Roundtable Discussion: Vesole Looks at Treatment Options in Transplant-Eligible Multiple Myeloma

David H. Vesole, MD, PhD

During a Targeted Oncology^TM Case-Based Roundtable event, David H. Vesole, MD, PhD, the director of the Myeloma Program at MedStar Georgetown University Hospital, professor of Medicine, Georgetown University in Washington, DC, as well as the codirector of the Myeloma Division and director of Myeloma Research at John Theurer Cancer Center at Hackensack Meridian School of Medicine in Hackensack, NJ, discussed the case of a 51-year-old patients with transplant-eligible multiple myeloma with 6 peers.

VESOLE: Who would not at least consider sending this 51-year-old patient to transplant?

ALI: In a gentleman like this, I would always offer transplant. Recently, there was somebody who went to see our group, and around the same age, who decided against transplant and that’s fine, but I want to give my patients the benefit of having all possible options. If they ask me, I usually tell them that at their age group, even though myeloma’s not curable, I think we would get a much deeper remission if we were to go through transplant.

MENDOZA: He’s not high risk, so I would probably start the regimen, and I would not hold treatment until you see him, but I would probably send him with a question posed to see whether you could consider a 4-drug regimen if he has either a complete response or very good response. Then you could consider delaying the transplant if we offer him a 4-drug regimen, for instance. However, I don’t know whether the 4-drug regimen would apply to him, but he’s young, so I at least would start treatment and then send him for a transplant evaluation.

VESOLE: For discussion’s sake, what if he was 71? Would that change anyone’s opinion?

SHARMA: At 71, I would probably do the standard treatment. I would not offer him the transplant, because he’s 71. He may develop some comorbidities so I would offer him a standard treatment with bortezomib [Velcade] or [another appropriate regimen].

VESOLE: Medicare has no upper age limit for transplant. I didn’t say there shouldn’t be an age limitation, as far as physiological organ function or other reasons such as comorbid medical conditions, but there’s no financial restriction for transplant. I just want to clear that up. There are ASCO guidelines that came out about a year and a half ago on how to manage patients with multiple myeloma.¹ I will tell you that in the guidelines, the recommendations are that potentially all patients should be sent to the transplant center, and let the transplant doctors decide if the patients should or should not be considered transplant candidates. When you look at who is transplant eligible, if you don’t have good performance status, the transplant doctors aren’t going to take the patient either, or that’s a manifestation that is picked up with their performance status as well. They must have adequate organ function. Every transplant center does pulmonary function tests, they do liver function tests, they do cardiac function tests, and all transplant centers have criteria for who they consider transplant eligible or not, based on the physiological organ function.

Now, there are 32,000 patients that are projected to be diagnosed with multiple myeloma in 2021.² [There are approximately] 27,000 patients with active myeloma patients who need treatment, and a little bit more than a third of the patients are over 75 years old, so let’s cut a third out of our total and we end up with 18,000 individuals that are under 75 that would be considered candidates for transplant. The number of transplants that are performed in the United States is about 8,000, and so we have [less than half of eligible patients] getting a transplant, which is true for the whole population. When you look at subgroups, only about a third of Black patients get transplanted; Hispanic patients are in the 20% to 25% range of the same group of patients I just called out that get transplants. Yes, some of it’s patient preference, but the predominant issue is that patients don’t get referred to the transplant center [and it’s not an insurance issue as Medicaid and Medicare pays for it].

SHARMA: What limit of creatinine [in the patient] is OK to undergo transplant?

VESOLE: In experienced transplant centers, you could transplant anyone with any renal function, including [if they had] dialysis. Dialysis patients have a higher morbidity and mortality, but it’s still less than 5%, even on hemodialysis, so it’s not a renal function limitation by experienced transplant centers. I wouldn’t want to send a hemodialysis patient, or an amyloid patient for that matter, to a place that doesn’t have a high volume of transplants, because they don’t really know how to care for them, but a mature transplant center could do transplants easily in patients on dialysis.

VESOLE: In the National Comprehensive Cancer Network [NCCN] guidelines, keeping in mind if [it’s a treatment] listed in the NCCN guidelines as a 1 or a 2a, Medicare pays for it, and if Medicare pays for it, essentially, all the private carriers pay for it.³ In the category 1s [in the guidelines] are bortezomib, thalidomide [Thalomid], and dexamethasone and other category 1 treatments include VRd, which [most of you] picked in the poll. However, VCd [bortezomib, cyclophosphamide, and dexamethasone] is listed as the preferred regimen and other regimens include KRd, which is my personal preferred one, and dara-VRd is listed in the NCCN guidelines but it’s not FDA approved. IRd [ixazomib plus lenalidomide plus dexamethasone], which is something I sometimes use in patients who refuse to come in for frequent visits, because I’m still giving them a proteasome inhibitor, an immunomodulatory drug, and dexamethasone.

RAJAGOPAL: The MRD negativity with RVd vs dara-VRd] is 27%, and that number seems terribly low compared with, let’s say, the IFM [study from] 2009, because that’s also RVd, right?

VESOLE: We don’t know what level or what technology they’re using, and that’s why you really shouldn’t compare across trials. You are correct, and these patients are not out that long, and they still may be having deeper responses, where the IFM data are much, much more mature. Their median follow-up was over twice as long, so some of the patients still are becoming negative over time in the GRIFFIN trial [NCT02874742], which you may not see yet on the data I showed you. Even then, at the same time point, I will not deny that the 27% seems low, but no matter how you look at it, the dara-VRd was superior to it.⁴

RAJAGOPAL: The reason I’m saying that is all the other numbers [in the study] are around 60%. It then raises the question that if the numbers are similar, is it worth the cost of adding the fourth drug, or modality?

VESOLE: You have to keep in mind that the MRD negativity may not be the same. Some of them may be 10-5, some of them may be 10-6, and they also don’t use the same technology in all these trials, and you don’t have a variation based on the depth of the MRD assessment tool, and they don’t all use the same tool. That’s why it’s very difficult to compare between trials. But the biggest difference you’re seeing between those 2 is that the IFM study had a median follow-up that was 44 months, and the median follow-up for the GRIFFIN trial [is about 20 months].

MANCHANDANI: If the overall survival [OS] at this point is not different between the triplet vs quadruple therapy, then how would you justify the use of daratumumab ahead [of using a] potent second-line regimen, which we could use if there is disease recurrence? If the patient recurs on this modality, then it becomes kind of a triple-refractory disease.

VESOLE: I sort of agree with what you just said, but let me just say that the people that want to use the 4-drug regimen will tell you that the depth of response is the key. If you get MRD negative, which is the goal of therapy, it’s a surrogate marker of disease control and you’re more likely to get it with 4 drugs than 3 drugs. MRD negativity is associated with a better progression-free survival [PFS], so you’re right: Their OS may not change but the duration of their remission may be longer. Can you salvage them with the daratumumab?

The answer is yes, you can, and the reason none of the myeloma trials use OS for an end point is because we have a number of drugs just approved in the past year. We’ve had belantamab [Blenrep], the antibody-drug conjugate, CAR [chimeric antigen receptor] T cells just got approved, selinexor [Xpovio] is approved, and melflufen flufenamide [Pepaxto] got approved. You can’t use OS for an end point when you have so many options for treating the patient when they relapse and you have to use depth of response, as well as the progression-free survival [PFS].

MANCHANDANI: As a follow-up, do we have the MRD test available commercially in the community?

VESOLE: You can do MRD testing; it’s commercially available and it’s covered by most insurers from a company called Adaptive. ClonoSEQ’s the test from the company.

ALI: And you just have to call the company up and they set you up.

VESOLE: It’s not easy to do because they need archival bone marrows, because they have to compare what their clone was with their original bone marrows, to see if that clone's gone now. So if the patient is MRD negative, it’s not easy, technologically, and it takes them forever to do.

GAFFAR: Playing devil’s advocate, if you just salvage the patient with CAR T anyway, besides the cost and inconvenience of being on continuous therapy, what do you say to that argument [of using CAR T]?

VESOLE: The most recent data on CAR T came from a study called KarMMa-2 [NCT03601078], which looked at 153 patients and showed a 76% response rate [and approximately a] 27% complete remission rate. These are very heavily treated patients, with a median PFS of 8.8 months, and in myeloma, there’s no plateau on survival curves.⁵

The CAR T-cell therapy that was recently approved is called Abecma [idecabtagene vicleucel] and has a very good response rate, and the average number of prior therapies is approximately 7.6 These are very beat-up patients, so the question you should ask is, “If you give those CAR T cells earlier in the disease course, what is the PFS?” Well, I don’t have that data for you yet. Now, I wouldn’t defer the transplant saying, “I can do CAR T cells.” The only advantage of the CAR T cells is you do get 8.8 months free of [using the] drug vs continuous therapy their entire life.

_REFERENCES:

_{1. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of multiple myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol. 2019;37(14):1228-1263. doi:10.1200/JCO.18.02096}

_{2. Key statistics about multiple myeloma. American Cancer Society. January 12, 2021. Accessed September 20, 2021. https://bit.ly/3CAaLzT}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2022. Accssed September, 21st, 2021. https://bit.ly/3ufQM6w}

_{4. 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}

_{5. Munshi NC, Anderson LD Jr, Shah N, et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med. 2021;384(8):705- 716. doi:10.1056/NEJMoa2024850}

_{6. FDA D.I.S.C.O. Burst Edition: FDA approval of Abecma (idecabtagene vicleucel) the first FDA approved cell-based gene therapy for the treatment of adult patients with relapsed or refractory multiple myeloma. FDA. Updated April 7, 2021. Accessed September 20, 2021. https://bit.ly/3kntJU6}