Looking At Therapy Past Transplantation in Newly Diagnosed Multiple Myeloma

CASE SUMMARY

A 54-year-old woman diagnosed with Revised-International Staging System stage II/III IgG-κ multiple myeloma who was transplant eligible. The patient was eventually given the quadruplet regimen of daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) and achieved a very good partial response (VGPR) post-induction therapy. The patient then underwent stem cell mobilization and 2 months later autologous stem-cell transplant (ASCT) where she achieved another VGPR. Here they discussed managing toxicities with these therapies, the choices of induction therapy, and their approaches to consolidation and maintenance therapies for long-term care.

ALFRED GARFALL, MD: Any thoughts on managing patients through that sequence of therapies, or comparing the experience with quadruplet vs triplet [therapy]? Are you getting patients back from transplanters for consolidation and continuing the quadruplet for a few cycles after the transplant?

Alfred L. Garfall, MD

Director, Autologous Hematopoietic Stem Cell Transplantation

Assistant Professor of Medicine

Hospital of the University of Pennsylvania

Philadelphia, PA

BERNARD KULPER, MD: I'm getting some back [from the transplanters]. I think it all depends on the patient's relationship with the transplanter and how far it is to go back and forth [for them], as to whether they want to continue with the transplanter for that. Regarding adverse events [AEs], I would say the main question would be: How aggressively do you want to use growth factor supports for the hematologic toxicity?

GARFALL: For your patients who develop neutropenia on these regimens, are you giving a lot of growth factor support or managing [neutropenia] with dose reductions and periodic holds?

NEHA CHAWLA, MD: I use mostly dose reductions and holds. I don't usually use growth factors.

GARFALL: What are your thoughts about the role of transplant in modern myeloma therapy, and has any of this affected your likelihood to refer patients for transplant, or are you pretty much referring all patients who are in the transplant-eligible category?

KULPER: I think with [current] data, it certainly would make you think more of their eligibility for transplant, especially if there's unfavorable cytogenetics where you want to refer them and get another opinion.

SABRINA MARTYR, MD: I think all the data that I've seen so far confirms that if we can do the transplant, and the resources are available, that we should continue to do transplants.¹ [Transplant] seems to give them better outcomes than not doing the transplant, or it's only delaying the transplant if you don't do it up front.

GARFALL: Even though we might consider a delayed transplant approach more often, especially if we're more confident we can get patients in the second-line responses if they progress, it's still important…that the stem cells have been harvested in first-line therapy. So, even if you want to think about a delayed transplant approach, it's still important to refer patients early to consider the stem cell collection.

MARTYR: I get all my patients back from the transplant centers, but I've not had the recommendation to continue full dose quadruplet or triplet therapy. Most of my patients come back on a maintenance regimen, and it's usually either lenalidomide or lenalidomide with daratumumab. I've not been advised to continue D-VRd in the post-transplant setting.

GARFALL: That is our practice as well, and the way a lot of these trials were constructed that enrolled patients from the start of initial therapy, they had strictly prescribed induction that was short, about 3 to 4 cycles of induction, where patients may not have even reached their plateau in their response before they went to transplant.

I think the way most of us practice in the transplant centers is that we receive patients and consultation for transplant, often after they've already received a couple cycles of first-line therapy. By the time they get to the transplant, they’ve received 4 to 6 cycles, maybe even 7 or 8 cycles of induction therapy, which is quite different from those clinical trials where patients went to transplant strictly after 4 cycles. In that setting, where somebody has received between 4 and 8 cycles of induction, and their response has reached a nice plateau, it means our group doesn't think there's much value added to additional multi-agent therapy after the transplant.

Then there is a nice simplicity for the patient [when we tell them] they’ve done all the hard work of induction and transplant, and now we're just going to transition…to low-dose maintenance therapy. That's how our group has worked, and I think is probably the more common arrangement in the United States where there's often a longer induction therapy than in some of the trials in enrolled patients with an early diagnosis.

MARTYR: I do have an increasing number of patients that ask me [if they] need to do 2 years of maintenance therapy.

GARFALL: We haven't done a randomized comparison of indefinite maintenance vs 2 years of maintenance, but…I think it's important to note that in all these trials there were a lot of patients who discontinued maintenance therapy for intolerance. So, I always tell patients that starting maintenance is not an irrevocable commitment.

Start it, see how it goes—I would say there's a lot of dose adjustment for AEs, [but] any maintenance you get for patients is beneficial. [Ultimately] you meet them where they are, and some of them continue [maintenance therapy] for a long time. For others, it's a year or 2, but I think anything you can give them is beneficial, and…I think it's important to think about proactive management of AEs and adjustment of doses….

I almost always use a 3 week on, 1 week off regimen with the maintenance therapy, and clinicals trials have done it both ways, either continuous [treatment] or 3 weeks on, 1 week off. However, I find that there are a lot less cumulative AEs and a lot less need for dose adjustment and longer holds if you do the 3 weeks on, 1 week off approach.

Diarrhea is more a problem in the maintenance setting than in the first-line therapy setting, and it's important to know [that] the mechanism of diarrhea in myeloma is this poor bile acid reabsorption, so use of medicines such as cholestyramine or welchol can be life-changing for patients on maintenance therapy.² They're effective, and it makes more sense to go to those agents earlier, rather than make patients struggle with Imodium. So those are some important tricks, if you haven't used those yourselves for helping patients stay on maintenance therapy. But still, even with management of the diarrhea, there are some patients who feel the fatigue and malaise that some people feel with lenalidomide, and it's a case-by-case decision how long to continue it.

CHARLESSE HUANNOU, MD: I'm approaching the point now where I have a patient who is probably going to be at the 2-year mark, and the recommendation was to check for minimal residual disease [MRD] to decide whether we were going to continue vs stopping [therapy]. Is that something that's common practice, or that you are doing as well?

GARFALL: We're not doing that, but…that is a component of the SWOG1803 study [DRAMMATIC; NCT04071457]. That study is looking at daratumumab and lenalidomide vs lenalidomide alone and has a second randomization at 2 years.³ After 2 years of maintenance therapy, MRD testing is done, and the patients who are MRD negative are randomly assigned to either continue or to stop, and so that's still an open question, how long the MRD-negative patients should continue and whether there's benefit to continued therapy.

I would say, absent the results of that trial, I think that the best standard now is to continue [treatment], even in MRD-negative patients, if they're tolerating it. However, if patients are on the fence and they're tolerating [their therapy] but they would like to stop, I think it's not crazy to think about the MRD result in making that decision, because you know that your MRD-negative patient probably has a better progression-free survival on average without the lenalidomide.

You're [asking] the patient if [they’re] going to be happy, and maybe they would do better with the lenalidomide added on, but they're still going to do pretty well without the lenalidomide if they're MRD negative. [That is] a reasonable basis to make the decision, but somebody who's doing very well on maintenance therapy and isn't having a lot of problems, I think right now, the evidence would suggest continuing it even if they're MRD negative, until we have results of those prospective trials that are designed to address that question.

^References:

^{1. Sborov DW, Laubach J, Kaufman JL, et al. Daratumumab (dara) + lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): final analysis of GRIFFIN. Presented at: 19th International Myeloma Society Annual Meeting; August 25-27, 2022; Los Angeles, CA. Abstract OAB-057}

^{2. Faiman B. Diarrhea in Multiple Myeloma: A Review of the Literature. Clin J Oncol Nurs. 2016;20(4):E100-5. doi:10.1188/16.CJON.E100-E105}

^{3. MD Anderson Cancer Center. SWOG1803: Phase III Study of Daratumumab/rHUPH20 (NSC-810307) + Lenalidomide or Lenalidomide as Post-Autologous Stem Cell Transplant Maintenance Therapy in Patients with Multiple Myeloma Using Minimal Residual Disease to Direct Therapy Duration (DRAMMATIC). 2023. Accessed July 5, 2023. https://tinyurl.com/yufkfh24}