Advances in the Treatment of Relapsed/Refractory Myeloma - Episode 13
Sagar Lonial, MD: The one area that everybody is very interested in is immune therapy. Every patient wants some form of immune therapy or another, whether it’s PD-1 [programmed cell death protein 1] or PD-L1 [programmed death-ligand 1]. And in myeloma those didn’t really pan out as they have in other diseases. But one area of immune therapy that has been effective is the use of CAR [chimeric antigen receptor] T cells. And there are now multiple trials demonstrating efficacy with the use of CAR T cells, as well as durability in some patients with CAR T cells as well.
One thing that differentiates myeloma, perhaps, from ALL [acute lymphoblastic leukemia] and lymphoma is that patients that achieve an early CR [complete remission] may not necessarily be as durable as we see in ALL and with diffused large B-cell lymphoma. But that may be a factor of how we’re testing for CR and when we’re testing for CR. But there’s no question that patients can have quite durable responses with CAR T cells in the current environment.
The target for many of these CAR T cells is BCMA [B-cell maturation antigen]. And we know that BCMA probably, at least in my view, is one of the best targets in all of myeloma. Now, while CAR T cells are going after BCMA, we also have BiTEs [bispecific T-cell engagers] and bispecifics that are targeting BCMA, and we have antibod-drug conjugates that are targeting BCMA as well.
All of them, in preliminary data, show efficacy. And the real question is, is there a timing question? When do you use a CAR T cell? When do you use a BiTE? When do you use an antibody-drug conjugate? Are their responses similar? Are their durations similar? And are their adverse events similar? Those are the questions we just don’t have answers to right now.
Probably one of the CAR T cells that’s farthest along in development is bb2121. And that trial was presented recently and updated in the phase I portion. And the phase II portion is almost done with enrollment actually. And what we know is that the response rate is over 90%, that a significant fraction of patients can achieve a complete remission. More importantly, what we know is the median progression-free survival [PFS] for that early experience was about 11.8 months.
Now when that data first came out, there were people on one side who said, “11.8 months, that’s not long enough considering all the work that goes into making CAR T cells.” But I want to put that 11.8 months in perspective. When we look at the early CAR T-cell data, in lymphoma particularly, the median PFS was about 3 to 4 months. So we are significantly longer than that. The difference was that in lymphoma, if you achieved a CR and were in CR at 6 months, you were likely done and you did quite well. And that’s the data everybody remembers.
In myeloma, it’s not so sure that achieving a CR at 3 months or 6 months is necessarily as durable as what we’ve seen in lymphoma. But we need longer follow-up to know that.
Whenever you see a CAR T-cell study, there’s always some level of patient selection that occurs, because of the process, the limited number of slots, the month that it often takes to manufacture the cells—all of those things will often have patients drop out.
I can tell you that, at least at our center, the patients we’ve enrolled have not really been the good-risk patient. They’ve been patients where getting them on or not getting them on was 1 or 2 days away. And so I think there is a certain level of patient selection in that you’re not taking the worst of the worst, but these are by no means the best of the best that are going on these trials. These are patients who have very aggressive disease.
Ajai Chari, MD: Checkpoint inhibitors have had a rough course in recent years in myeloma. We know that this pathway is important in myeloma. For example, in our investigator-initiated study with pomalidomide, cyclophosphamide and DEX [dexamethasone], when patients became resistant there was an upregulation of PD-1 and PD-L1 at the time of progression, begging the question of what adding a checkpoint would do. And we actually did see some encouraging efficacy. And, indeed, the initial checkpoint studies with both lenalidomide and pomalidomide showed very high response rate.
So the pomalidomide, PEMBRO [pembrolizumab]/DEX study in particular, had a really high PFS of 17 months, which has really not been seen with any other POM [pomalidomide]/DEX-based regimen. LEN [lenalidomide] /DEX/PEMBRO also showed a response rate of around 30%, even in LEN-refractory patients. So clearly there’s a signal there. But I think what we learned from the randomized phase III studies is that the IMiDs are really potent immunomodulatory drugs. And we kind of, we call them IMiDs, but we really often don’t think about their immunologic profile. And what the addition of checkpoints showed is that when you do this triplet combination, there is an increased risk of immune complications and it can be of any organ and including death.
So for those reasons, appropriately, the FDA [US Food and Drug Administration] halted these studies, and it highlights the need for randomized phase III studies because it may look promising in a phase II, but until you do the phase III and really look at the risk-benefit profile, you may not see it. So I think the future of checkpoint will be probably not with IMiDs, but perhaps with other novel agents. And clearly we’ll have to go in a slow fashion to not compromise patient safety. But the activity of these drugs are well known in other tumors, and we just have to find the right way of using it in myeloma.
We were waiting for a long time for monoclonal antibodies in immunotherapy and myeloma, and we got the ELO [elotuzumab] and DARA [daratumumab] in 2015, but obviously there’s still a need for more. And we’re looking at a lot of different types of antibodies. We have both naked antibodies, which include, I would lump them into this T-cell—engaging category. They’re bispecific, or they basically have 2 warheads. One in CD3, the other targeting a different antigen that’s expressed on the myeloma cell, such as BCMA. There’s also GPCR, which in another protein that’s overexpressed on myeloma cells. So these dual antibodies, or bispecifics, can try to bring the T cells into close proximity with the myeloma and have already shown very exciting preliminary data.
In contrast, another strategy would be conjugated. Probably the best example of this is the GSK [GlaxoSmithKline] compound, which was presented by Dr. Trudell at last year’s ASH [American Society of Hematology] meeting. This is an anti-BCMA drug that’s not a dual warhead. It’s BCMA targeting, but it carries a payload of an auristatin, which is a cell cycle inhibitor. And it showed a very impressive response rate of 60% of PFS, of upwards of 7 months, including a response rate of about 40% in penta-refractory patients, although there are only about 12 patients there. So small numbers but I think very encouraging signal there. The main side effects that were seen were thrombocytopenia and some ocular issues. But if the larger study confirmatory support these same numbers, this is why the FDA gave this a breakthrough designation as well. So I think we’re very excited about this compound as well.
Andrzej Jakubowiak, MD, PhD: As far as vaccine strategies or peptides, which we can potentially use in myeloma, again, these strategies are in early phase or not advanced enough to really determine, in my opinion, at least interpretation of data which I have seen so far. They could potentially make a difference in myeloma. I wouldn’t make this as a statement to not to evaluate these drugs. I think they need to continue to be evaluated, but we naturally are focusing and moving earlier to those candidates for the next wave of active therapies in myeloma, which already have shown good activity.
But I would add to that point that selinexor, in initial evaluation, as well as elotuzumab, improved drug, Empliciti, have not shown much of 3 simple-agent activity, especially elotuzumab. And they have been found to be active in combination.
So I think that if there is a rationale and that can be potentially explored further, combining some of these candidate drugs with other agents may potentially bring new treatment regimens, which you can use in myeloma, especially for patients who don’t have any other options.
Transcript Edited for Clarity