & Lymphoma Society, which can help with copay assistance. But still, that's going to be a driving factor in how do we choose treatment.
In addition, one of the big questions is the fragility. We've had a lot of conversations where we have said, “Oh, well, if it's over the age of 65, we do this. If it's under 65, we do this.” Well, a lot of us have seen 75-year-olds who are in terrific shape and running marathons, and 30-year-olds who have terrible comorbidities, so we have to look at that fragility scale. So, in order to just get by that first step, which is, “Okay. You've got myeloma. What are we going to do?” We have to ask a series of questions of how willing they are to go, what they're willing to do, what we can provide to them, can they actually participate in that, and what kind of support they have.
Now, with relapse, as we were talking about with Dr. Lonial's idea, we have those things. But we come to a certain point where most patients hit what's called penta-refractory status, which means they've received both immunomodulators, both lenalidomide, and pomalidomide, and they've received both proteasome inhibitors, meaning bortezomib (Velcade) and carfilzomib, and they have received daratumumab, a CD38 monoclonal antibody, so that's five drugs penta-refractory.
There are a number of other medications that we have, but it wasn't so long ago that we were then in a bit of a quandary. Venetoclax (Venclexta) is a wonderful medication for a very specific group of people with a translocation (11;14), and that's a very useful drug in that specific population. And there are a host of other new medications that have come out, including selinexor (Xpovio), belantamab (Blenrep), and elotuzumab (Empliciti), which is a very useful SLAMF7 medication but has to be combined with an immunomodulator.
But where we came up in the past few years was the introduction of CAR T with Abecma which had a phenomenal response rate in penta-quad and penta-refractory patients – meaning all those medications – and a very good progression-free survival in that sense of about 11 months. And then later came Carvykti, which was also another CAR T- cell, which also had these phenomenal responses in heavily-pretreated patients with a progression-free survival of about 20-plus months. So we made this jump from being penta-refractory and going like, “Well, okay. How can we extend this overall survival? How can we get another impact against this disease?” and these two medications come out.
More recently, with the FDA approval of teclistamab (Tecvayli), which is a BsAb or a bispecific antibody, we've got another medication that is phenomenally effective against heavily-pretreated patients and is hopefully going to be a medication that can be widely available in a number of different settings. And so, again, we're coming back to the question of sequencing of it. Okay. So when do we introduce bispecifics versus CAR T? When can we introduce all of these different medications, and how do they really impact patient quality of life?"
