Vescio Discusses the Important Factors in Treatment Decisions in Transplant-Eligible Multiple Myeloma

Robert A. Vescio, MD

Medical Director

Multiple Myeloma and Amyloidosis Program

Samuel Oschin Comprehensive Cancer Institute

Cedars-Sinai Medical Center

Targeted Oncology^TM: Would you recommend autologous stem cell transplantation (ASCT) for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM)?

VESCIO: The IFM 2009 study [NCT01191060] from France investigated this question. Transplant-eligible patients with NDMM received 3 cycles of lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [VRd] followed by ASCT collection. [Then, patients in 1 group received another 5 cycles of VRd] and patients in the other had a stem cell transplant followed by 2 more cycles of VRd. Finally, all patients were put on [10-15 mg daily] lenalidomide maintenance for a year.

After 90 months of follow-up, the study found an advantage in progression-free survival [PFS] at 47 months vs 35 months for patients who did not receive ASCT. But the overall survival [OS] at 8 years of follow-up is still quite comparable between the 2 groups.^1,2 One of the issues is that three-quarters of the patients who did not receive ASCT initially had a stem cell transplant at first relapse.² Even though I was trained by somebody who’s not the biggest fan of doing stem cell transplants, this is something that needs to be mentioned as most people ended up getting a transplant. This might be why the PFS was worse for the nontransplant group, but the OS wasn’t much different between the 2.

The subgroup analysis by minimal residual disease [MRD] status, or by risk status, showed that the patients with high-risk cytogenetics seemed to derive less benefit from high-dose chemotherapy and a stem cell transplant,² which is the opposite of what you would expect. I think that this result has been repeated in many, many trials. It’s not that they don’t benefit, but the benefit seems, in fact, to be less. This just shows you that if you were MRD negative, you did better than if you were MRD positive. The patients that did the best were MRD negative who had the transplant, which makes some sense. People had proposed that if you test for MRD, and it’s negative, then maybe you don’t have to do a transplant, but this study showed that it was better if patients had the transplant, at least for their PFS.

Please discuss the design of the FORTE trial (NCT02203643) and its impact on this patient population.

[This study] evaluated the efficacy of carfilzomib [Kyprolis] as an up-front regimen, randomized as a triplet with either lenalidomide-dexamethasone [KRd] or with cyclophosphamide-dexamethasone [KCd], with half the patients getting KRd, just continuing without a transplant, and the others doing a stem cell transplant and then getting some further therapy afterward.

There was a KRd vs KCd comparison, in which the lenalidomide arm did better; and then there was a KRd without a transplant vs KRd with a transplant comparison. Finally, there was a second randomization for the maintenance drug, which could be lenalidomide alone or combined with carfilzomib, with the carfilzomib being given in a cumbersome way for patients where they get 4 doses of carfilzomib a month for 2 years.^3,4 The KRd with a transplant had the best PFS. At about a little over 3 years, [the PFS rate] was 78% for the transplanted group vs 66% for the nontransplanted group, while the worst arm was the KCd treatment. So it suggests that this is not a good opening regimen for patients.

In the second randomization, the patients who got carfilzomib combined with lenalidomide had a better PFS than those on lenalidomide alone, with benefits both for standard- and high-risk cytogenetics.⁴

So I think it’s clear that lenalidomide alone isn’t adequate if patients have high-risk disease. I think adding proteasome inhibitors—in this case it was carfilzomib, but bortezomib has been shown to be effective as a maintenance therapy for high-risk patients—to lenalidomide makes a lot of sense. There are not a lot of data about daratumumab [Darzalex]. The question is do you do 2 drugs—which I tend to do—and then which 2? Do we need lenalidomide, or should we use daratumumab with a proteasome inhibitor? That’s a little less clear.

What other trials impact your decision-making?

The phase 3 CASSIOPEIA study [NCT02541383] was mostly done in Europe. And I don’t know that it’s applicable to the United States. In any case, this was probably the first study looking at a triplet vs a quadruplet. So they randomized younger patients to bortezomib, thalidomide [Thalomid], and dexamethasone [VTd] with or without daratumumab. In Europe they use thalidomide a lot more than lenalidomide because of the cost.

After the transplant, which all patients received, patients were randomized either to observation alone, or daratumumab, in this case given every 8 weeks as a maintenance.⁵ First of all, I don’t know that we could ethically do this trial anymore, because by observation alone it has been disproven as a therapy post-transplant. It’s kind of like we go to all that effort to get somebody in remission, then to do nothing seems to not be the best thing to do. But nevertheless, that’s what they did.

Adding daratumumab to VTd resulted in a better PFS, a higher incidence of complete response, and, more importantly, their OS was substantially better.^5,6

The people that never got daratumumab, they were randomized to the VTd, and then they were randomized to observation after the transplant instead of the daratumumab, had the worst PFS. The other groups, whether they got daratumumab both times or just in one of the 2 randomizations, were somewhat equivalent in terms of PFS. Although for patients with MRD negativity, PFS was a tad better, at 64%, if they had daratumumab both before and after the transplant.⁶

If you give VRd plus daratumumab (dara-VRd) as the initial treatment, do you give daratumumab again in the maintenance phase? If so, how would you dose it?

I’m starting to see patients like this [patient case] and I like daratumumab as a long-term type of therapy. Eventually, it’s a shot once a month, and patients usually don’t mind that too much, but the question I deal with is: How do you dose it? Do you have to load them, which makes intuitive sense to do the weekly recipe to get it in their body if you delayed it for a long time. Because the way daratumumab works is the reason we give it weekly for 2 months and then every other week for 4 more months. It takes a while to load the drug into the tissues to keep, pharmacokinetically, the dose of daratumumab—the concentration—the same. So when somebody’s had a 3-month holiday, I assume that the daratumumab has leached out and that maybe they need the loading again, then I just start from beginning but I don’t know if that may be overkill.

The GRIFFIN trial [NCT02874742] is being talked about a lot. This was a randomized trial of VRd vs dara- VRd and then a transplant.⁷ I’m not sure exactly why they do 4 months of treatment, then the transplant, and then 2 months of consolidation. Personally, what I usually do is 6 months of treatment, but the last treatment without lenalidomide to allow the stem cells to be collected better, because lenalidomide kind of inhibits one’s ability to collect stem cells. And then I don’t do a consolidation phase; I just do 6 cycles followed by the transplant and then figure out what to do for maintenance.

Patients either got randomized to daratumumab the whole way through, or no daratumumab. Then maintenance therapy was lenalidomide with or without daratumumab given every 4 weeks, and in the induction, bortezomib was given on days 1, 4, 8, and 11 (4 doses) every 3 weeks.⁷ A common dosing regimen for bortezomib is a 28-day cycle. It would be interesting to know how clinicians are usually dosing bortezomib, and if this regimen, 4 doses every 3 weeks, would dissuade them from using VRd.

I’ve been fearful of giving people neuropathy, especially since these patients do well [otherwise]. Therefore, I don’t like doing 4 doses of bortezomib every 3 weeks indefinitely. I may start patients with aggressive disease that way, but I tend to switch to a weekly regimen of bortezomib after that because I still think patients get neuropathy, unfortunately. I’m hopeful that the subcutaneous preparation will have fewer cases of neuropathy.

Adding daratumumab in the quadruplet group deepened the response. So by the end of 2 years of maintenance, 82% of the patients who got daratumumab were in a complete remission vs still a quite good 61%. The PFS was also better in the daratumumab arm.⁸ In addition, there was a higher MRD negativity rate, 64% overall with the less sensitive technique vs 30% after 2 years of maintenance therapy. In the subgroup analysis, adding daratumumab seemed to be beneficial regardless of disease type, although maybe a little less beneficial for the high-risk patients.⁸ Again, I think that may be because lenalidomide isn’t the best choice as a maintenance drug if you have high-risk disease. I wonder if daratumumab and bortezomib, or something like it, would have been a better choice for these patients as a maintenance therapy.

Would you recommend switching therapies to achieve MRD negativity?

In my opinion, if a treatment got you to MRD negativity, well, wonderful. Keep it going. If a treatment got you to almost MRD negative, but they’re tolerating it, well that’s pretty darn good. I don’t know that we should switch their treatment. We all have patients who are MRD positive and still do well for years, for example, a patient with smoldering myeloma who just smolders along and never gets to be MRD negative. Given a choice, yes, I would love to be MRD negative, but I don’t know how that changes what we should do. I think for studies they do it because it takes so long to see survival outcomes, [so it is reasonable] to look at MRD negativity as a sign of deeper responses and a quicker way to predict outcomes. So for studies, it’s useful.

What is more important for MRD negativity, the number of drugs used or the types of drugs used?

Sometimes when treating patients, you can identify which drug seems to be the more important of the triplet or quadruplet. Sometimes one of the drugs is started later, for various reasons, and by the time you start it, the patient has already responded, and that clues you in that maybe that drug is not so important. I think all these studies are going to have their little place for a very brief time and then we’re going to have better drugs, and it’s going to be kind of irrelevant.

How is MRD measured? Is it standardized?

It’s not fully standardized and seems to vary from study to study. Some do it with flow cytometry, which is easier, and some do it with ClonoSEQ. It’s always done with a bone marrow sample at the moment. But you can’t compare MRD from one study to the next. Within the study you can.

The phase 3 PERSEUS trial [NCT03710603] was basically the same study as the GRIFFIN trial but with subcutaneous daratumumab. Again, there was a group of patients that never got daratumumab and a second group that got daratumumab plus lenalidomide. After 2 years of treatment, if [patients in the combination arm were] MRD negative, for at least 12 months, they stop the daratumumab and just keep the lenalidomide.⁹

I don’t know if that’s the right way of doing it. If something works well, and you’re MRD negative, does that mean you should stop it, or just be happy that the treatment got you there and not stop it? So I don’t know if that’s the right approach, but that’s the study.

One thing I want to point out is that if you add daratumumab to a regimen like VRd, it does cause a little more neutropenia, particularly during the first cycle.⁷ This is a different topic, but daratumumab with pomalidomide [Pomalyst] and dexamethasone can cause some substantial neutropenia, more than you would see with pomalidomide and dexamethasone alone, although that tends to lessen in the subsequent cycles. Some of the early cells express CD38, and presumably that’s why daratumumab can add to neutropenia.

_REFERENCES

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_{2. Perrot A, Lauwers-Cances V, Cazaubiel T, et al. 143 Early versus late autologous stem cell transplant in newly diagnosed multiple myeloma: long-term follow-up analysis of the IFM 2009 trial. Presented at: 62nd ASH Annual Meeting and Exposition, December 5-8, 2020; virtual. Accessed April 29, 2022. https://bit. ly/3vA0jYg}

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_{4. Gay F, Musto P, Scalabrini DR, et al. 141 survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized FORTE Trial. Presented at: 62nd ASH Annual Meeting and Exposition, December 5-8, 2020; virtual. Accessed April 29, 2022. https://bit.ly/39wO9Hf}

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_{6. Moreau P, Sonneveld P. Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2. J Clin Oncol. 2021;39(suppl 15):8004. doi:10.1200/JCO.2021.39.15_suppl.8004}

_{7. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/ blood.2020005288}

_{8. Laubach J, Kaufman JL, Sborov DW, et al. 79 Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Presented at: 63rd ASH Annual Meeting and Exposition, December 11, 2021; Atlanta, GA. Accessed April 29, 2022. https:// bit.ly/39yg8X5}

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