Roundtable Discussion: Fonseca Compares Frontline Therapy in Newly Diagnosed Multiple Myeloma

Rafael Fonseca, MD

Various frontline treatments can be administered to a patient with newly-diagnosed multiple myeloma. Rafael Fonseca, MD, director and chair of the Department of Internal Medicine, and professor of Medicine at the Mayo Clinic Cancer Center, compares the available agents during a Targeted Oncology, Cased- Based Roundtable event.

FONSECA: How do you discuss prognosis with patients in 2021?

SHEQWARA: That discussion by itself can take an hour, perhaps. But in general, when I see patients, I try to determine if they are transplant candidates or not. The decision, historically, used to rely on age and comorbidities, but nowadays we know that age might be just a number. So we try to utilize the frailty and [comorbidity] index. There is one the International Myeloma Working Group recommends, so I utilize it sometimes.

I try to see how fast they can walk, [their ability to] grab, how functional they are, and their endurance. Based on that, I determine if I think that they are transplant candidates or not. I think the decision there, up front, is not really definite; you can always start and then revisit this. But you try your best from the beginning to [decide if] they have a fair chance to be evaluated for receiving transplant or not. I usually tell them that multiple myeloma is potentially not a curable disease; however, there is a small percentage of patients that might be cured with conventional therapy, including transplant. That’s a very quick, 1-minute answer.

FONSECA: You’re right, this conversation can go on for a full hour, of how we discuss prognosis. I have to admit, I talk about the possibility of cure with patients, emphasizing it’s a small fraction. We don’t know if, 5 or 10 years from now, it will be more patients. But I believe it’s within reach with some of the treatments we have.

DABAK: I don’t think it is an easy answer, deciding transplant eligibility just by looking at the patient the first time that you meet them. But age [is not a large consideration] unless they are of extreme age. We can take into consideration their comorbidities and organ dysfunction. A majority of the patients can still be transplant candidates, so I usually don’t say no to [using] transplant unless I get them through a few cycles of treatment, see how they are responding and how their performance status is improving. Then I may [still] send them for a transplant referral, even if I think they are borderline. I do not tell them up front that they are transplant eligible or ineligible unless they are 90 years old or they have extreme comorbidities.

FONSECA: It’s true that with growing familiarity with transplantation, a lot of patients can move forward. I use a cutoff of around 75 years, but even with 75-yearolds, even when they look very fit, transplant can still be a big burden.

BILBEISI: I agree. It’s usually based on where they’re able to receive transplant. Our transplant center will generally [perform a] transplant if they’re otherwise healthy and they’re under about 70 to 75 years of age. When I talk about prognosis, I talk about multiple myeloma as being like a chronic illness, and I try to compare it with something like diabetes, where the majority of people can [have their disease] controlled very well with medication and can live many years. They may need to be changed from medication to medication to get control over the years, but we usually don’t talk about life expectancy as being a matter of months, or a couple of years, with multiple myeloma because of all of the good treatments that are available.

But of course, if you don’t treat it, then you get significant complications and risk of death. So when I talk to patients who are [getting their] diagnosis, I remind them that not all cancers are terminal and that when we talk about treatment for multiple myeloma, it’s more a matter of getting them on the right treatment—getting them on something that is appropriate for them, that their disease is controlled on, trying to keep them on that as long as possible, getting them into remission, maybe for long periods of time, and not looking at this as a constant downward spiral for their health.

FONSECA: Absolutely, and I think that the chronic disease term applies very well. It may be a bit more intense with the treatment than what you normally do with diabetes or hypertension, but it applies. I use general descriptors, too, like “several or many years,” for instance, as opposed to “something that’s going to get you into next few months or years.”

FONSECA: VRd [bortezomib (Velcade), lenalidomide (Revlimid), dexamethasone] is, by far, the most common regimen that is being used. I think it’s fair to say that, even though we have had a special place in our heart for CyBorD [cyclophosphamide, bortezomib, dexamethasone] at Mayo Clinic, there are better regimens. So with some rare exceptions such as amyloidosis, and perhaps in patients who have renal failure, we’ve moved on from CyBorD. I use a lot of KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone].

FRONTIERA: I’ve still been using VRd as the primary regimen for patients. I have not initiated the quadruplet by adding the daratumumab yet, although I’ve thought about it for a few patients with more advanced or significant disease. I would say a very small percentage of my are young, fit, and transplant eligible, maybe 10% to 20%. I tend to see an older population with lots of comorbidities for my multiple myeloma group.

FONSECA: That’s probably a reflection of the population. It should be about, in general, United Stateswide, maybe 40% of patients, so that’s a little bit lower than the average.

FRONTIERA: I think it’s more just the group that I see in the clinic. Then, regarding aspects of a therapy, the most important aspect is getting their disease under control with minimizing the amount of toxicities.

KARAMLOU: The quadruplet therapies are quite exciting, but I think the data for standard use of them are still a bit premature. Generally, at our institution, a majority of the time we are using VRd, a triplet, for induction therapy. Some of that, to some extent, is risk adapted. Our front-line therapy may differ for a higher-risk patient, and if we have a high-risk patient, we may, potentially, go to a quadruplet with the goal of achieving minimal residual disease [MRD] for that particular patient, different from the standard-risk patients.

I think, in my patient population, probably about 40% of them would be transplant eligible. Sometimes you have about 10% of patients that sit right on that border line and still potentially could get transplant. I think for the patients with new diagnoses, we know that our goal is always to be able to try to achieve the deepest, most sustainable response for that patient. I think the deep response by itself may not be enough; we need that sustained response, and that’s the goal that we essentially go for.

In the higher-risk patients, you may want to push for MRD, but in the standard-risk majority of the patients, you’ll treat the best response and then try to maintain them with what should be the best maintenance for that particular patient.

FONSECA: I think there’s a lot of value in that concept, that if patients can sustain that level of response, they will do well.

BALLOUZ: If the patient is able to achieve a complete response and MRD before transplant, and if you push those patients to complete remission, you’re going to see those patients [responding] for a long time before they relapse. So I’m not surprised that a complete response, or MRD, is translating into a better outcome [in the current data]. We notice that in practice, there’s no question about it.

Still, standard of care is transplant. I still do that because we’ve done that for years, and we have not seen any data to say otherwise. So for now, I think it’s still standard of care. Even if we have other wonderful options, I still recommend transplant for my patients when they are eligible for it.

FRONTIERA: Something I struggle with in regard to recommending transplant for patients, especially for borderline patients, is the overall survival isn’t necessarily better.

FONSECA: This has been a matter of great controversy…. In my mind, most of the trials show results that are at least hinting at or trending in favor of the transplant. There are older and some more recent data that transplant up front versus delayed appears to be about the same. I think the challenge is to know if you do have enough information to say that they’re equivalent versus saying “We haven’t noticed a big difference,” which I think are fundamentally 2 different questions.

As for the best way to phrase the answer to that question— and I’m greatly biased in favor of transplant because I know most of the long-term survivors have been through transplant—I tell patients I’d prefer that they do transplant up front, although if they don’t, it’s not the end of the world. I know that there might be a few differences in the data, but if they tell me to try to maximize everything we can do, I still go for transplant.

GARG: We have been taught, and we have learned from all the trials, that the standard of care is transplant. But we have certain patients who will achieve excellent responses. So the question becomes if we should wait on those patients and do the transplant when they first relapse. You are right that we have seen these patients live a long time after they get transplant. So the bias is that those that are below 70 years old, if they’re in great health, all get transplant.

Then, in terms of 3-drug versus 4-drug, I don’t think that the 4-drug is ready for prime time yet because of all the different toxicities and adverse effects. We are achieving great results with the 3-drug regimens. But down the road, I think that we will move to 4-drug, and the question becomes “If you have a high-risk patient, would you use 3 drugs or 4 drugs in those patients?” We don’t know the answer.

I’m not monitoring with MRD yet. I don’t know if you monitor with MRD, because we don’t know what to do if they start relapsing with MRD. Do we intervene and change the treatment at that time, or do we just monitor them?

SHEQWARA: I would like to measure MRD. I am eager to get this as a standard-of-care practice for us. A lot of studies are showing us excellent data in regard to the correlation between MRD negativity and better outcomes. There are a lot of data now, I believe, correlating MRD with progression-free survival and overall survival.

We are trying to establish that practice in Henry Ford [Health System] in regard to validating MRD testing in our center. The question is, which MRD are we going to do, 10-5 or 10-6? But usually, my goal is to achieve the deepest response that I believe studies show that if patients did achieve a complete response but they were MRD positive, in real life they did as good or as bad as if they had a partial response. I believe there was a study recently, published in Blood Advances, confirming that if patients achieve an MRD negativity, whether in the front line or at relapse, they are going to do better.1 So, based on that, I’m really encouraged. I was one of the people who voted in favor [of] utilizing, potentially, 4 drugs.

Based on that, my question to you is “How long should we wait?” Why should we wait until progression-free survival or overall survival, if we know that MRD correlates strongly with that?

FONSECA: That’s a great question, and I know it’s open to interpretation, as well as different levels of comfort…. For some people, they want to have the data on overall survival and progression-free survival. I tend to be more on [the side of] adopting early. [I ask myself], “Should I be using 4 drugs in all my patients? I’m not, but I think I probably should. This internal voice is telling me I should be moving in that direction.

_References:

_{Munshi NC, Avet-Loiseau H, Anderson KC, et al. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv. 2020;4(23):5988–5999. doi:10.1182/bloodadvances.2020002827}