Surbhi Sidana, MD

Assistant Professor

Department of Medicine

Division of Blood and Marrow Transplantation & Cellular Therapy

Stanford University School of Medicine

Stanford, CA

DISCUSSION QUESTIONS

SURBHI SIDANA, MD: Im a transplanter, so of course Im biased. What do you think about ASCT based on the results of the DETERMINATION study? Progression-free survival [PFS] was better [but] we dont see an overall survival [OS] difference.1 Did that change how you practice? Do you think it favors doing ASCT early [or shows that since] theres no difference in OS, we should not do the transplant?

ASHKAN LASHKARI, MD: As we incorporate MRD [minimal residual disease] assessment or diagnostic evaluations into our management of our patients with multiple myeloma, we might have a better way of determining whether we need to [transplant] or not. Thats a question that may be answered with the incorporation of MRD, at least in more clinical trials.

SIDANA: You bring up a great point, which is if youre MRD negative after induction, do you need a transplant? I dont think any of these trials answer that question because they did not randomly assign patients who were MRD negative versus MRD positive to ASCT versus no ASCT. I think we need to do these trials in the future.

Some of these trials are starting to happen in small phase 2 trial format. Currently, at least in the IFM 2009 trial [NCT01191060], even if you were MRD negative post hocthey were never randomly assigned based on MRD negativitythe MRD negativity did appear to be somewhat deeper and more sustained with the transplant.2 Those patients had a slightly better PFS. Whether that will hold true for DETERMINATION remains to be seen. I think what the transplant did was make it more sustained, at least in the IFM 2009 trial with 1 year of lenalidomide maintenance, versus no [transplant].

ANDY JANG, MD: I think the DETERMINATION trial is probably dampening the enthusiasm for ASCT for a couple of reasons. If I have a brand-new patient today whom I put on quadruplet therapies, I probably can [avoid transplant] for at least 7 years. Then you have CAR [chimeric antigen receptor] T-cell therapy, which gives you a very high overall response rate [above] 90%.3 The complete response rate is very high. Then you have other targets that are coming and CELMoDS [cereblon E3 ligase modulators]. Based on what I see right now and how effective the quadruplet therapy is, the transplant is probably going to get less emphasized.

SIDANA: Some of our standard-risk patients can get to [7 years on first-line therapy], but a lot of our high-risk patients [will not]. Do you change your practice patterns based on whether they have standard risk versus high risk?

JANG: Yes, of course. Butyou buy them so much [time]. Five years from now, the standard of care for multiple myeloma is definitely going to change. There may be a whole slew of other therapies. Because frontline therapy nowadays is so effectiveIm looking at the transplant value in general and looking at whats coming and whats already here. The CAR T-cell therapy data and even the bispecific antibody data are excellent in triple- or even penta-refractory patients.

SIDANA: Even though I am a transplanter, I hope one day ASCT will go away because every few years you want newer therapies that are less toxic to take over for older therapies. I think of it with a standpoint [where] were still not curing anybody, so lets use all of our treatments, ASCT included. But I hope one day that there is a treatment that can give us similar PFS and hopefully its less toxic and ASCT does go away.

SAM YEH, MD: I like the ASCT arm [in DETERMINATION] because I feel like patients do much better on maintenance than going back on treatment. You get [almost] 20 months extra PFS on the transplant arm based on DETERMINATION.4 Those [nearly] 2 years can give patients a good quality of life versus [if] the disease comes back, and they have lytic bone fractures and quality-of-life issues. There is going to be more toxicity going back on triplets or quadruplets versus when they go on ASCT, then they have a longer PFS and their quality of life may be better.

JANG: If you look at CAR T-cell therapy, it is also one-and-done, the patient has fairly good quality of life, and youre not giving them melphalan. The question is, do you go CAR T-cell therapy or ASCT; they are both one-and-done therapies. But with the transplant, you have to put them on maintenance. So you can argue the other way, [that CAR T-cell therapy is] one-and-done and gives patients a good quality of life.

YEH: CAR T-cell therapy is not indicated in that setting. Its much later.

JANG: That is why I said there is going to be less emphasis on the transplant [in the future] because a CAR T-cell therapy is one-and-done and the patient doesnt have to be on lenalidomide, you dont have to be on dexamethasone, and thats a tremendous selling point for the patient.

SIDANA: Both of you have good points. CAR T-cell therapy is one-and-done, but the indications are completely different. Right now, its fifth line for CAR T-cell therapy, first or second line for ASCT.5

JANG: Thats [true in this] moment in time. We know its not going to [require] 4 lines of therapy [in the future]. Its just because the trial was done that way. When Im going to refer CAR T-cell therapy, Im not going to wait for fourth-line therapies. Im going to start referring them when they have triple or quadruple failures. But right now, I understand the label. Looking atthe future of myeloma therapies, its not going to [require] a fourth-line therapy [before] you refer to CAR T-cell therapy. Its going to change.

SIDANA: I hope its a one-and-done but in all the trials that were designed in early lines, were adding maintenance to the CAR T-cell therapy. Theres a trial coming comparing ASCT to CAR T-cell therapy [CARTITUDE-6; NCT05257083] and theres going to be [lenalidomide] maintenance in the CAR T-cell therapy arm. Im hoping with CAR T-cell therapy we can continue it because patients love the treatment-free interval. They tell me thats the best few months of their life, but because patients still relapse, we are [acting like] ASCT used to be, with no maintenance. But then we added maintenance.

I see whats coming down the pipeline and worry that were going to add maintenance to [CAR T-cell therapy], too, but perhaps not for everybody. We will find out in the future if we need to do that for everybody.

References:

1. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma.N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925

2. Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma.N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750

3. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8

4. Richardson PG, Jacobus SJ, Weller EA, et al. Triplet therapy, transplantation, and maintenance until progression in myeloma.N Engl J Med. 2022;387(2):132-147. doi:10.1056/NEJMoa2204925

5. NCCN. Clinical practice guidelines in oncology. Multiple myeloma, version 3.2023. Accessed March 30, 2023. https://bit.ly/2T0mDYS

Continued here:
Discussing the Future Role of Stem Cell Transplant in Multiple ... - Targeted Oncology