Trials Shed Light on Transplant and Maintenance in NDMM

Susan Bal, MD

Assistant Professor-Medicine

The University of Alabama at Birmingham, School of Medicine

Birmingham, AL

Targeted Oncology: What studies were most important in exploring the use of autologous stem cell transplantation (ASCT) after frontline therapy for newly diagnosed multiple myeloma (NDMM)?

BAL: The IFM/DFCI2009 study [NCT01191060] was the original French study looking at upfront vs delayed ASCT.¹ This utilized lenalidomide [Revlimid] in maintenance scheduled for just 1 year following VRd [bortezomib (Velcade), lenalidomide, and dexamethasone]. What we saw was the 3-year median progression-free survival [PFS] was 50 months with ASCT vs 36 months without. It’s about a 14-month difference. This was updated showing that the 8-year overall survival [OS] was not different between the 2 arms.²

The DETERMINATION trial [NCT01208662]…is more relevant to the United States practice because we use lenalidomide until progression. What we saw was the addition of ongoing lenalidomide added about 1 year to the non-transplant arm and almost 2 years to the transplant arm, so that was the benefit of the additional maintenance.³ Overall, we saw the median PFS was 67.5 months with ASCT vs 46.2 months without, so it was about 21-month difference in outcomes between the 2 groups. I think that if the patient is going to receive a transplant, they should continue lenalidomide maintenance. Regardless, you should get continuous lenalidomide maintenance, which is the standard in the United States.

There are no OS data because it still was not mature. I think this is because there are so many amazing therapies for multiple myeloma that patients are not dying. Based on the data that were published last year, they did show the OS was not reached vs not reached, but the HR was [1.10] so it’s about the same.

In both studies, about a third of the patients received transplants.^1,3 The point we always make from both of these studies is if you’re going to do a transplant, do it now, because even if you intend to do it later, you probably won’t, based on multiple things. The second is to give lenalidomide until progression, which is something that we all do…. We’ll see more data for daratumumab [Darzalex]/lenalidomide. There is still a subset of disease where I think this is applicable, and we should still continue to refer these patients out so that they can hear from a transplant physician.

What do recent studies show about the use of carfilzomib (Kyprolis) in NDMM regimens?

The FORTE study [NCT02203643] is where we talk about KRd [carfilzomib, lenalidomide, dexamethasone]; this is less pertinent because we’re not talking about triplets anymore. Quadruplets have taken their place. [Concerning] KRd vs VRd, we all saw from the ENDURANCE [NCT01863550] data that they’re very similar.⁴ That trial did not include high-risk patients. There are smaller single-center studies that show that particularly in the high-risk patients, there may be a benefit for KRd.⁵ But this discussion has been completely taken over by the fact that this triplet is no longer pertinent, and we’re using quadruplets for all. I think the bortezomib vs carfilzomib dust has settled and nobody’s considering carfilzomib upfront.

The only thing that I will make a note of here, based on the FORTE study, is that FORTE was the first study where we got the concept of ultra–high-risk myeloma. FORTE was the first trial that looked at 0, 1, or 2 [high-risk cytogenetic abnormalities], and then everybody else decided to look at their data in that manner. Everybody was amazed at how relevant 2-plus high-risk features were. That’s why we still have to credit them.

The other very interesting things that came out is after you do KRd for 4 cycles, ASCT, then KRd for 4 cycles; or KCd [carfilzomib, cyclophosphamide, and dexamethasone] for 4 cycles, ASCT, then KCd for 4 cycles; or KRd for 12 cycles, there was a second randomization that was looking at carfilzomib/lenalidomide vs lenalidomide. Those data looked very good even for the patients who were minimal residual disease negative.⁶ There are lots of discussions we can have about those data, but it appears that that doublet maintenance in that setting resulted in improved PFS. I think that was very interesting to everybody, [although] I think that nobody uses carfilzomib/lenalidomide maintenance. I have never done it myself. I think the doublet maintenance that’s more relevant and pertinent to the discussion is daratumumab/lenalidomide.

_References:

_{1. 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}

_{2. Perrot A, Lauwers-Cances V, Cazaubiel T, et al. Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial. Blood. 2020;126(suppl_1):39. doi:10.1182/blood-2020-134538}

_{3.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}

_{4. Kumar SK, Jacobus SJ, Cohen AD, et al. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(10):1317-1330. doi:10.1016/S1470-2045(20)30452-6}

_{5. Tan C, Nemirovsky D, Derkach A, et al. Carfilzomib, lenalidomide and dexamethasone (KRd) vs bortezomib, lenalidomide, and dexamethasone (VRd) as induction therapy in newly diagnosed high-risk multiple myeloma. Blood. 2022;140(suppl_1):1817-1819. doi:10.1182/blood-2022-169161}

_{6. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/S1470-2045(21)00535-0}