Discussing the Future Role of Stem Cell Transplant in Multiple Myeloma

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

• With the introduction of novel induction therapies, is there a continued role for transplantation in patients with newly diagnosed multiple myeloma?​
• Do the results from the DETERMINATION study (NCT01208662) of bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone with or without autologous stem cell transplant (ASCT) influence how you consider ASCT? ​

SURBHI SIDANA, MD: I’m a transplanter, so of course I’m biased. What do you think about ASCT based on the results of the DETERMINATION study? Progression-free survival [PFS] was better [but] we don’t 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] there’s 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. That’s 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 you’re MRD negative after induction, do you need a transplant? I don’t 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 hoc—they were never randomly assigned based on MRD negativity—the 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. But…you 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 effective…I’m looking at the transplant value in general and looking at what’s coming and what’s 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] we’re still not curing anybody, so let’s 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 it’s 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 you’re 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. It’s 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 doesn’t have to be on lenalidomide, you don’t have to be on dexamethasone, and that’s 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, it’s fifth line for CAR T-cell therapy, first or second line for ASCT.⁵

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

SIDANA: I hope it’s a “one-and-done” but in all the trials that were designed in early lines, we’re adding maintenance to the CAR T-cell therapy. There’s a trial coming comparing ASCT to CAR T-cell therapy [CARTITUDE-6; NCT05257083] and there’s going to be [lenalidomide] maintenance in the CAR T-cell therapy arm. I’m hoping with CAR T-cell therapy we can continue it because patients love the treatment-free interval. They tell me that’s 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 what’s coming down the pipeline and worry that we’re 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}