Roundtable Discussion: Dingli Discusses Treatment Options in Transplant-Eligible Multiple Myeloma

David Dingli, MD, PhD

David Dingli, MD, PhD, professor of Medicine at the Mayo Clinic, discussed the treatment options available for patients with transplant-eligible multiple myeloma with a group of peers during a Targeted Oncology Case-Based Roundtable event.

FIRWANA: I think the prognosis would be excellent for a patient with no high-risk features who is young. There are so many treatment options, including transplant or multiple tandem transplants.

Probably for younger patients, [treatment is based] mainly on performance status rather than the actual age because transplant [can be used for] people up to 70 to 75 years old.

BANDI: If we are looking at 75 years as the cutoff, physiologically they could be older, but still with good performance status and retaining their nerve function. [The question is], would they be considered young and be eligible for transplant?

LIN: I would start with a young patient [and explain that] multiple myeloma diagnosis is not curable, but now we have many effective choices that put patients in remission for a long time. Having said that, of course, I would explain to him what the treatment options are, and also…I normally would like to refer patients to a transplant team just to get a consultation and make sure what we’re going to offer in the community [setting] is in line with their potential transplant in the future. The definition of young patient—I think that has changed significantly in the last 5 to 10 years.

ZOGHBI: [For] prognosis, I include the fluorescence in situ hybridization analysis. With molecular testing, we know more about the patient and the treatment options available. I use those in talking about prognosis with that patient either on their first or second visit after, for example, they undergo a bone marrow biopsy. Where I practice…we coordinate very closely with the transplant center so we can offer the best to those patients, give them the right timing, and not miss an opportunity to be on the same page with the transplant center. We both coordinate because what’s happening is that we are getting more new drugs, new indications, drugs changing from [later lines] to up front, so we want to make sure we are on the same page when we are choosing first-line therapy.

DINGLI: A natural question that has arisen: Is transplant still needed in the newly diagnosed setting? Another question is how to treat a [patient just given a diagnosis] with multiple myeloma, whether with or without transplant.

LI: The primary therapy options that you mentioned—the doublets, triplets, and the quadruplets—all certainly have data, and they’re reasonable. The common approach used is a combination of lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [VRd]. I think for a high-risk patient, it’s reasonable to consider adding daratumumab [Darzalex] up front or use the quadruplets in the induction setting.

For the proportion of patients, I think in our practice probably around 35% to 40% are young, fit, and transplant eligible. In terms of what aspect is important, of course we want an effective regimen, but we also want to make sure the treatment won’t interfere with the stem cell harvesting, and [it needs to have] an acceptable toxicity profile.

LIN: I agree with Dr Li’s comment. Typically for a goodor average-risk patient, often in our group we start with VRd. For a high-risk patient, we’ll use either Rd-D [daratumumab, lenalidomide, dexamethasone] or KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone] as a primary therapy. For the young, fit, transplant-eligible patient, it depends on what we have.

In our practice, I think it’s about 30% young, fit, and transplant eligible. [These] patients normally do not have many comorbidities, so we have to consider the toxicity profile [of the drug we use]. They’re all effective triplets, but we have to pick and choose. It depends on the patient’s comorbidities.

VIJ: We’re certainly in evolution, I think. Right now, for standard risk we are going with the 4-drug regimen of VRd/daratumumab, and for high risk we’re giving KRd.

DINGLI: I think that’s [how] most centers are treating patients. I think if there is any doubt, it is better for the patient to be seen at the transplant center for eligibility criteria because sometimes one might think the patient is not eligible, but the patient may be eligible or can be optimized to be eligible. The median age of patients with multiple myeloma diagnosis is about 69 years, and we perform transplants in people up to the age of 75 sometimes.

Age is really not that important. It’s possible to perform transplants even in older patients; I think the oldest patient with transplant was 79, and we did not perceive any significant difference in toxicities, for example, or tolerance of the transplant. By my estimate, it’s probably closer to 60% who can, in principle, undergo transplants. Now, many of them aren’t for a number of reasons—either because they are not referred or because the patient decides to delay the transplant. But there is still quite a bit to be said about transplant in multiple myeloma.

I think 2 of my goals when I treat a [patient just given a diagnosis] are [that] I want to get disease control, and I want to control disease rapidly, because that is the best way to protect the patient’s kidneys from multiple myeloma and also to protect their bones from the risk of multiple myeloma bone destruction. There are rare situations where you want to lower the paraprotein quickly, and that will be hyperviscosity syndrome, for example, which, fortunately, is not common. But I think we’re seeing more data that good control of the disease, deep control of the disease, is going to likely translate into better long-term outcomes.

I would argue that [regarding] prognosis in patients with multiple myeloma, half of it depends on what they get with initial therapy. Right now, many patients with multiple myeloma can expect to live 8 to 10 years, especially with standard-risk disease, and half of that, if not more, is defined by the initial therapy. If by initial therapy we’re talking about induction, transplant, and maintenance, we’re looking at an average of 4 years. So what we do with first-line therapy, I think, has a major impact on long-term prognosis of the patient, and I think it’s important to keep that in mind.

LI: The primary therapy options that you mentioned—the doublets, triplets, and the quadruplets—all certainly have data, and they’re reasonable. The common approach used is a combination of lenalidomide [Revlimid], bortezomib [Velcade], and dexamethasone [VRd]. I think for a high-risk patient, it’s reasonable to consider adding daratumumab [Darzalex] up front or use the quadruplets in the induction setting.

For the proportion of patients, I think in our practice probably around 35% to 40% are young, fit, and transplant eligible. In terms of what aspect is important, of course we want an effective regimen, but we also want to make sure the treatment won’t interfere with the stem cell harvesting, and [it needs to have] an acceptable toxicity profile.

LIN: I agree with Dr Li’s comment. Typically for a goodor average-risk patient, often in our group we start with VRd. For a high-risk patient, we’ll use either Rd-D [daratumumab, lenalidomide, dexamethasone] or KRd [carfilzomib (Kyprolis), lenalidomide, dexamethasone] as a primary therapy. For the young, fit, transplant-eligible patient, it depends on what we have.

In our practice, I think it’s about 30% young, fit, and transplant eligible. [These] patients normally do not have many comorbidities, so we have to consider the toxicity profile [of the drug we use]. They’re all effective triplets, but we have to pick and choose. It depends on the patient’s comorbidities.

VIJ: We’re certainly in evolution, I think. Right now, for standard risk we are going with the 4-drug regimen of VRd/daratumumab, and for high risk we’re giving KRd.

DINGLI: I think that’s [how] most centers are treating patients. I think if there is any doubt, it is better for the patient to be seen at the transplant center for eligibility criteria because sometimes one might think the patient is not eligible, but the patient may be eligible or can be optimized to be eligible. The median age of patients with multiple myeloma diagnosis is about 69 years, and we perform transplants in people up to the age of 75 sometimes.

Age is really not that important. It’s possible to perform transplants even in older patients; I think the oldest patient with transplant was 79, and we did not perceive any significant difference in toxicities, for example, or tolerance of the transplant. By my estimate, it’s probably closer to 60% who can, in principle, undergo transplants. Now, many of them aren’t for a number of reasons—either because they are not referred or because the patient decides to delay the transplant. But there is still quite a bit to be said about transplant in multiple myeloma.

I think 2 of my goals when I treat a [patient just given a diagnosis] are [that] I want to get disease control, and I want to control disease rapidly, because that is the best way to protect the patient’s kidneys from multiple myeloma and also to protect their bones from the risk of multiple myeloma bone destruction. There are rare situations where you want to lower the paraprotein quickly, and that will be hyperviscosity syndrome, for example, which, fortunately, is not common. But I think we’re seeing more data that good control of the disease, deep control of the disease, is going to likely translate into better long-term outcomes.

I would argue that [regarding] prognosis in patients with multiple myeloma, half of it depends on what they get with initial therapy. Right now, many patients with multiple myeloma can expect to live 8 to 10 years, especially with standard-risk disease, and half of that, if not more, is defined by the initial therapy. If by initial therapy we’re talking about induction, transplant, and maintenance, we’re looking at an average of 4 years. So what we do with first-line therapy, I think, has a major impact on long-term prognosis of the patient, and I think it’s important to keep that in mind.

DINGLI: The National Comprehensive Cancer Network [NCCN] recommends primary therapy for transplant-eligible patients.¹ Typical with NCCN, the guideline is quite extensive; it provides a lot of flexibility when it comes to choosing the right regimen for the right patient.

This is one of the luxuries of having multiple agents available that we can tailor or target for a specific patient depending on comorbidities and the presentation.

BANDI: Recently, after having [a patient] evaluated by a local transplant [physician], I started a patient on the daratumumab 4-drug combination, and he will be sent back to the bone marrow transplant unit [to receive] transplant. The [NCCN regimens] are all effective, useful, and proven even in the community practice, not just in academic centers. I agree with [using] any of [the NCCN] regimens.

ZOGHBI: If you have a high-risk patient, even though [this population had less benefit on the GRIFFIN] trial [NCT02874742], would you offer them the 4-drug therapy? I didn’t see much benefit [in those data for high-risk patients]. Are you adapting that to say those high-risk patients may not benefit with the quadruplet therapy?

DINGLI: It’s not that they do not benefit.² The confidence interval was too wide to be statistically significant. But if you look at the actual value, the value favors the quadruplet therapy. It’s the confidence interval that does not make it statistically significant. The number of patients was not large enough. With 15% of patients [having highrisk disease], that’s not enough; this study had [about] 200 patients. So I think the study was not powered to look at it. There is benefit. [In Germany], they are conducting a study right now where they use quadruplet therapy in high-risk disease, and they’re using isatuximab [Sarclisa]/carfilzomib/lenalidomide/dexamethasone [NCT03104842]. They’re seeing very high response rates.³

I think we’ll all agree that with high-risk disease, we want high response rates, and we want MRD negativity states. I would argue that as the extent—if we want to maximize the chance that the patient achieves an MRD-negative state— if they’re high risk, we should probably consider offering quadruplet followed by transplant, followed by maintenance or consolidation before maintenance if they do not achieve a deep response.

Some are using tandem transplant for patients with high-risk disease. For example, this is what the German school [of thought] recommends, and there is at least 1 study that has looked at this and shown that patients with high-risk disease, at least deletion 17p and translocation (4;14), seem to benefit from transplant. There are other studies where, if you dig into them, tandem transplant seems to help. The issue becomes: Would the patient be willing to do a tandem transplant? We can often get them through a first transplant relatively smoothly, but a second transplant soon after—generally, the patient is [affected] substantially more.

In my practice, if the patient achieves MRD negativity with the first transplant, I find it’s rather difficult to push a second transplant. If the patient tolerated the first transplant well, it’s high-risk disease, and they’ve not achieved MRD negativity but did achieve a deepening of the response, I think I’ll have a conversation with the patient and see whether they would be willing to do a second transplant.

Secondly, I would collect [stem cells] for more than 1 transplant in that type of patient. If they’re younger, I would collect for 3. If the patient says no, then I would offer consolidation. It’s reasonable to do that because we have the STaMINA trial [NCT02322320] from the United States that shows that single transplant, consolidation, and maintenance could be similar to tandem transplant [in efficacy]. One can argue about the design of the STaMINA trial, but I don’t think we have the final word about tandem transplant. I think that high-risk patients, even if they achieve a deep response, should probably go to transplant. Patients who go to transplant and achieve MRD negativity and sustain MRD negativity are going to do quite well.

VIJ: I agree. I don’t think there is any right answer, and everybody has their own practices. I think that for highrisk disease, we favor KRd—not that I’m conclusively convinced that it is better than the 4-drug regimen. It’s just that several trials have shown the same thing in highrisk disease: Daratumumab doesn’t seem to add much. There are at least 4 or 5 trials that have that trend. But all of these are underpowered, so I think that there’s no right answer to that.

In regard to tandem transplant, we haven’t done a tandem in a long time. I do, however, give consolidation to those high-risk patients who have not achieved a deep response, and I usually tend to continue the KRd for 4 cycles before putting them on double maintenance. But I agree that tandem transplant is a valid strategy, shown in Europe especially.

DINGLI: I find it’s a bit tough, the second [transplant]. Sometimes I do it, but it’s tough. The patients really [feel] beaten up with the second one. That has been my experience.

ZOGHBI: I wanted to mention 1 more thing that might face a physician when ordering a certain treatment. Sometimes [when ordering the] regimen I would choose, insurance does not always approve that regimen. For example, I have a high-risk patient, and 2 months ago I ordered KRd. Insurance would not approve it; I had to go with VRd. Today I ordered the 4-drug regimen for 1 of my patients, so I’m interested in seeing if they are going [to] tell me] I must go with the VRd regimen. That’s something we face in the community setting; sometimes insurance will not approve what you recommend as a physician.

DINGLI: I think this is something where the NCCN or Stratification for Myeloma and Risk-Adapted Therapy [mSMART] guidelines become very important, because one can refer to them as being recommended regimens in the field. That usually can help with appeals or even preempting an appeal by saying something in the notes; for example, that the decision-making included the discussion about guidelines on how to treat these patients based on NCCN or mSMART or International Myeloma Working Group criteria. That sometimes helps with the approval. Lately I haven’t had many problems with approvals for quadruplet therapy. My experience has been that initially when we start such a trend, it’s difficult, but then in time it becomes accepted.

DINGLI: Is anybody using MRD testing as an outcome and using it in some way to make decisions on therapy?

BANDI: I don’t think it’s easily available or available in a timely fashion in a community setting to get the MRD results; maybe at the academic centers, but not in the community setting. I have not been able to use that.

DINGLI: So this is not something that you can send out with the bone marrow when you evaluate the patient.

BANDI: Possibly, but I have not used it so far.

DINGLI: That’s OK. We think that MRD negativity is very important from a prognostic perspective. I think that in time it will also become a useful tool for decision-making with respect to duration of therapy, for example. But I do not think we are there yet, and this is something that is being addressed in clinical trials right now. MRD-negative testing is probably something very relevant for transplant [physicians] because they will often evaluate the patient post transplant for MRD negativity.

BANDI: In this day and age, with so many viable options even before transplant, is it absolutely necessary to transplant right away? When you have such good response and a good regimen on different lines of therapy, could we postpone the transplant as long as possible—as long as disease is kept stable?

DINGLI: We’re not sure, I think is the best answer, but I can tell you what my practice is. I’m thrilled when the patient achieves MRD negativity before transplant, but I still proceed with transplant. If you look at the data, I’m sure that embedded in those hundreds of patients are those that received induction and became MRD negative before they went to transplant and they went to transplant, and there’s a cumulative effect of this. In my mind, delaying transplant is not a very good idea in multiple myeloma, at least as things stand.

Why? We evaluate the patient and collect stem cells, so we’re halfway there. Let’s say we decide to delay the transplant, and the argument to delay the transplant will be, there’s no difference in overall survival yet and this has never been shown. I think that’s an argument that is valid and has been met. But there is much more to the issue of transplant than just overall survival, because a transplant is associated with risk and we all recognize that, but that risk is going to be there whether we do the transplant early or later. We have to accept that that risk is going to be the same and may be even higher later. In my mind, the question that has to be asked is “For the same risk, how much benefit does the patient stand to gain if we do the transplant early versus later?”

In general, the gain by doing early transplant is better in the sense that the quality of the response, the durability of the response, is almost certainly going to be better. The French answered this question somewhat by showing that the patients who had early transplant had better quality of life. The other argument in favor is what was shown with the FORTE trial [NCT02203643].⁴ Patients who received KRd with transplant and KRd consolidation—one could argue that this is one of the best regimens that we have, and yet even progression-free survival was already superior in patients who got transplanted. On top of that, you have to remember that the patients who got KRd for 12 cycles received heavier therapy compared with the patients who got transplant. So I still think that there is a lot to be said for a transplant—that it can simplify care.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma, version 6.2021. Accessed April 16, 2021. https://bit.ly/3fa9Yx5}

_{2. 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}

_{3. Weisel K, Asemissen AM, Besemer B, et al. Depth of response to isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa-KRd) in front-line treatment of high-risk multiple myeloma: interim analysis of the GMMG-CONCEPT trial. J Clin Oncol. 2020;38(suppl 15):8508. doi:10.1200/JCO.2020.38.15_suppl.8508}

_{4. Gay F, Musto P, Scalabrini DR, et al. Survival analysis of newly diagnosed transplant-eligible multiple myeloma patients in the randomized Forte trial. Blood. 2020;136(suppl 1):35-37. doi:10.1182/blood-2020-136907}