Adverse Event Management in Transplant-Eligible Multiple Myeloma

Amandeep Godara, MBBS (Moderator)

Assistant Professor, Internal Medicine

Division of Hematology/Bone Marrow Transplant

University of Utah Huntsman Cancer Institute

Salt Lake City, UT

DISCUSSION QUESTIONS

• How do you manage adverse events (AEs) for patients receiving induction therapy? Does it differ for triplet versus quadruplet therapy? ​
• Does your choice of induction therapy impact your choice of consolidation and maintenance therapy in patients with transplant-eligible multiple myeloma?​
• With the introduction of novel induction therapies, is there a continued role for transplantation in patients with newly diagnosed multiple myeloma?​

AMANDEEP GODARA, MBBS: How we manage toxicity for the patients [is]…an individualized decision based on what drug are we considering…[and] what kind of toxicities. What kind of toxicities are you seeing in your experience with a quadruplet regimen versus a triplet regimen?

ROOPESH KANTALA, MD: I’ve seen more rash for some reason.

GODARA: You mean the rashes that we usually attribute to lenalidomide [Revlimid]?

KANTALA: Yes.

GODARA: I think part of it has to do with dose adjustments. I make quite a few dose adjustments as patients are concluding a quadruplet regimen [based on] the responses. So, within weeks, we know that these patients are responding and when they are responding, if there are signs of toxicity, I have basically reduced the dose. Especially if it’s a rash that is bothering the patient, we reduce lenalidomide doses there. We take help from dermatology from time to time as well, especially when it’s like something of an atypical rash to make sure that we’re not missing anything in the picture there.

Has anybody has seen more neuropathies as a part of a quadruplet regimen, or more infections?

ROHIT SUD, MD: I have not seen much neuropathy but diarrhea has been one thing that I have seen happen, both with VRd [bortezomib (Velcade), lenalidomide, and dexamethasone] and with Dara-VRd [daratumumab (Darzalex) plus VRd] regimens. That requires interventions and, at times, dose reductions.

GODARA: That's quite a common AE and it’s something that a lot of times patients don’t even mention in the clinic unless you inquire about it. One thing that I would suggest there, if you haven’t done so already, is using bile sequestering agents like colesevelam or cholestyramine. I have some patients who had their lives change when they started some bile sequestering agents when they were having diarrhea related to lenalidomide. If it’s diarrhea from the bortezomib, then I think it becomes a different story, but some of the patients respond very well to these bile sequestering agents because of the mechanism of how the diarrhea occurs with lenalidomide. That would be a consideration there if you are not already using that.

Another question is whether you care about the type of induction? When a patient is going to go have a stem cell transplant in the future, should induction regimens be of special consideration? What regimens should be used, or ultimately, is what happens after transplant what matters for the disease course and for the patient as well?

SUD: The choice of induction therapy impacting the choice of consolidation and maintenance, would depend on the risk categorization, whether the patient is high-risk transplant eligible or standard risk. Using bortezomib/lenalidomide as well as using lenalidomide alone also depends on the patient’s performance status, age, and many considerations in that regard. I’ve used both lenalidomide alone in standard-risk patients as well as lenalidomide and bortezomib in some situations.

GODARA: I see patients who are starting treatment with me, [and] I see patients who come for transplant evaluation. We see a fair share of VRd or Dara-VRd being used, whether that’s in the academic setting or in the community setting. I’ve seen…that a lot of our patients present later, so we do see a lot of disease burden in those who are getting diagnosed with multiple myeloma. In those patients, my preference has been to use Dara-VRd, so that we can quickly get a response and achieve a deep response. I’ve used some of these factors in my decision making as well.

I think the biggest consideration goes to if somebody had preexisting neuropathy, I prefer using carfilzomib [Kyprolis] and that comes with its own risk of cardiotoxicity.1 But in the patients that I have seen so far with cardiotoxicity, when I go to an alternative drug instead of carfilzomib, the cardiotoxicity has usually been reversible. It’s something that we are seeing in maybe around 4% to 5% of our patients.

If we take a look at the ENDURANCE trial (NCT01863550) results which compared VRd to KRd [carfilzomib, bortezomib, and dexamethasone], there was no difference in progression-free survival [PFS] but we saw the unique toxicities that are attributable to bortezomib, and unique toxicities that are attributable to cardiotoxicities with carfilzomib.² I think physicians are divided there between the choices in terms of what is more acceptable in terms of toxicity. No toxicity is acceptable, but when we have drugs that have some toxicities, is there something that’s better than the other? I think that question is a difficult one to answer because cardiotoxicity does lead to a lot of long-duration treatment interruption, and that could have [counterproductive] results.

DISCUSSION QUESTION

• What is your approach toward maintenance therapy for patients who receive a quadruplet regimen?​

GODARA: What are you doing for maintenance therapy? Are you making those decisions? Are those decisions made at the [institution] where patients are going for a stem cell transplant?

SHIVEN PATEL, MD: I refer my patients to you or one of your colleagues if they need a transplant, so I usually do whatever is recommended. But I found that sometimes the bone marrow doesn’t have the reserve to tolerate a lot of therapy. I’ve used daratumumab plus lenalidomide. I’ve used daratumumab by itself if the marrow can’t tolerate the lenalidomide. I haven’t done too much of the carfilzomib plus lenalidomide, so I don’t have too much experience with that. I generally see what the transplanter recommends, then I often have to tailor it to what the patient can tolerate. How do you decide which proteasome inhibitor to use?

GODARA: Regarding the decision between carfilzomib and bortezomib, for anybody who has significant preexisting neuropathy, I prefer to use carfilzomib. For anybody who has a history of cardiac disease or uncontrolled hypertension, I don’t prefer to use carfilzomib there unless absolutely necessary. But, beyond that, we have been categorizing patients into different categories based on the cytogenetics and their R-ISS [Revised International Staging System] staging. Based on the data from the FORTE trial [NCT02203643]—another carfilzomib/lenalidomide trial that was done out of Chicago, which also included a good number of high-risk patients—some of that data indicates that the carfilzomib-based regimens are showing responses that are much more durable than what you see anecdotally with a bortezomib-containing regimen.³ So, for anybody who has high-risk cytogenetics or high-risk myeloma, we use KRd as our induction here [at Huntsman Cancer Institute]. For all of the [other] patients we go with either VRd or Dara-VRd, and that’s the way we have been dealing with some of the complicated questions here.

A lot of physicians would refer to the ENDURANCE data and say that KRd is no better than VRd, but that trial also did not include any high-risk patients.² So that question has been answered indirectly from the FORTE trial. We’re scrambling data there and making decisions based on that. In terms of maintenance therapy, we’ve been going to maintenance therapy based on the risk categorization of myeloma and cytogenetic data on myeloma. For high-risk patients, we like a doublet or a triplet maintenance therapy, and those data comes from the FORTE trial,³ and those data comes from the Emory experience where they treated patients with a triplet regimen after transplant.⁴ For anybody who is standard risk, we use lenalidomide or a clinical trial, and we have a few clinical trials that are going on here as well as nationally at a lot of other places. These are comparing lenalidomide with daratumumab plus lenalidomide to see if it has a better rate of minimal residual disease [MRD] negativity, better rate of MRD transformation to MRD negativity and whether that leads to better PFS on patients who have whichever type of response after a transplant.

_References:

_{1. Kyprolis. Prescribing information. Amgen Inc; 2019. Accessed January 12, 2023. https://bit.ly/3CHIauS}

_{2. 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}

_{3. 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}

_{4. Nooka AK, Kaufman JL, Muppidi S, et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (VRD) in high-risk myeloma patients. Leukemia. 2014;28(3):690-693. doi:10.1038/leu.2013.335}