We’re going to briefly go through a case report. Here is a 68-year-old male with IgG kappa multiple myeloma, diagnosed in 2017, Durie-Salmon stage 3a, ISS [International Staging System] stage 2. Normal karyotype and FISH [fluorescence in situ hybridization] showed a 13q–. At presentation, the patient had an M spike of over 3 g, an elevated kappa light chain, was somewhat anemic, normal renal function, a bit of a low albumin, and a borderline upper limit of normal calcium. The patient received RVD [bortezomib-lenalidomide-dexamethasone] for 4 cycles followed by stem cell harvest and autologous stem cell transplant. Received their auto mel [melphalan] 200 [mg on] day 0, April 19, 2018, and was then placed on lenalidomide maintenance starting in August of that year. The patient ultimately achieved a VGPR [very good partial response], M spike went down to 0.12, and kappa normalized. So the patient remained in a VGPR for quite some time between August 2018 and September 2021 when we started noticing a slow increase in the paraprotein. From August to September to October, the M spike rose from 0.13 to 0.42, and then up to 0.75, fulfilling criteria of concern for progression of disease. Based on this progression and these labs, we decided to transfer the patient to another type of treatment, and the patient was started on therapy with daratumumab, pomalidomide, and dexamethasone [dara-pom-dex]. Now, in terms of following some of the AEs [adverse events] the patient underwent, we started with a dose of pomalidomide at 4 mg daily, days 1 through 21 on a 28-day cycle. However, early on in the course, we noticed several episodes of neutropenia. First on cycle 1, day 15 with an ANC [absolute neutrophil count ] of 0.9, and then on cycle 2, day 8, the ANC went down to 0.4, at which point we added not only white cell growth factors, but we decided to dose reduce the pomalidomide down to 2 mg for 3 weeks on and 1 week off. Subsequently, once resumed, the patient continued on treatment and no further episodes of neutropenia were noted. The patient responded quite well to therapy, and we see over the course of several months, the patient achieved another deep remission down to an M spike of 0.08. However, of note, what we see many times when we start patients on anti-CD38 therapy, there was a compensatory hypogammaglobulinemia that went along with it. As a result, the patient had a minor URI [upper respiratory infection] in December 2021, treated with a Z-Pak. However, developed a more serious bacterial pneumonia in February 2022, requiring hospitalization and IV [intravenous] antibiotics. As such following discharge, we initiated the patient on monthly IVIG [intravenous immunoglobulin], and over the course of the next few months we saw improvement in IgG levels. No further episodes of respiratory infection, and at the time of this recording the patient remains on continued maintenance with IVIG, dara-pom-dex at the lower dose of pom, and is doing quite well. So I’d love to open it up for thoughts about options at first relapse and management choices.

There are a number of options to choose from these days, and dara-pom-dex is one of the favorites. It’s got excellent phase 3 data, especially for a patient who hasn’t had anti-CD38 antibodies before. I’ve been enthusiastic in this setting also about daratumumab and carfilzomib based on the CANDOR study [NCT03158688] for patients that you think can tolerate carfilzomib for long duration and don’t have cardiovascular comorbidities, [who] have some of the best PFS [progression-free survival] that’s been recorded in [the] second, third, or early relapse setting. And so I think those are both great options, and this patient also had some of the classic adverse events that happen with the neutropenia and the infections. But as you illustrate here, [they] are manageable [adverse] effects that allow the patient to tolerate the regimen ultimately and enjoy a nice myeloma response.

Is everyone here [starting at] 4 mg and [going] down to 2 mg, or 2 mg and [going] up to 4 mg?

 I’d say 2 mg and hold. Particularly when we’re talking about frailty in older patients, I think 25 mg of lenalidomide…most people cannot tolerate that very long. So for pomalidomide, I usually don’t start at 4 mg. But to Al’s point, if I had a high risk relapse, I would go straight to carfilzomib. The longest PFS is the IKEMA data [NCT03275285] right now with isatuximab. And if the new delivery system, the subcutaneous formulation, comes out, you go to every other week faster. But their PFS is pretty good, it’s like 34 months.

 And the important thing too is, you’re coming off lenalidomide and you’re going into a proteasome inhibitor. So that’s one of the desirable things about switching to a carfilzomib-based regimen with a monoclonal antibody.

Although your former colleague published a paper that if you…

 No, but if you were lenalidomide-exposed, they were looking at [daratumumab- pomalidomide-dexamethasone] responses, and it didn’t make a whole lot of difference as long as you’re using the dara-pom-dex. But that’s the No. 1 choice in America right now. 

 There is a phase 2 study by Dr Yi Lin [MD, PhD] that is also looking at the quad. So patients who’ve not had daratumumab upfront. So…again, that’s an interesting option in terms of a high-risk patient as well. This patient had 3 years of remission, but if it was less, that’s an attractive option as well.

It’s hard to get people through 4 mg of pomalidomide as…was wonderfully illustrated in this case. And I start my fitter patients on 3 mg, and then the frailer on 2 mg. And most patients can’t handle the 4 mg dosing with the daratumumab.

Now, one thing to think about with neutropenia on IMiDs [immunomodulatory drugs], especially for a multiple myeloma patient population, that’s in reach for Black patients is Duffy-associated neutrophil count, which was previously turned [into] this benign ethnic neutropenia. It is associated, now recognized, with a certain Duffy blood group phenotype and can be tested in blood banks. And now I’ve seen clinical trials start to incorporate different neutrophil count dose adjustments based on the presence of this. And if we identify this in our patients, we probably should not be as aggressive with dose reduction, which probably should be tolerating lower neutrophil counts in these patients, maybe around 1000. Whereas otherwise we would dose-address and maybe undertreat these patients. So [it] can be tested for and should inform our management of neutropenia in Black patients.

It was mentioned, this patient is CD38 naïve. CD38’s going to be part of it. Are we all saying…ALM is more common in CD38, Kyprolis [carfilzomib]only for the more aggressive? Or does anyone have any feelings about how you would choose one versus the [other]?

I had recently a patient who has a spouse who’s also undergoing cancer treatment. And the statement that was made to me, give me the thing with the highest response rate and first relapse. And it is with K [Kyprolis]. There’s no way that you can’t say that based on the data that’s out there. But I will say another regimen that I found very useful for people who are coming in on CD38 or recently treated with CD38 is [pomalidomide-bortezomib-dexamethasone], which has also I’ve been pleasantly surprised. It’s pretty easy.

I’ve been optimistic about that regimen as well.

But I’ve had a couple of our MASTER [trial; NCT03224507] patients who’ve done very well on that. That’s also in the portfolio.

Are you doing the bortezomib once or twice weekly?

Oh, it’s all once weekly. I’ll just ask: Does anybody use any of these drugs twice weekly?

So, of course, I’d be different. When I use Kyprolis in the upfront setting, where it’s going to be for a limited duration, and just in terms of proteasome inhibition, it’s better twice than once weekly. I go more to the Jakubowiak, Chicago, 36 [mg] twice weekly. When we’re in the relapse setting and we’re at the moment until we all figure out when to stop, I do it once weekly.

And people can get to your place? Subways or traffic and all that twice a week?

If you’ve got a MetroCard, you can get there. Or a Citi Bike.

It’s a complex interplay of what you choose. The patient in front of you helps dictate some of that. Their comorbidities may lean you one way or the other as they do in upfront therapy. And that’s what we learned from ENDURANCE in the upfront setting. And depending on their tolerability for a PI [proteasome inhibitor], it’s a K [Kyprolis] vs PALM decision. That’s where we think [we’re at], knowing the data that we do have. To answer your question about the twice weekly, the only time that I’ve ever used twice weekly is a patient presenting in renal failure where you want to get a deep response in the light chains to help recover their renal function. That’s the only setting I’ve used.

I was going to say the exact same thing. I do that for 2, maybe 3 cycles and then transition.

Videos

Key opinion leaders review the case of a patient at first relapse with multiple myeloma and consider optimal treatment strategies in this setting.

Patient Scenario: Treatment Options in MM at First Relapse 

And along those lines of tailoring, I’m going to turn to this side of the table. Because 2 things you have both spoken about in our discussion of induction is, are we treating to MRD [minimal residual disease] negativity? Are we treating to fixed duration? Treating to intolerance? Would love to hear either of your thoughts about upfront; is it, keep them going?

We’re just waiting with bated breath to see whether MRD ends up being actionable because we all agree that it may be a biological phenomenon right now. Better patients do better, so they become [MRD] negative, and it’s not clear that that’s going to tell you when you should treat somebody or not. So, as I said, the [phase 3] SWOG 1803 study [NCT04071457] is an incredibly important study. We also [learned] with [the phase 2] MASTER [trial; NCT03224507], you have 2 consecutive MRD negative assessments 6 months apart. It still didn’t help you if you’ve got bad myeloma. So there are a lot of things we have to learn. The other big unexplored area is, does it matter if you become MRD negative at salvage therapy? We’ve got a bit of data, which we’re going to talk about later with CAR T [chimeric antigen receptor T-cell therapy], that that might be good, but again, it may be biology. Of course, you’re MRD negative if you’re a better patient, or, I shouldn’t say [better] patient, but your myeloma is more amenable to treatment.

I agree with Dr Callander. And you published on the [phase 2] GRIFFIN [trial; NCT02874742] and the MASTER data combined looking at high risk vs standard risk. And one of the things we always think about from the MASTER data is, [do] the high-risk patients do poorly because we stop therapy? And it was humbling to see the GRIFFIN data, and the curves look exactly the same. And you look at the data from the carfilzomib-pomalidomide-dexamethasone [KPd] study presented by Dr Nuka, and the curves look exactly the same. So that risk certainly plays into our decision, both risk that’s assessed by the dynamic MRD measures, but also their baseline cytogenetic risk. And there are as we study sustained MRD negativity better, and we have data from the MRD2STOP trial [NCT04108624], etc, to look at who are these patients. I’m not sure that that that is quite ready for prime time, but as you said, [we] eagerly await data from the SWOG study to see if we can de-escalate therapy in some of these patients.

Some other data that’s not ready for prime time is some of the work being done by Bruno Piva about this MGUS-like phenotype, and we all have these patients in-clinic [who] never get [to] MRD. We don’t even get complete response, and that M spike at 0.5 keeps going. So I am hopeful that maybe ChatGPT 12 will be able to tell us if you have this type of risk and this type of myeloma and this type of immune system underneath it. Maybe that’ll point us in a way to stop.

These averages—we have to be careful applying averages to individual patients because if we have good, randomized data in subgroups, that’s actionable. But otherwise, we know about these outlier phenotypes, the long-lived low M spike, the patients who are very slow to respond to therapy that may be scary at first, but those are often patients who are also very slow to progress and can have quite indolent myeloma. And we have all this stuff that we observe clinically that we don’t understand the biologic basis of and can sometimes be misleading if we’re thinking about the big averages about MRD positive, MRD negative.

A panel of experts reflects on treatment duration and its role in optimizing management of patients with newly diagnosed multiple myeloma.

Treatment Duration in Patients With Newly Diagnosed Multiple Myeloma

Jumping off from history, and I will always say this, regardless of all the regimens at any of these congresses and all the drugs out there in the US, the No. 1 most prescribed regimen is based off of a paper you wrote. So, being honored to sit next to you as the first author on the VRd [bortezomib/lenalidomide/dexamethasone] lite version, understanding that that [INAUDIBLE] is looking at an older frailer patient, how do you define frailty in clinical practice and how do you go about looking, not for someone just chronologically old, but truly frail?

It's fantastic. More and more attention [from] the IMW [International Myeloma Society] has put into appreciating and studying, incorporating frailty into our clinical trial design. Frailty is a state of vulnerability; patients are deconditioned, have increased risk of poor outcomes, due to increased risk of infection. Often you can have associations with mood disorders, depression, anxiety, and so it's an overall state of compromise that occurs with chronologic aging, how we study that. So, there are a lot of different tests that have been evolved over time that help to do a quote, frailty assessment, the Charlson Comorbidity [Index], but that was not specific to myeloma. So now we've evolved to have more myeloma-specific that include things like the activities of daily living and come up with this frailty risk score and we can then start to stratify patients based on that risk. And frailty is something that you can assign a score to, but also in clinical practice, we would all agree it's a gestalt as well and having objective tools is what we feel is the best thing to do in terms of standard of care. But again, what we do in practice is often different. And so, what is a frail person in practice? This is someone who may have had recent weight loss, who has sarcopenia, so not a lot of muscle mass. That is one of the most important things in frailty. And it's very relevant, too, when we think about dexamethasone because when you're taking somebody who already is frail and has sarcopenia and giving them something that causes lean muscle loss, these are unintended but important side effects in a population that is at risk for falling and having the compliment complications with that. So, upfront dose modifications is an important part of therapy. And so, what was nice about RVD lite is we took the 25 mg and right off the bat dose reduced that; Velcade, we moved to once weekly dose reductions by age, going down to 20 mg once a week in patients over [the age of] 75. And what we saw was that it was overall very well tolerated, and we had excellent progression-free survival, so you can achieve great results. So, the take-home message, at least for me, for RVD lite, is don't be afraid to do upfront dose modifications. Tailor your therapy to the patient and the comorbidities that they present with.

Focused discussion on the importance of patient frailty in determining optimal treatment pathways in newly diagnosed multiple myeloma.

Determining Frailty in Patients With Newly Diagnosed Multiple Myeloma

But I want to veer off for 1 minute because there's 2 studies that you both mentioned. You mentioned SWOG S0777 [NCT00644228], you alluded to MAIA [NCT02252172], so VRd [bortezomib/lenalidomide/dexamethasone] versus Rd [lenalidomide/dexamethasone] for transplant- ineligible DRd [daratumumab/lenalidomide/dexamethasone] versus Rd for transplant-ineligible. And yes, we’re all going to transplant lot of people. But let’s switch to [those who are] ineligible, those that we’re just deciding, we may collect but we’re not doing it. And I’d love to know anyone’s thoughts about, does everyone get VRd or VRd lite, as was published by Dr [Elizabeth] O’Donnell [MD] or are they getting a MAIA-like regimen? Any thoughts?

For the real transplant-ineligible population, the MAIA study provides really high- level phase 3 evidence—safety, long-term overall survival benefit—over Rd and a real ease of administration. And, so, I think that is my preference for the true transplant-ineligible population. Although, again, you have to look in real time at how patients are doing if they're not responding well. Some patients really do need a proteasome inhibitor. And I have patients that I have started on DRd who have really kind of lackluster responses and you would like to reduce the dose of Revlimid (Rev) [lenalidomide], but you can't because they're not in a good enough response. You add on the proteasome inhibitor and everything just melts away. So, you do need some real-time decision-making there.

You said exactly what I was going to say. You can't dispute the MAIA data, it's phenomenal, and that it's a great standard of care for this population. However, there are those patients who need the proteasome inhibitor. And it's nice to be able to have the flexibility to adjust your therapy based on what you're seeing. And unlike the transplant-eligible population, we do want to get the greatest depth of response and we know we can. And so that's a clear picture, is we can achieve MRD [minimal residual disease] negativity in transplant-ineligible patients even if they're not getting a transplant. That has to be the guiding principle as you treat, particularly in the frontline setting.

I was going to say, and when we look at the SWOG SO77 data, I think it's really helpful to think through the age of that population. The median age was so much lower, 63 versus 73 for the DRd. And when we looked at the benefit, most of that was coming from the younger patients. So, in our practice, I'm sure there's patients that do find benefit from proteasome inhibitor. But looking at the SWOG data and looking at where that benefit mostly came from, the DRd data supports a monoclonal antibody-based induction in most patients.

I'm very interested in the French study that was presented at ASH [American Society of Hematology] this year. Now, going to dara-Rev-nodex, that their data, obviously, they just presented, I think just 12-month follow up, I think. But it really looks great. And we, I'm sure we would all agree dexamethasone is a real problem in our elderly patients. Even if it's 20 mg a week, it's a problem. So, I was very excited looking at that data that it looks good. Andthat may be our next new standard for elderly non–transplant-eligible patients.

Also, a problem in our nonelderly patients. I look at every chance I can to get rid of the data.

We've talked a lot about quads and triplets and Susan, I'd like to ask your thoughts, are there still patients out there that just get a doublet?

 There are, and we all see them even in our practice, the most frail, the very elderly. There are patients who are over 85 or 90 years of age that present that are still well enough to be treated. And in some of those patients, I think a doublet is reasonable. And that helps you establish as a stress test, if you will, if they could handle a triplet. And sometimes I have started with, mostly, many times, due to availability and rapid ability to get the lenalidomide, but you've started them on daratumumab with dexamethasone, and then added in the IMiD as you're able over time. And we've been amazed at the responses that we've seen just with that doublet itself and [it] enables quality of life for these patients. So, yes, in thevery frail, the very elderly, there's still a small but real role of a doublet.

And, as you said, the goal is you start with a doublet, if it's a sick patient, if it's a frail patient. And if you can build in, and I agree with you that dara-dex is a very nice combination. It's well tolerated and you see surprisingly good results.

And sometimes you're getting back to the doublet, too, even if you get to the triplet. Patients either want to remove the lenalidomide [Revlimid] or maybe remove the daratumumab if they're handling the IMiD well and don't want to come in. And, so, you have that flexibility, if you get a good response.

And living in a state in the US where we have a big rural population, sometimes an oral regimen is what you're going to have to do in terms of logistics. They [patients] can’t come in weekly for the first couple of months for daratumumab.

I even have a few patients where they were older but also had significant respiratory issues where I started with bortezomib [Velcade] [and] dexamethasone. And I know it's a bit of an older approach, but Velcade, to me, has been the Swiss Army knife of myeloma. You can use it with anything weekly, every other week. Doesn't matter.

And it's easy to give. People take it so well, but if we look at the recent publication on the, my idea of looking at frail patients, what you see is that, yes, there were patients who had to come off study more so than the younger patients, but they derived the same benefit. So, when you looked at the 2 arms and you saw the triplet versus the doublet, the benefit was preserved. So, it should encourage us that we can give these triplet combinations in frail patients as well.

And a point that both Natalie and Al made about the dexamethasone [dex] [Alessandra] Larocca [MD, PhD] published, to me, [is] one of the most important studies in recent years comparing Rev[limid](Rev)/dex, continuous versus Rd-R Rev/dex for 9 months, then dropping the dex and dropping the dose of Rev to 10. So, I think, one of these, you know, these new drugs allow us to do is we don't have to give Rev 25 and dex 40. You can give Rev 10, dex 12, and add Velcade, or dara[tumumab] and get some great outcomes.

I would love to see some more studies to just get rid of the dex entirely from the beginning. It's going to take some time, but as we incorporate more immunotherapy in the early lines of therapy, as we appreciate that even the drugs that weren't devised as immunotherapies actually have immunologic components to them, like the IMiDs, dex just cannot be helping with the immunologic effects.

What I explain to patients because when, especially when patients don't want to come off drugs necessarily, but when you think about the history of, of dexamethasone for myeloma, you talked about before we had terrible drugs. And so, dexamethasone was given 40 mg, 4 days in a row. And the study that determined the dose that we currently used, which is still high dose, was high dose vs our quote low dose. But there's never been a study of what, there's no dose escalation. There's been no phase 1 study of dexamethasone and multiple myeloma, [at least] not to my knowledge. And so, I don't think we even know what the right dose is, or the minimal dose is. So, we're, we're de-escalating, but we never escalated to know what the appropriate dose was to begin with.

Expert perspectives on the treatment armamentarium for transplant-ineligible newly diagnosed multiple myeloma. 

Treatment Options for Transplant-Ineligible Newly Diagnosed Multiple Myeloma 

Natalie brought up the notion of 1Q [gain in chromosome] and Susan talked about…the double hits—could you give us your thoughts [on] what is high risk? And don’t give me the cop-out answer—everyone has it. But as a newly diagnosed person coming in, how do you define high risk?

 I really trust the staging systems that have tried to integrate the clinical factors and the cytogenetic abnormalities—so [the] revised ISS [International Staging System] stage 3 or the R2-ISS that gives you a bit more granularity and incorporates the 1Q gain. So the [patients] who are revised ISS stage 3 or the revised R2-ISS stage 4—that’s a good reliable system for high risk. There’s high risk in terms of [not only] long-term prognosis but also the clinical complexity of the presentation. Patients who come in with acute renal failure who are very sick from their myeloma may not necessarily have the high-risk prognostic factors for long term, but they clearly are quite sick with their initial presentation and often require some specialized management. They’re high risk from a different perspective, in terms of the complexity of their initial management. Maybe they need therapy started in the hospital [or] maybe they’re on dialysis. Some of those clinical factors may be not reflected in the staging system, maybe more in the Durie-Salmon staging system with renal insufficiency and aggressive lytic bone disease. Those also color the risk of the presentation.

 Any other thoughts that anyone else in incorporate into their definitions?

The risk is not necessarily static. We may see a patient who presents with what appears to be standard-risk multiple myeloma without significant end organ damage, but we see that refractory presentation and difficulty getting them into a deep remission. MRD [minimal residual disease] helps prognosticate that, and the patients [who] stay MRD positive overall don’t do quite as well. Some of the risk is also evident as we go through therapy and find those patients [who] we originally didn’t think appeared to be standard-risk disease but are behaving more aggressively because we can’t control their disease to the depth we desire.

 I completely agree. We see this reflected as a functional high risk in our colleagues who have their mSMART [Stratification for Myeloma and Risk-Adapted Therapy] guidelines. The difference between the newly diagnosed [patients] and [those who have] relapsed [is] that one [gets] sent to the top. If you relapse within 12 months of your initial therapy or within 12 months from transplant, something bad is going on. We’re also starting to incorporate outside factors, [such as] social frailty and other comorbidity indices, because you may not have a 17P [loss of the short arm of chromosome 17] and you may not be relapsing immediately, but if we can’t even get a triplet into you for some reason—either travel or comorbidities—that might put you at some disadvantages.

And we focus a lot on the choice of induction regimen for patients based on the risk status. But [what is just] as important—maybe more important—is the real bread-and-butter medicine that happens as you start therapy, [as well as] the adjustments you make in response to what’s going on clinically, where a lot of those other factors that are maybe not in a risk that was derived from clinical trial data but are very present in our everyday practices—frailty, social support, the toxicities that emerge in patients’ comorbidities, and the interactions there. It’s just as important to make the adjustments along the way based on how your patient’s doing as the initial choice of regimen.

One point I want to make, because this always gets lost these days now that we have more choices, is [clinicians] will say, “Well, if my patient didn’t get at least a partial remission to my induction, I’m not sending them for transplant. I’m going to give them 4 more regimens.” It’s important to realize that [stable disease got you in] all our transplant trials. We’ve all seen patients who convert after they get their transplant. We’re still struggling now with more drugs to say [whether you] should now go to a different triplet or quadruplet before I take them to transplant. But that gets lost sometimes in these discussions.

I would make the argument that those are the patients [who] should go to transplant. If you’re not getting a benefit of a triplet or a quad, then those are the patients [who] I’m most likely to take to transplant.

But we tend to see [patients] sent in the community who’ve now had 3 lines of therapy and they’re stuck there, racking up more [adverse] effects and not necessarily better control.

We are spoiled by these amazing responses. For decades, autologous transplant was done on the back of relatively ineffective regimens that only got patients into less than PR [partial response]. Many transplants were done that way, and we can still do transplants in patients who are in PRs.

One of the points I always like to make to the patient is [to] think of how we can change therapy pretransplant to improve the depth pretransplant. If you think about it, you are changing therapy. What is a transplant? It’s a way to deliver a high-dose alkylator, and that is a change of therapy, which is really where we derive most benefit.

It’s a completely different type of therapy than anything we’re going to get.

One point I want to make, being a physician who does work through the VA [Veterans Affairs] as well, is that we now have excellent data, that when we talk about health disparities—differences between Black and White [patients with] myeloma—if Black patients get the same treatment through the VA system, there’s been a wonderful data set looked at. They do great with transplant. I almost feel like we shouldn’t be pulling back from transplant, we should be expanding the use in many ways.

There’s 5 of us, [and] we’re all agreeing on 1 topic, which never happens in myeloma.

Shared insight on the impact risk status has on the selection of optimal therapy for patients with newly diagnosed multiple myeloma.

Impact of Risk Status on Treatment Pathways in Newly Diagnosed Multiple Myeloma 

This is a great segue. We’ve all hinted at this to some degree about [how] we’re using regimens [such as] VRd [bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone], dara [daratumumab]-VRd, dara-Rev-dex [daratumumab, lenalidomide, dexamethasone] in some patients, and I know there’s been some really great data recently. A lot of [these] data generated from the institutions of the panel members, and I’d love to hear [your] thoughts on some of the more recent studies…. [What are your] thoughts about GRIFFIN [NCT02874742], and how [does it] impact your induction regimen choice?

That is the basis for quadruple-based induction and tells us a couple important factors. No. 1, it’s very safe. No safety signal should make us concerned about adding daratumumab or using a quad-based induction. These patients do get onto autologous stem cell collection in transplant. Even though there does seem to be a bit of a decreased stem cell yield, [and] maybe a bit more difficulty collecting, it doesn’t preclude transplant in anybody. You might have to hold the daratumumab a little longer to get the stem cell collected, but it’s not going to preclude that transplant option. [It also has] remarkable efficacy in terms of higher response rates, and now we’re seeing a progression-free survival advantage. Even though I said we’re not using this universally for our patients, we’re comfortable using it when we think we need it and [in] patients [who] we’re worried about. I could easily see this becoming the standard. Just like we moved from RD [lenalidomide/dexamethasone] to VRd with SWOG S0777 [NCT00644228], we may see the same transition eventually, if we see long-term overall survival improved.

One of the things you alluded to earlier was the ENDURANCE trial [NCT01863550], which although [it] didn’t focus on this setting, there were some fascinating subgroup analyses, especially for the 1Qs when you start incorporating [carfilzomib]-based induction. I’d love to hear your thoughts on things like the MASTER study and GMMG [HD7; NCT03617731].

Part of the difficulty of looking at 1Q is that the data out there about what is amplified—meaning 4 vs what is gain vs 3—[are] so complicated. There is an attempt underway to try to look at some of these big data sets to see [whether] we can understand this better. So yes, there was an analysis that suggested maybe [carfilzomib] is a bit better. What we and Dr Bal, who also participated in the MASTER trial, found out is that it’s the double-hit [patients]—1Q plus in most cases—who seem to do the worst, who went into remission, [and] they were MRD [minimal residual disease] negative. But then you start to see them relapse really quickly. By a year, we’re starting to see a fair sizable amount. And then at almost a 2-year follow-up, [approximately] 60% of them are still in remission or have not undergone progression.

Have you incorporated [carfilzomib]-based quadruplets into your practice?

We do for high-risk patients. Certainly, for somebody with plasma cell leukemia; that would be without question. We would go to that rather than DT-PACE[dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide]. I don’t know how many [clinicians] use PACE for those patients routinely. And then what’s coming from the German group is the combination of cetuximab KRd [carfilzomib (Kyprolis)/lenalidomide/dexamethasone] in a very aggressive regimen designed for higher-risk patients; they get induction, [and] they get transplant. If they’re young enough, then they get more KRd, then a triplet maintenance. They’ve got MRD data—it’s 60% when they looked at posttransplant—and we’ll see whether that holds up. But I will say that particular regimen—[due to] the intensity, the induction transplant, [and] more chemotherapy—[has] a high complication rate [and] a pretty high [adverse event] rate.

 It’s interesting. We have a study at Massachusetts General Hospital, which is the same combination—the SKYLARK trial [NCT04442503].

Yes. It was well tolerated [and] highly efficacious. We presented it at [American Society of Hematology]. We’ll be publishing it shortly. But one of the things that’s nice about that vs the twice-weekly [bortezomib] is the fact that you give the carfilzomib once weekly. And in general practice, we [often] give [bortezomib] once weekly, but I don’t know that that’s appropriate in a high-risk patient. So one of the nice aspects of the carfilzomib design is the once-weekly administration…it’s much more feasible, strongly effective, and [is] pretty well tolerated. But again, it’s a younger population and the [patients] who are going on this study—there’s a bias toward putting the healthier, more fit patients. So it’s not surprising that we’re seeing it’s better tolerated in that group.

Also from MASTER, we learned that we traditionally think of the younger vs older populations, but there was a subgroup analysis published by our colleague, Dr Geary, looking at patients who are older vs younger. What we saw was there was no difference in their tolerability overall. As long as they were eligible for this study and met other criteria, they did quite well with the quadruplet.

Another way to incorporate early carfilzomib into these high-risk patients’ treatment is in the maintenance setting. The data from the FORTE study [NCT02203643] on the KR [carfilzomib (kyprolis)/lenalidomide (revlimid)] maintenance and using it every 2 weeks [intravenously] is a nice, sustainable maintenance regimen. A lot of these super high-risk patients will still respond very well to [bortezomib]-based induction. It’s just the early relapse that you’re worried about. Maybe you could incorporate the carfilzomib in the maintenance setting combined amid proteasome inhibitor [PI], more potent PI, and that’s been safe in the FORTE trial. That’s another strategy to include early carfilzomib. 

I will mention that I was very impressed yesterday looking at Dr Ajay K. Nuka’s [MD, MPH, FACP] presentation about carfilzomib, pomalidomide, [and] dexamethasone maintenance, and they still had the same results that we did in MASTER and in GRIFFIN, that those high-risk patients are still falling out. We would probably all agree—and we’ll be talking more about this later—that this is the area where we’re going to probably incorporate different agents with different mechanisms.

That’s part of the challenge now in all these patients: What is appropriate maintenance? That’s a hard question to answer because it takes many years to arrive at that conclusion. But for your high-risk patients, is it a triplet? SKYLARK employs a triplet for high-risk patients vs standard risk, which [administers] lenalidomide alone. But what is the right combination? The Perseus study [NCT03710603], which is very much like GRIFFIN, has a randomized maintenance. These are important factors that we need to build into our trial design to ultimately [figure out] what our patients—particularly even standard risk, too, to your point earlier—what is the ideal combination for the maintenance setting for the duration? Can we take [patients] off? Is there [a certain] amount of time? We don’t have good answers for that yet.

 You 2 brought up phenomenal points about the difference between what the trial says and did in their protocols and what’s actually done. You mentioned FORTE. I think KR maintenance is tremendous. In the FORTE study, carfilzomib is given [on] days 1, 2, 15, [and] 16; every 28 days, 4 times a month, to me, is not maintenance. And I don’t think [most] of us in the United States use carfilzomib in that fashion. To your point—GRIFFIN and the up front—we’re mostly using bortezomib once a week. So, I love the concepts that you’re all talking about. Yes, great regimens for maintenance high levels, but we need to make them applicable and more tolerable long term.

That’s right, and that is a hard thing. We want to talk about things as they’re studied and unlabeled, but the practical considerations—especially when you’re talking about years of therapy—we do often administer these very differently. Again, once weekly [bortezomib] is simple, easy, and probably the most done thing, but that’s not how our trials are designed.

Key opinion leaders on multiple myeloma management review available induction therapy regimens in the transplant-eligible setting. 

Induction Therapy Regimens for Transplant-Eligible NDMM

Along those lines of alkylators, I'll throw this one back to you. So, a patient comes into your clinic and obviously it's a complex dynamic, who gets transplant, who doesn't, patient may have biases for or against it. But is there a specific phenotype of patient from your standpoint who is eligible by criteria but should absolutely get it or should absolutely not get a transplant?

: Of course, this is a nuanced decision and discussion with the patient, taking into account what they value deeply, however, from my perspective, the patients who I certainly will try to discuss transplant and keep that on the table, would be the patients with ultra­–high risk multiple myeloma. Those patients who have 2 or more high-risk cytogenetic features. We've seen for theme after theme from all the quadruplet studies that those are the patients who are an unmet need, still. And those are the patients who we've seen derive the greatest magnitude of benefit from autologous stem cell transplant. And I often even discuss a tandem, although that's not something routinely done in our country, but I have discussed that data, so that they're aware and at least know that that's something that the field studied and could be a recommendation.

That's the CTN 0702 STaMINA is still showed in that subgroup, the intention to treat the benefit there. So, for me, those patients who I give one of our standard modern-day regimens and they don't do so great, and transplant gets it, there still is a role for some people to get tandem. So, I agree.

But we need to be a little careful about undertreating our standard-risk patients. Because everybody has high-risk myeloma, some people take longer than others to get there, right? We all have these patients who look like they had very calm myeloma and then 10 years later, they have very angry myeloma. And you have to ask yourself, if you held back on therapy early on, could you have maybe expedited the emergence of that high-risk phenotype. And the patients with standard risk disease, if you take them through that evidence-based first line of therapy that includes transplant and maintenance therapy, maybe these are the patients who are going to have decades of survival, or maybe they're never going to relapse after first-line therapy. And so, I agree there's some room for risk adapted approaches, but remember that there has never been a randomized trial that looked just in the standard-risk or just in the high-risk and asked transplant vs no transplant. Overall, it does seem like the benefit of transplant does cut across these subgroups.

And I would imagine, every single person here has patients in their clinic that are 10 years plus out now that used to be a rarity. And now we see them all the time. I would say without an exception that all of those patients have had a transplant somewhere along the line. And you could say, well, that's because that's what's around, but at the same time, I guess, I'm convinced that, that has added something to their care over the years. And many of those patients, I'm sure you've seen them 5, 6 years, post auto transplant doing fine.

 But I want to echo your point. It's important that just because someone has standard disease upfront does not mean you should hold back on optimal therapy. You should always go with your best, most aggressive regimen upfront to give people the opportunity to have that durable progression for…

Well, and I would highlight a trial that doesn't get a lot of publicity right now. ECOG is doing EAA181 (NCT04566328), which is an interesting trial, standard-risk deferred transplant. Everybody gets 9 months of DRD, so daratumumab, lenalidomide, dexamethasone, but then, at 9 months, people are randomized to add in Velcade (bortezomib) for an additional 9 months. And what they're trying to figure out is whether stepping up the therapy is going to make a difference or not, or whether you need to do that, which is an interesting question.

: And the theme that we've often seen is that any therapy that helps high-risk helps standard-risk more. We are all trying to say the same thing is that anything that we do that helps high-risk is certainly something that's going to go a long way in helping our standard-risk patients. So, I completely agree, we shouldn't take the breaks off on those patients.

Comprehensive insight on patient and disease characteristics that help to inform best available therapy for patients with newly diagnosed multiple myeloma.

NDMM: Identifying Patient and Disease Factors to Select Appropriate Therapy 

Hello, and welcome to this OncLive Peer Exchange® titled, “The Evolving Treatment Paradigm in Multiple Myeloma, Recent Updates.” I'm Dr Richter, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, and the director of myeloma services at the Blavatnik Family-Chelsea Medical Center at Mount Sinai. I'm joined today by a panel of experts in multiple myeloma. I would like to welcome my esteemed fellow panelists and invite them to introduce themselves.

Hi, I'm Natalie Callander from the University of Wisconsin Carbon Cancer Center.

Hi, I'm Susan Bal. I'm an assistant professor of medicine at the University of Alabama at Birmingham, O'Neill Comprehensive Cancer Center.

Hi, I'm Betsy O'Donnell from the Dana-Farber Cancer Institute in Boston.

Hello, I'm Alfred Garfall from the Abramson Cancer Center at the University of Pennsylvania.

Welcome everyone and thank you for joining me. Today we're going to discuss recent updates in the treatment of multiple myeloma. We'll discuss the data in context of guidelines, the treatment landscape, and its impact on clinical practice. Let's get started.I'd like to ask the panel their thoughts about how transplant-eligible, newly diagnosed myeloma was traditionally treated and how this landscape has evolved over time. Anyone with any thoughts?

There's a role for autologous stem cell transplant right now. It certainly is associated with the longest PFS [progression-free survival] DETERMINATION (NCT01208662). There is nothing else out there that has given a PFS that long. And particularly in standard-risk patients, who it was 81 months, if I've got that correct. And I feel confident about recommending that to patients. And particularly, we also would agree with our [patients with] high-risk myeloma that that's an option that we are wanting them to consider.

You're quoting DETERMINATION, which is one of the main state trials that got us here. Couldn't agree more. And I know through some of your work, I'd have to ask because DETERMINATION gave VRD [velcade/revlimid/dexamethasone]. Are you giving quads to everyone on their way to transplant?

And I will tell you why. We were a big accrue to the ENDURANCE trial (NCT01863550), which was a transplant deferred trial for standard-risk patients. And I feel comfortable right now, I suspect there's going to be an update coming next year, between VRD and KRD [kyprolis/revlimid/dexamethasone] induction, but high response rates in the mid 80s. And what we've also done in that particular trial is patients have been able to go on to autologous stem cell transplant and be salvage successfully, at least in my experience. So, no. We are certainly giving high-risk patients—we could also quibble here how we want to define high-risk—but those patients, we are giving a quad to.

And I agree with you on that, Natalie. Many patients do well with VRD. And there's always the potential to convert a triplet to a quad if you're not seeing the response you like in the first couple cycles. It's very clear that it's safe to give quads and that's reassuring data for the patients that we think need it and you're worried about disease control in those early months. We haven't adopted it universally for everybody at this point in the absence of long-term overall survival data that tells us that we need to give quads to everybody for the best long-term outcomes.

 As a group, we've been early adopters of anti-CD38 monoclonal antibody-based therapy and upfront therapy both for the transplant-eligible and -ineligible patients. And routinely, we are incorporating a monoclonal antibody in our transplant-eligible patient and using it in a quadruplet setting, mostly because the benefit that high-risk patients achieve is certainly worthwhile, but we see a magnified benefit in the standard-risk patients who do…so remarkably well. And as long as the patient is eligible in terms of their biological, not just their chronological age, it's reasonable to offer it to everybody. But more importantly, transplant plays a great role in the high-risk patients. And we've seen that theme across multiple different studies is how transplant certainly benefits the high-risk patients regardless of how we define high-risk or the ultra­–high risk.

But the flip side of this is, why are so many people not transplanting as well? And so, myeloma is a field that's divided in terms of when and how to use transplant currently. And so, with the addition of monoclonal antibodies to frontline therapy, we are seeing tremendous depth of response. And we know from determination and the IFM study that you're not necessarily seeing an overall survival benefit; you're certainly seeing the progression-free survival benefit. So, when you give patients the option, and we do have phase II studies that we've done in our center, patients often prefer the deferred approach. Everybody should be collected unequivocally, that's just money in the bank. But there are downsides of transplant too, and they're not perfect or right for everybody. And it's also about timing, life circumstances. So, there are a lot of factors, that go into my own decision making about whether I transplant someone upfront vs collect and defer.

And I want to second your point about the early collection because the broader oncology community might get the impression that there is some disagreement or lack of consensus about the need for frontline transplant. There is consensus that this needs to be preserved as an option for our younger patients. And that all the trials that have tested this deferred transplant approach, it does rely on collecting stem cells in the first line of therapy. And it is a somewhat nuanced discussion, with the patient that probably should happen at a transplant center with a physician that does transplants. And so, I would still want to encourage everyone, even if the patient is equivocal or not sure about transplant, to refer to the transplant center to have that conversation. And even if you decide to take a deferred transplant approach, consider the early stem cell collection before the patient has had too much therapy.

 But I would want to comment that there's a couple of publications. We did one maybe a decade ago, and there's been one you did recently, where people who have stem cells collected, often they're not getting used. That's a real issueand it's interesting in the DETERMINATION trial, it's 25% of people got the salvage auto. So, I sometimes feel people who are very emphatically anti-transplant don't take care of the patients who've had an auto transplant because I believe, yes, their quality of life is lower vs chemo for that first 3 months, but then they have great quality of life. They travel, they take their maintenance. And if we get to the point with SWOG 1803, when that gets read out, randomized study between lenalidomide, indefinitely if you're in an MRD [measurable residual disease] negative state vs 2 years or lenalidomide plus daratumumab, we're going to have a great new standard. And if you have an opportunity to take a person off treatment for a prolonged period of time, that's going to be a major benefit. And I think we would all agree that we've seen patients go through transplant, maybe who've been sent progressing and get into that good deep response, get into a CR [complete response]. And transplant really is a good steppingstone to do that.

While I agree that if you look at IFM09 and DFCI (NCT01191060) that the overall survival is comparable. Remember, those studies weren't powered for overall survival.

 And it’s still early when you think about the long survival that these patients have. It's too early to conclude that there is not going to be an overall survival difference emerge with more follow up, especially if patients in the deferred transplant arm aren’t getting the deferred transplant. And if you look at EMN02 (

), which is probably the one generation earlier in the transplant vs no transplant trials, it took a long time for the overall survival difference to emerge, but I think it was ASH 2021 when we finally saw that it emerged. And that was with less potent induction than what was used in DETERMINATION and IFM09. And so, I still think it's possible that there will be an overall survival advantage emerge with the transplant arm if the control arm is not getting transplant in the second line of therapy.

And if you look at measurable residual disease or MRD, which is where the field is moving towards, we see that of course in the context of triplet therapies, that there is a depth improvement in the depth of response, including minimal residual disease negativity. But what was interesting to us is, going back to that MASTER (NCT04601116) data, if we look at patients who got a quadruplet, including a potent proteasome inhibitor, so we got daratumumab, carfilzomib, lenalidomide, and dexamethasone, and even in that context, after potent quadruplet therapy, we saw a decrease in MRD in 86% of the case patients. So, I thought that was encouraging data for transplant. Of course, that needs to be carefully weighed against the patient's preferences and all of the other things that we know of autologous stem cell transplant. But it was great to still see benefit of alkylators in that setting.

Expert panelists reflect on the continuing role of stem cell transplant in patients with newly diagnosed multiple myeloma.

Elizabeth O’Donnell, MD, Dana-Farber Cancer Institute

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