Optimizing CAR T-Cell Therapy Prep in Multiple Myeloma After Relapse
During a live event, Jack Khouri, MD, discussed options for patients with multiple myeloma after relapse and choices to consider before CAR T-cell therapy.
Jack Khouri, MD
Assistant Professor
Cleveland Clinic Lerner College of Medicine
Case Western Reserve University
Cleveland, OH
CASE SUMMARY
- Mike is a 60-year-old man diagnosed 6 years ago with IgG-κ multiple myeloma; 60% plasma cells; translocation 14;20
- Most recent labs show recurrence of M-protein (0.6 g/dL) and imaging shows a new hypermetabolic lytic lesion.
- Medical history: hypertension controlled with lisinopril
- He normally works in his garden and walks 2 miles daily; he noticed a progressive decline in his stamina where he needs to take breaks more often and has shortened his walking route.
- ECOG performance status: 1
- He previously received daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone; autologous stem cell transplant; and lenalidomide maintenance with a complete response (CR) and time to relapse of 5.5 years.
Targeted OncologyTM: What are the options for this patient with multiple myeloma after first relapse?
Jack Khouri, MD: In the NCCN guidelines, there are a lot of options for the first to the third line of relapse.1 Carfilzomib [Kyprolis] base with daratumumab is an option, or with pomalidomide [Pomalyst]. We can also go back to bortezomib, because the patient was not really on bortezomib when he relapsed. So you can go back to bortezomib and combine that with daratumumab or even pomalidomide.
CAR [chimeric antigen receptor] T-cell therapy with cilta-cel [ciltacabtagene autoleucel, Carvykti] is also approved at the first relapse when someone is lenalidomide refractory, so he would technically qualify for early CAR T.
Other options include selinexor [Xpovio]-based regimens. I don't know how many people use selinexor, but you can combine that with bortezomib and the first relapse setting or beyond, based on the BOSTON study [NCT03110562], Elotuzumab [Empliciti] as a base is also an option. I'm not really a big fan of elotuzumab, so I try not to use that, especially if they've had daratumumab before, but that's also an option.
CASE UPDATE
- Mike and his oncologist have discussed his treatment options based on his response to his initial therapy.
- As he is lenalidomide-refractory his options include:
- Another combination treatment regimen
- CAR T-cell therapy
- After discussing potential outcomes, adverse events, and treatment logistics, Mike received daratumumab, carfilzomib (Kyprolis), dexamethasone (DKd).
- Achieved a CR lasting for 13 months
- Mike then relapsed for a second time after receiving DKd and now wishes to proceed with CAR T-cell therapy.
Can you discuss the different types of therapies used before CAR T-cell therapy?
Three different types of therapies are used when we are talking about doing CAR T-cell therapy. There is holding therapy, which is the treatment that we give before we collect [cells] for CAR T; there is bridging therapy, which is the treatment that we give when we're awaiting manufacturing of the CAR T cells; and there is lymphodepletion, which is the treatment that's given before we infuse the cells to cause immunosuppression for the patient not to reject the CAR T cells.2
Holding therapy is important, because that's the treatment that you're giving to the patient when you send them to us, potentially, for CAR T. What we tell people to do a lot of times is to avoid certain treatments that we know could compromise T-cell count and T-cell fitness, and those are mostly alkylators. I tell [referring physicians] to do their best not to use cyclophosphamide before we collect for T cells, if we can. We've had to do it in a lot of patients because we ran out of options and we had to do cyclophosphamide, for example. But we know those treatments can compromise the T cell repertoire.
Another class of drugs that could help with enhancing T-cell fitness would be daratumumab or immunomodulatory drugs such as lenvatinib and pomalidomide. These drugs can help a little bit before we collect the patient's cells. They could improve memory T-cell count, T-cell proliferation, and so forth. But in general, if there's something to remember from this, it is to avoid alkylators as much as you can before you send patients for CAR T-cell collection.
What do you suggest for bridging therapy before CAR T cells?
With bridging therapy, we can do whatever we want, especially if someone really needs therapy. We just have to do whatever it takes to keep them going until we can infuse the cells, although you don't always have to do bridging therapy. This is usually decided by whoever is doing the CAR T [infusion] and the patient's local physician, or just by [the CAR T specialist], if the patient wants to be with the larger center for that period of time. For many people, I don't do anything. I let them be if they have little disease, especially in that we're doing more early CAR T, [so] they don't have as much disease.
One thing that we've done for some people, if we ran out of options and we want to do something, is using bispecific antibodies—non-BCMA [B-cell maturation antigen] bispecific antibodies, not BCMA bispecific antibodies, because you want to avoid targeting the same protein that the CAR T cells are targeting. We know that by targeting BCMA before CAR T, you tend to get less responses and lower progression-free survival. So do your best to avoid BCMA-directed therapies before CAR T, because we do see less response, if you use teclistimab [Tecvayli], for example, or elranatamab [Elrexfio].
I use a bispecific antibody that targets a different antigen, which is GPRC5D. We've used GPRC5D blockade with talquetamab [Talvey]...to bridge patients after their cells are collected. So if you collect cells and then the patient is relapsing, you're still manufacturing the cells, and you don't know what to do, it's OK to use talquetamab. I would not use BCMA-targeted agents because of the lower response that we've seen in these patients and the lower progression-free survival. But talquetamab is fair game, and we do have data to support that.3
