Roundtable Discussion: Shain Looks at the Role of Transplant Eligibility in Patients With Newly Diagnosed Multiple Myeloma

Kenneth Shain, MD, PhD

During a Targeted Oncology Case-Based Roundtable event, Kenneth Shain, MD, PhD, of Morsani College of Medicine at the University of South Florida in Tampa, FL, discussed a 51-year-old patients with newly-diagnosed multiple myeloma with a group of peers.

MANCHANDANI: For most of my patients I tell them they’re OK. [Although myeloma is incurable], depending upon if it’s stage II disease, the chances of their survival are good with the newer treatment options out there. Considering the young age [of this patient] and…good performance status, he will be a candidate for transplant.

KREM: I take people through the ISS and I explain the general life span estimates associated with [each stage]. I also explain that any patient’s prognosis can be different based upon the responsiveness of their disease and their willingness, and ability, to undergo transplant. While cytogenetics and other prognostic features such as ISSR give some prediction of how people will do, they’re not absolute predictors. I’ve had people with stage III disease do wonderfully and people with stage I be almost refractory to treatment.

I always let them know there’s some wiggle room in that, but I give them a general expectation that this is thought to be incurable, but we can manage it for a fairly good number of years with all the different therapies we have out there. I also explain that with transplant, we probably get the best duration of survival but we don’t know…for sure [how long that duration will last] and that I’ve had some patients go 10 to 15 years with multiple myeloma. I also tell people to try to hang in there if they can, because the longer they hang in there, the newer agents we’ll have to manage their disease down the road. But I leave a little bit of a glimmer of hope open while also telling them they have a chronic disease and [that] they’re likely to be seeing me or [some] of my colleagues for a prolonged period.

SHAIN: Does anybody else have a different way of approaching [their patient] or [an opinion] that would be a little counter to [that line of thinking]? Or are we all pretty much in agreement?

ATRASH: In terms of how I run that discussion with my patients, it’s one of the most challenging discussions, especially for patients with multiple myeloma. Since [2014 there have been a] lot of new drugs added to the market, and if you look at the overall survival for these patients it’s getting better and better. Still, it’s very difficult to predict survival for patients based on the ISSR, [although] it’s a helpful tool in the discussions about transplant or maintenance and [their long-term treatment plan]. But survival is changing [because of] newly approved drugs, so I try to avoid any discussions about survival, especially when we know that some data are showing numbers that are completely different from myeloma centers. It seems like multiple myeloma is a disease [from which], if you have access to novel treatments, you get better; but it depends, and there are a lot of variables there. I think in myeloma centers, where the research is ongoing, the survival almost doubled. It means the researched new drugs that are coming to the market are probably more powerful than the drugs that we have right now.

SHAIN: You kind of have to use the ISSR [scores] as guidelines or guide markers…but they are the only ways of categorizing patients. We all know their [ISSR scores] don’t quite behave, and we also know that they were really based on very specific high-risk cytogenetic features. There are ones that have not been incorporated and there are things…evolving along the way. Not all patients with myeloma read the book, [so to speak,] and their disease doesn’t behave the way it’s supposed to or they can’t tolerate drugs. [Getting patients] on the right path of therapy is probably the most important thing. Balancing that hope and that reality. I think hope is something they need to hold onto, because there’s a lot more hope than there’s ever been in the past with this disease. But it also leads into what is the most appropriate way to take care of these patients…a lot [of which concerns] this transplant-eligible case. I don’t really [perform] transplants [in] individuals, but I have them all [receive] transplants when possible.

KREM: I say transplant eligibility is there until they prove they’re not eligible, so for patients 75 or younger, but I’ve [performed transplants in] people up to [age] 76 or 77 if they look right, and they have to have a caregiver. They have to have adequate cardiac and pulmonary function and they have to demonstrate good treatment [adherence], and they can’t have an active infection. Of course, their disease has to show some glimmer of chemotherapy response and you don’t want to put someone through high-dose [treatment] if all the indications are they’re not going to get any mileage out of that. I would say that this patient has painted a picture of someone who’s purely a transplant candidate but…who presents another difficult situation because he’s not someone who’s going to reach his expected life expectancy with standard therapies.

SHAIN: Does anybody else have a different opinion about transplant or a similar [one]? How do you think about that and when do you introduce it?

EPNER: I sell it as, I would take care of them at all phases of their care and oversee them rather than having to refer them and then having communication with the transplanting doctor….There are several FDA-approved drugs, such as ibrutinib [Imbruvica] and…post transplant, cyclophosphamide [Cytoxan]. There are a lot of ways that we can probably make graft-vs-host disease more livable as opposed to giving them another disease that’s worse than the disease they had to begin with. I will have that discussion with people and tell them they would have to do it under a clinical trial and have to go [to a bigger cancer center].

KREM: I think that also brings up the question of how you define young patients and what is young.…Some people might say that young [patients] are patients under 65 years old, but I think there’s especially young. Who’s really young? Because there are some patients who are in their 50s or their 40s and you might want to bring that discussion up with them. Maybe you get them under control with the first [autologous stem cell transplant] and then you have a plan ready at first relapse of how you’re going to handle them. I think for someone in their 40s or early 50s, just the standard cells for 2 transplants aren’t quite enough [for] planning and thinking about the future.

SHAIN: Allogeneic transplant is one of the things that I discuss much less than I did even 5 or 10 years ago. That’s because of therapies that exist. I have people that have [had] allogeneic transplant and they’ve done very well, and I have people who have [had] allogeneic transplant and they’ve done very poorly. So, it’s still a question we have to think about.

SHAIN: VRd [bortezomib (Velcade) plus lenalidomide (Revlimid) and dexamethasone] is the standard of care and has been the standard of care for a long time for [patients who are] transplant eligible.¹ It looks like everybody recognizes that CyBorD or [daratumumab (Darzalex) plus] VRd is only effective in patients with renal failure and probably shouldn’t be a standard of care based on data we have. No KRd [carfilzomib (Kyprolis) plus lenalidomide (Revlimid) and dexamethasone] individuals, that’s reasonable, though there are some questions there. I would tell you that today I’m a DRVd [daratumumab, lenalidomide, bortezomib, and dexamethasone] guy, and I think [that with] the data [from the GRIFFIN trial (NCT02874742)], and if you marry in a little bit of Cassiopeia [NCT02541383 data], there’s really strong evidence for 4 drugs to drive the disease down.

KREM: I think it’s an important point to make that bortezomib is not in all the publications, but there are more and more data starting to come out about the efficacy of the bortezomib dosing schedule.

SHAIN: We know our question is really triplet vs quadruplet. So how are we doing bortezomib in those dosing regimens and what do you think about it?

KREM: With the bortezomib, [data have] suggested that giving bortezomib twice a week for more than a cycle really beats people up. Whether you do it subcutaneously or intravenously, 1.3 mg/m² in that dose density of cycles 1, 4, 8, and 11 really isn’t tolerated long.

PAUL: I also exclusively use weekly bortezomib with the GRIFFIN regimen. I’ve had patients [whom] I’ve converted to a 28-day regimen as opposed to the 21-day regimen that’s currently being evaluated. If I do the 28-day regimen, I do not do weekly daratumumab for cycles 1 through 3, which is what is being evaluated for the current trial. I do that to minimize toxicities and also for patient convenience. We have a lot of patients who come from far away to get their treatments and it’s challenging to make them come twice a week or even weekly for 12 weeks in a row.

SHAIN: I [also think weekly treatment] makes life a lot easier. Whether it be 1 or 2 cycles of twice weekly [treatment] is probably not terrible, but I’ve moved away from it. I was a stickler for a long time to get some dose-dense bortezomib in the beginning, but I think it’s an important point that we all really understand that keeping people on the drug is more important than getting them a little bit of dose-dense [drug] to begin with.

EPNER: I had a patient with [a recent] myeloma [diagnosis], a couple [of them], in the COVID-19 era, before the vaccines were available. I was concerned about bringing them into the infusion room and exposing them to the risk. What I did was start them on ixazomib [Ninlaro] until they could get vaccinated and then I switched it over to bortezomib. Now, I sent them for their transplants to Emory [Transplant Center] and talked to some of the members of the team there, and they didn’t have a very strong opinion about the use of ixazomib in terms of its efficacy.

SHAIN: Ixazomib is a good drug but it’s not bortezomib. It’s a very good drug for the right person who doesn’t want to come in or who can’t come in. I’ve seen it work outstandingly for patients in combination. I’ve used it multiple times, but it is not what I walk in thinking about and it’s not something I often pick for…patients [with a new diagnosis].

KREM: On the plus side for ixazomib, it has great tolerability. I have seen much [fewer] adverse events…compared with the other therapies. I would politely say that I’m not sure how good the single agent or the doublet efficacy is for that drug. It does reasonably well in combination with other agents, but I think it does have a specialized setting, and as you said, Dr Shain, I don’t think it replaces bortezomib.

ATRASH: I don’t think I had much luck with ixazomib 4 mg, but yes, some patients do get a lot of benefits from ixazomib. In [a phase 1/2 study (NCT01217957)] that showed us that [the] high-risk population did get benefits from ixazomib, all the new data are [indicating that] perhaps ixazomib is not as effective as bortezomib.² At the beginning of COVID-19—at the very beginning—I did a similar approach where I tried to avoid infusion center visits, but later we figured out that perhaps going very aggressive, despite COVID-19, is the best approach.

_References

_{1. 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}

_{2. Kumar SK, Berdeja JG, Niesvizky R, et al. Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance. Leukemia. 2019;33(7):1736-1746. doi:10.1038/s41375-019-0384-1}