Saad, tell us about your own work with CANDOR, particularly the value of a PI [proteasome inhibitor] combined with a monoclonal antibody. It was pivotal work. Congratulations on the FDA approval very recently. That was terrific, Saad. In that same spirit, I would love for you to comment on IKEMA, recognizing that has also been fascinating and very much validates CANDOR. Finally, if you wouldn’t mind spending time on BOSTON, I think that’s a very important study.

I can talk about CANDOR and IKEMA, because in many ways they’re validating the PI/anti-CD38 monoclonal antibody combination regimen efficacy, safety, and tolerability. Even though the clinical trial designs were different, the schedule of giving the anti-CD38 monoclonal antibody is different. Both studies came out positive in favor of the 3-drug combination vs the 2.

CANDOR is a 2-to-1 randomization, whereas the IKEMA study was a 3-to-2 randomization. The number of patients and all those nuances of median follow-up would be a little different. Regarding patient populations, even though they’re a little different, about a third or more of the patients in both studies are lenalidomide refractory, especially as the previous line of treatment. That’s the patient population that’s perhaps more relevant to clinicians in the United States. We’ve talked about continuing maintenance until relapse or progression, and we’ve talked about looking at improving on that lenalidomide maintenance platform. But many of our patients are going to have good exposure to lenalidomide maintenance and then escalated doses of lenalidomide in many cases as well. Overall, that’s where the most value is.

The CANDOR data, after a median follow-up of about 27 months, showed a median PFS [progression-free survival] of about 28.6 months compared with 15.6 months on the Kd [carfilzomib, dexamethasone] arm. In the IKEMA data set, the data are not mature, so the median PFS on the isatuximab–Kd [carfilzomib, dexamethasone] arm has not been reached, but that on the Kd [carfilzomib, dexamethasone] arm has been reached.

One of the striking differences, and the credit goes to the IKEMA investigators, is for the immunofixation-positive patients who are not getting evaluated for MRD [minimal residual disease]. The investigators went back and looked at mass spectrometry to see if it’s the antibody interference, and that may have played a role in not having enough MRD assessments on that study. From the look of it, if you look at the MRD-negativity rates, in CANDOR they’re about 23% compared with 6% or 7% on the control arm. Whereas in the IKEMA trial, they’re about 30% vs about 11% or 12%. Overall, a stark difference between the 3-drug platform vs the 2-drug platform.

For the safety profile, there are higher rates of infection when you combine an anti-CD38 with a PI like carfilzomib, and that’s what was observed in both the studies. Interestingly, there was a lower incidence of grade 2 or higher cardiac events in the daratumumab-containing arm of CANDOR compared with the Kd [carfilzomib, dexamethasone] arm. In the IKEMA study, the grade 3 or higher was similar across the 2 arms. Therefore, no major cardiac signal was observed by addition of an anti-CD38 to carfilzomib. Notably, that was 1 of the main concerns early on with the initial phase 1 study experience.

Turning to the BOSTON trial, I think David has already highlighted how important the exportin 1 inhibitor mechanism [XPO1] of action may be, especially for the high-risk patients. He talked about the TP53 protein enrichment within the nucleus in patients with deletion 17p. The BOSTON trial validated the PI plus XPO1 inhibitor platform in the BOSTON study in early relapse setting. The most impressive part of that study to me was that deletion 17p, as well as translocation 4,14 patients, benefited in terms of PFS to the same degree as the standard-risk patients. The median PFS in those subgroups of patients was like the overall population. That difference was not seen for the translocation 14,16 group, but with the caveat that they were even a smaller number of patients with that. They also commented on the 1q21 amplification patients; the benefit was similar.

Tolerability was certainly better with the once-weekly lower dosing of selinexor at 60 mg. Even though this is not part of the current discussion, I was very impressed with the carfilzomib-selinexor arm of the STUMP trial because the data were better. That’s probably where we will find a lot more use of the selinexor triplet combinations in relapsed/refractory disease.

I totally agree with that. I think SKd [selinexor, carfilzomib, dexamethasone] is the best selinexor combination. Not to get off topic, but that’s where people might have been exposed to bortezomib before. I want to see SKd [selinexor, carfilzomib, dexamethasone] vs K-POM-d [carfilzomib, pomalidomide, dexamethasone] because it could possibly be useful for our high-risk patients, as Paul was pointing out.

I agree. The carfilzomib data from Cristina Gasparetto were excellent. In fact, to that end, in the groups in the Alliance [for Clinical Trials in Oncology] and hopefully SWOG and ECOG-ACRIN [Cancer Research Group], they’ll be actually developing ideas looking at selinexor, carfilzomib, pomalidomide, and dexamethasone, to see where we might go with platforms as powerful as that to overcome this particularly dangerous high-risk group. Excellent summary, Saad. Thank you so much.

Videos

Saad Z. Usmani, MD, leads the discussion on new and updated data for novel PI-based combinations in RRMM as seen in the CANDOR, IKEMA, and BOSTON trials.

Using PI-based Combinations in RRMM

: David, I want you to talk about something you and I have worked on for many years together, and that’s IMiD [Immunomodulatory imide drug]-based strategies in relapsed/refractory disease. I want to especially acknowledge the work you’ve done with POM [pomalidomide], and all the work that has followed from that with pomalidomide. In that spirit, I wondered if you could touch on your impressions from your own work with [trial] MM-014, joint work with OPTIMISMM, and the APOLLO study. Notably, there was a nice abstract from the Canadian groups with ASH [the American Society of Hematology annual meeting] 2020, abstract 413, which was DARA/CYCLO/DEX [daratumumab, cyclophosphamide, dexamethasone]. Additionally, there was ICARIA-MM from our own group. Most encouragingly, there was the STOMP data, which Christine Chen, MD, did a nice job on with abstract 726. Overall, there is a lot there to talk about. Finally, the other piece is that there are a lot of questions from community doctors asking why wouldn’t we use pomalidomide early? Why would it not be in newly diagnosed patients? We would love your thoughts, David.

: The answer to the last question is that we weren’t allowed to use it in newly diagnosed patients, not that it shouldn’t have had a role. I think you bring up an excellent topic. I think that pomalidomide is a very underutilized drug. Obviously, all of us have a fair amount of experience with pomalidomide-based combinations, but in the community, you see it used relatively sparingly. Paul and I were co-authors on the first paper that led to pomalidomide’s approval, so we do have a long history of working together on pomalidomide. However, there was a whole section of abstracts from the 2020 ASH meeting that brought more to the forefront. Specifically, several pomalidomide-based regimens that were used relatively early during relapse.

The first of them was presented by you, Paul, the OPTIMISMM trial, which is the combination of bortezomib, pomalidomide, and dexamethasone. As Nina pointed out, there are many patients out there who get into second- and third-line therapy, and they may have been exposed to bortezomib, but were never refractory bortezomib, particularly patients who went onto transplant. As such, the combination of bortezomib, pomalidomide, and dexamethasone should be on everybody’s short list of second-line salvage regimens. Bortezomib is safe and relatively easy. I don’t use a lot of bortezomib because of my concerns in relation to peripheral neuropathy, but this is certainly a legitimate combination that needs to be used.

The MM-014 trial was designed to address a very specific problem in the multiple myeloma [MM] community, but in the more global oncology community as well, and that is this instinct that if a patient is on lenalidomide, that pomalidomide is not a legitimate choice. This was a 2-arm trial. The initial arm of this trial was to take patients who were progressing on lenalidomide-containing first-line therapies or second-line therapies and treat them with pomalidomide and dexamethasone.

Refractoriness…the response to pomalidomide, then refractoriness to lenalidomide. The point being, that pomalidomide is a legitimate and basically fully active drug even in patients who had gotten previous lenalidomide. The arm that was presented at ASH was the combination of pomalidomide and daratumumab, one of the most popular combinations. Overall, the point was that patients who were progressing on lenalidomide have about the same response rate to that DARA/POM [daratumumab, pomalidomide] combination as patients who had not been exposed to lenalidomide in immediate prior lines. Therefore, lenalidomide to POM/DARA [pomalidomide, daratumumab] doesn’t compromise the activity of that combination, and I think that’s something very important to understand. Pomalidomide is its own drug; it is not an extension of lenalidomide.

The APOLLO trial was interesting because it confirms that the DARA/POM/DEX [daratumumab, pomalidomide, dexamethasone] combination using subcutaneous administration of daratumumab is active, is well tolerated, is certainly a premier regimen and one that is growing in popularity in the United States as well.

The Canadian trial that you were talking about is a little more complex. They use a lot more cyclophosphamide for the management of multiple myeloma in Canada than they do in the United States. This was a trial to look at whether the 4-drug combination with the addition of pomalidomide to DARA/CYCLO/DEX [daratumumab, cyclophosphamide, dexamethasone] had activity. In fact, response rates were close to 90% in relapsed patient populations. Certainly, it is a combination that is a feasible one. How much the cyclophosphamide adds in that, the trial didn’t really address that. However, a 90% response rate in a relapsed patient population is impressive no matter how you look at it.

ICARIA-MM, this is always a difficult topic. Certainly, isatuximab is a viable drug. It is extremely active; it is well tolerated. Its early schedule is better than the schedule of daratumumab, but it is an intravenous [IV] drug with similar both toxicity and efficacy profile to daratumumab. Specifically, whether an IV drug that is given slightly less frequently can push aside a subcutaneous drug, I think this is going to end up being a financial question much more than it is going to end up being a clinical question. Nonetheless, there is no suggestion that isatuximab is in any way clinically inferior to daratumumab, and they are both monoclonal antibodies against CD38. Overall, it depends on payer issues as to how attractive that combination is, but certainly it is at least as effective in my opinion as the daratumumab-based combination.

I think STOMP is going to turn out to be one of the important studies. The part of this that I’m speaking to now is that one of the arms of this trial included selinexor. Selinexor is a very exciting drug that Paul touched on, and one that we’ve all touched on to some extent. A unique mechanism of action, it is a nuclear pore inhibitor and theoretically traps TP53 and perhaps some other tumor suppressor proteins in the nucleus, which makes the cell more easily convinced to undergo apoptosis, than if that TP53 was not trapped in the nucleus. As such, whether this drug is going to be uniquely active in some of the high-risk populations, I certainly hope so.

One of the arms of this trial was selinexor, pomalidomide, and dexamethasone, and it was very effective. If people had some early experiences that were negative with selinexor when it was being used as a single agent or with dexamethasone, where emesis and GI [gastrointestinal], weight loss kind of issues were prohibitive, they’re going to be very surprised about the new iteration of selinexor at lower doses with third compounds, where the toxicities are much more manageable. Moreover, even in very heavily treated patients, there are some surprising responses that are quite durable.

Particularly now in the COVID-19 [coronavirus disease 2019] world, the selinexor, pomalidomide combination is a very exciting one, very well tolerated once you get used to the antiemetic regimens and you’re using the selinexor at lower doses. Specifically, this treatment is 60 mg, not the 100 mg that people got scared of in the past. As a result, selinexor is going to turn out to be a very important drug, and we’re just starting to figure out how to use it now.

I think the moral to the story is use pomalidomide if you’re out there in the community. It’s an easy drug. If you’ve used Revlimid [lenalidomide], you’re going to know how to use pomalidomide, and it certainly has significant efficacy advantages over lenalidomide.

: I think you’re absolutely right, David, that’s it’s a partner drug that’s underappreciated in terms of its add-on value, and from those days 10 years ago together when we started just with POM/DEX [pomalidomide, dexamethasone], look at where we are now. I do agree with you about SELI [selinexor]. Obviously, the original STORM [trial] experience reflected just that. We had to go in as a monotherapy eventually with steroid. I was so impressed by what we’re now starting to see in terms of the once-a-week dosing and lower dose, recognizing the adverse effect profile is very real, but it is manageable, and especially with that lower dose weekly. Certainly, in my own practice, I’m using selinexor 20, 30, 40 mg once a week, and when you combine it with a PI [proteasome inhibitors], we see some real excitement.

Role of IMiD-based Strategies for RRMM

: Now we’re going to change gears a little bit, and in the second part of our conversation, we are going to move now into relapsed and refractory multiple myeloma. I was going to ask Nina to talk to us about how she considers what regimen to use in the relapsed/refractory setting; when do you pull the trigger on relapsed disease; how do you think about rate of progression; distinction between lines of therapy, classes of therapy; what’s early versus late relapse, what does that mean to you; and most importantly, what about the molecular characteristics of relapse? Nina, walk us through this forest of information.

: For most of those, one of the best things about keeping people on maintenance or observing them closely is that you can find out when they progress. There are 2 ways that people progress or relapse. I like to use the word progress because relapse, by definition, is just a reappearance from CR [complete response] and protein, and I don’t think that’s a reason to treat someone necessarily. But if they have a true progression, which is progression by bone marrow, progression by M protein, light chains, or by progressive disease based on imaging, then they need to be treated. Although, not all progressions are the same. There’s the biochemical progression, which is your IMWG [International Myeloma Working Group] met criteria of 0.5 g/dL on the M protein or 25%, or an increase of at least 100 m/L on light chains. Especially now, our patients are getting to those normal light chains and normal M protein numbers with our new therapies, so we see that, and it’s not that much tumor burden.

Then there’s the clinical progression. Someone shows up with a new fracture, a new plasmacytoma, new renal insufficiency, or you haven’t seen them in a while, and they show up and now their light chains have grown crazy and now they’re creatinine is a little abnormal. Overall, those are the 2 flavors of progression that you have if you had to categorize them.

What are the biochemical progressions? I think those people have time, usually. I think it’s worth it to then—and I used to be a little worse about this, but now I’m much more consistent—when you see the biochemical progression, make sure it’s confirmed by the next blood test. I have gotten away from the 24-hour UPEP [urine protein electrophoresis] as I am not a fan. But that’s OK, I hope no one gets on my case! However, I always get the blood test. Specifically, that’s the time you need to send them for imaging, to set the bone marrow up, you must look for clonal evolution. All these things are important because they tell you what urgency you must treat the patient. If there’s nothing new on PET [positron emission tomography] and it’s 15% on the bone marrow and it’s just numbers, you can think about a clinical trial, and you should because there are clinical trials for the 1 to 3 priors that are open. Specifically, there are CAR [chimeric antigen receptor] T trials open, etc. In the absence of clinical trials, I think there are myriad options. I think we’re going to discuss those later. However, there are a lot of options you can think about.

Next, there’s the people who need treatment right away. They come in with a new fracture, they have a new plasmacytoma, they might need radiation. As soon as you manage what the acute issue is, those people should get treated right away because they will have progression and clinical progression, and you want to prevent morbidity at this time. Overall, that’s how I think about if I’m going to start treatment or not. The people who have the biochemical progression at the 0.5 g/dL, you can wait. I would say once you get to 1.0 g/dL, you should probably start treating them. Notably, that moment that they hit the 0.5 g/dL, they can consider doing all their whole work-up like we talked about.

As far as thinking about what you’re going to do about the agents, we have our classes of agents, and most people have been exposed to lenalidomide either in induction or with maintenance therapy, and many of them will have been exposed to a proteasome inhibitor [PI]. As such, those are your classes that you’ve already been exposed to, and now your choices are, “OK, do I use a CD38 antibody, which is a new class, and do I combine it with a new IMiD [immunomodulatory imide drug], or do I try to re-expose these people to something they’ve had before?” For example, perhaps someone had bortezomib as an induction therapy and they weren’t refractory to it, they had their cycles, they went to transplant, and it’s been a while. You can consider treating those people again.

Finally, I want to talk a little bit about the molecular aspects of it. I think if ASH [the American Society Hematology annual meeting] of 2019 taught us anything, it’s that we have a biomarker to treat for the first time, which is [translocation] 11;14. For those people specifically, it’s not a wrong choice to give them venetoclax, even early in the first progression, because people can do well even on venetoclax/dexamethasone alone. I know that’s not FDA approved, but this is one of those few times where you can try to get at the core of their disease and think about what else they may have. The reason that it’s also important to do that bone marrow biopsy, is maybe you’re going to find out something new. Perhaps, the patient will have a new deletion 17p, or a new deletion 16q? Whatever it is, that’s going to help you decide how aggressive you need to be.

Ultimately, the patient’s clinical picture is the most important. Did they progress quickly after transplant? Did they progress years and years after transplant? Those things help you to understand how aggressive this is and how aggressive you need to be to maintain the goals of efficacy and quality of life.

: I think that’s an excellent point. I want to pick up on a nice point you made about t[11;14). I’m wondering if we are going to see 2 types of t(11;14), because I’m not sold that it’s a standard risk feature. I’ve been struck by what we’ve seen by the t(11;14) biology, and the clue perhaps lies in plasma cell leukemia, which is enriched for t(11;14). I agree with you, Nina, that there’s value to engaging venetoclax early. My challenge is when venetoclax fails in the t(11;14) patient over time, then what happens? We have the clear data that the non-t(11;14) can see Pandora’s box emerge and the disease behaves extremely badly. The fact is that your outcomes can be poor. Nonetheless, I agree with you. I think t(11;14) is a fascinating area, and I’m hopeful we’ll have an approval for t(11;14) in this year to help us with this because from a community practice perspective, having that approval can only be a good thing, particularly in the t(11;14) subset in BCL2 overexpressors.

The 17p always make me feel uncomfortable. I just wondered, Nina in terms of your approach, how do you think about that if you see that emerge? What guns do you then bring to bear?

: I get aggressive with these people because if you stop therapy for 3 weeks for example, their disease is going to grow. As such, you must find something that they can get on quickly. Sometimes if they’ve presented with high burden of disease, you might even consider like high-dose Cytoxan [cyclophosphamide] and get them reduced, and then get them on to something that they haven’t seen, such as daratumumab or carfilzomib. Nonetheless, it is really challenging. We’ve all said this before, but all 17p deletions are not the same thing. There might be 1, there might be 2 deletions, we don’t know, and sometimes we don’t take the time to find out because that’s just not how we get the bone marrow. Overall, not all 17p deletions are the same. However, when I see it, and especially if I see it new, I know that there’s been some badness going on in the evolution in that bone marrow.

: I think it remains a fundamental challenge. I’m struck by, for example, something I am going to ask David about. I think we’ve got new drugs like selinexor and the data from Boston, which tell us that regarding 17p, you’ve got some new guns in the cupboard that we can deploy if we need to.

Approaching Treatment of RRMM

: Regarding MRD [minimal residual disease], Saad, if you could bring up the rear of this section and summarize where you see MRD assessment. As you’ve heard so nicely, MRD is giving us clues to what works best, and there was a very nice presentation from Paula Rodriguez-Otero, MD, PhD, abstract #62, which I thought was particularly noteworthy. Saad, what is your take on the MRD perspective?

: Whether it’s by the next-generation flow cytometry or next-generation sequencing, MRD-negativity does provide prognostic information for newly diagnosed patients, as well as for early relapsed disease. Notably, this has been shown in several studies that were updated at ASH [the American Society of Hematology 2020 annual meeting]. I think the abstract you’re alluding to talks about the issue of having MRD-negativity in patients who may still be immunofixation-positive, and there has been this discordance in the past.

What Dr Rodriguez showed in her presentation was analysis on 2 older Spanish multiple myeloma [MM] trials with subsequent long-term follow-up, looking at MRD-negativity by flow cytometry, and looking at mass spectrometry and nature of the immunofixation and seeing if there is a difference between the survival of those patients long term. Dr Rodriguez demonstrated that there are similar PFS [progression-free survival] as well as overall survival benefits in those groups. Those immunofixation abnormalities do linger, but they get better over time as well, and that was part of the slides that she presented.

The gist of it was affirming what we already know about MRD as a prognostic tool. I think the real key for us as clinicians is going to be when we can utilize it to limit therapy in patients. Those are the questions that are being asked in clinical trials currently, including the SWOG 1803 that Amrita Krishnan, MD, FACP, is leading, comparing DARA/LEN [daratumumab, lenalidomide] versus LEN [lenalidomide] for maintenance, looking at MRD-negativity as a stopping point. I think Shaji Kumar, MD, is exploring that as an endpoint with the second randomization in the ENDURANCE trial as well.

The same is true for the CASSIOPEIA study. I think they’re looking at the DARA [daratumumab] versus no maintenance question in that study as well, with MRD as an end point and a guiding post as well.

: I agree. I think the Rodriguez abstract was so interesting, Saad, because it pointed to some of the complexity of assessing MRD, that you could have an immunofixation-positive patient who was MRD-negative. It pointed to somewhat different biology as well. I think that MRD, like all of these things, it resonates with everything we’ve discussed, is moving so quickly, and just as our therapeutics are moving so fast, so is the technology used, and the implications of MRD are evolving as well.

Future of MRD Assessment in NDMM

: I’m going to touch briefly on 2 important updates, one of which was the early versus late transplant study conducted by our French partners. I thought Aurore Perrot, MD, PhD, did a wonderful job of summarizing and showing that with a median follow-up of 8 years, the overall survival [OS] was identical in both groups at approximately 60% in both arms. Regarding the late transplant group, about 70% had gone on to late transplant. We were thinking there might be a survival benefit in favor of earlier transplant, and we didn’t see it, suggesting that for a subset of patients we can think about reserving transplant, doing stem cell collection, but keeping transplant in reserve. Overall, that was a very important takeaway. Also, an important takeaway from Aurore’s presentation was that MRD [minimal residual disease] in the research setting clearly matters and is prognostically important regardless of whatever therapy you got.

There were also fascinating data from Mehmet Samur, PhD. Specifically, his work derived from the IFM trial data set where we looked at mutational change according to therapy. Specifically, be it RVd [lenalidomide, bortezomib, dexamethasone] followed by delayed transplant, or RVd [lenalidomide, bortezomib, dexamethasone], early transplant, and there was really striking information.

You recognize in whole-genome sequencing the enormous mutational burden that we have in our patients at diagnosis, with a median of around 7000 mutations in each group. When you saw relapse after RVd [lenalidomide, bortezomib, dexamethasone] with transplant kept in reserve, the mutational burden increased by about a median of 1500, whereas in the transplanted group receiving high-dose melphalan, that was substantially greater at about 5600, which was really striking. I think what jumped out at me from those data, was that even in the MRD-negative patients who received high-dose melphalan, when they relapsed, at whole-genome sequence analysis, that same mutational difference was seen.

I think it begs the question as we look to the future, recognizing the real value of high-dose melphalan where it stands right now, we need to think about ways of targeting this minimal residual disease state in terms of intensification that don’t allow this kind of mutational thrust to emerge at a later date, fully recognizing that these are subsets of patients. Therefore, you must be very careful. I did think that Mehmet’s presentation was fascinating because it certainly convinces me that we need to target stemness. The question is how? Do we do so with something that buys us a problem later, or do we do something, to David’s point of your work, Nina, looking at approaches that could target this earlier that could achieve that MRD-negative state without the late complication of mutational burden?

Overall, I thought that was an interesting analysis. I would caution everyone not to necessarily over-interpret it because the numbers were relatively small. I think that’s tremendously important because we want to be careful about making too much of a limited amount of data at this point. We’ll obviously have information from DETERMINATION and other studies to help us with that.

I want to turn now to David and say that post-transplant, recognizing its value and that it may not be for everyone, although it’s importance for a subset of younger patients is clearly beneficial. How do you think about consolidation? At ASH [the American Society of Hematology 2020 annual meeting], the Pieter Sonneveld, MD, PhD, abstract #550 was helpful. Moreover, we already touched on Jonathan Kaufman, MD’s data from GRIFFIN and Francesca Gay, MD’s information from FORTE. David, any thoughts on consolidation here?

: Clearly, that’s what we need to do, and we can talk about the specific trials. However, I think it is difficult to interpret these things because in the end it’s about OS and the progression-free survival [PFS], and even PFS2 [progression on next line of therapy], which has been addressed in some of these trials where there does seem to be a continued advantage. In the end, mutational burden and additional therapy carries some long-term ramifications that we don’t understand yet.

I would go back to some of those transplant data that you were speaking of. Heather Landau, MD, was also a first author on a similar kind of analysis of patients coming out of Memorial Sloan Kettering Cancer Center. However, what they’re looking at in these trials are the early relapsers, specifically the patients who don’t have long-term remissions, even long-term remissions with the support of maintenance therapy afterward. And these are melphalan-specific mutations that are seen, but we’re seeing them in a population that is maybe not high risk by the molecular definitions that we use, but are behaving as high risk, and those are, in fact, the ones that are most important.

To reiterate what you were saying, these are small numbers, it’s early. But also, it’s the early relapsers that drove that analysis, and that’s a very interesting patient population that is not reflective of the more global population.

We have a lot to learn. Consolidation is clearly a very important paper, and Nina began to speak about the FORTE trial, and I thought FORTE was one of the more interesting trials. I think what was important specifically was the topic of discussion. If people don’t understand FORTE, a very complicated trial, an initial 3-arm randomization to the combination of carfilzomib, cyclophosphamide, and dexamethasone, and then 2 KRd [carfilzomib, lenalidomide, dexamethasone] arms, 1 of which was with continuous KRd [carfilzomib, lenalidomide, dexamethasone] for 12 cycles. The other was KRd [carfilzomib, lenalidomide, dexamethasone], stop, go through a transplant, and then get more KRd [carfilzomib, lenalidomide, dexamethasone] as consolidation afterward. And then a randomization to Revlimid [lenalidomide] as maintenance therapy versus carfilzomib and Revlimid. I don’t know whether you want to call that maintenance or not?

What it showed is that the transplant-based regimen, the KRd [carfilzomib, lenalidomide, dexamethasone]/transplant as opposed to KCd [carfilzomib, cyclophosphamide, dexamethasone]/transplant—and I think that’s an important point because there are a lot of oncologists, both community oncologists and people who work in multiple myeloma centers, who still use cyclophosphamide-based regimens as their major induction regimen—and this clearly shows the inferiority of the cyclophosphamide-based regimen. Overall, the discussion is about KRd [carfilzomib, lenalidomide, dexamethasone] to transplant versus KRd [carfilzomib, lenalidomide, dexamethasone] to more KRd [carfilzomib, lenalidomide, dexamethasone] to more KRD [carfilzomib, lenalidomide, dexamethasone] again, which shows a substantial advantage to the transplanted arm.

The advantage is even more pronounced in terms of hazard reduction in high-risk patients than it is in the larger population. This is one of the more important trials for several reasons. It continues to support early transplant as a modality, and we’re fortunate that transplant is relatively easy, and it’s ubiquitously available. Also, it is very inexpensive relative to other modalities, and it seems to be preferentially effective in the high-risk patient population, which is the one that we have still to grapple with much more so than others. I think that if I was to pick out a single large trial from the 2020 ASH meeting, I thought that was the most important one.

: Yes. I think, David, though to be fair, we must be careful about the sample sizes in FORTE, just as we were cautious about those. You’ve got several randomizations, and you’ve got 150 patients per arm, and you’ve got 3 arms. I wholeheartedly agree with you that clearly KRd [carfilzomib, lenalidomide, dexamethasone]/transplant wins on the PFS signal in higher risk. Obviously, we don’t have survival data. I agree with you, KCd [carfilzomib, cyclophosphamide, dexamethasone] was clearly inferior on all counts compared to either KRd [carfilzomib, lenalidomide, dexamethasone] and delayed transplant, or KRd [carfilzomib, lenalidomide, dexamethasone] early, and I think that was an important message.

I think the message for clinicians is obviously chemotherapy plus proteasome inhibition only gets you so far. The synergy with immunomodulation is critical, and then this whole goal of targeting stemness is a very important one. I think you’re right, especially in health care systems that don’t have access to multiple new drugs, transplantation is a gold standard because if you don’t have access to salvage strategies, you’re getting the best benefit. But certainly in US practice, we’re blessed by 12 drugs as we stand with more to come in the next month or so, and especially the CAR [chimeric antigen receptor] T platform, which I’m excited about, plus the BiTEs [bispecific T-cell engagers].

Going forward, we can be powerful about that. There is important quality of life [QOL] data that was moved across by Aurore in our presentation somewhat quickly because it wasn’t quite as straightforward as was implied in the presentation as there was a substantial dip in QOL across transplant. We need to be careful about saying it’s straightforward. In expert hands like your own, you do an amazing job. I think the patient perspective is a little bit more varied. That aside, I totally agree with everything you said.

ASH Updates on Transplant in NDMM

I think it’s a beautiful lead in for Nina then, to say if you now have an active patient who has clearly declared themselves, how do you think about an individualized approach to induction therapy? If we can, we can keep this relatively succinct, but Nina, if you wouldn’t mind taking a run at this in terms of frailty scores, clinical symptoms, molecular status, transplant eligibility, and age.

: I think one of the difficult things when you meet a patient with multiple myeloma [MM], it’s like snowflakes, no 2 are alike, and you have to think about each patient as somebody individual and what makes them qualify to get treatment. We just talked about smoldering multiple myeloma [SMM] and how even those criteria, going from SMM to symptomatic MM have changed over the years. In general, we do use the standard CRAB criteria: hypercalcemia, renal insufficiency, anemia—I usually use the rule of 2 grams below the lower limit of normal for that gender—and the presence of lytic bone lesions. Now that we’ve gotten better at diagnostic procedures and found better ways to look at things, I generally send the patients for a PET [positron emission tomography] scan to look at those bone lesions, because I get a good idea of those that are active and not hypermetabolic, etc.

Now we have the SLiM CRAB, which includes the light chain ratio of 100, so that’s involved over uninvolved of 100 or greater, and then the bone marrow plasmacytosis of 60% or more, and more than 1 lesion on MRI [magnetic resonance imaging], which tends to be a narrow-based lesion. Those are a little bit difficult sometimes to find because rarely do you send your patient for a whole-body MRI, although some insurance companies prefer that over PET CT. I have no idea why. If I knew the code to the insurance company peer-to-peer thing, I would probably not be sitting here right now.

In any case, any of those things can lead to the diagnosis of MM, and it’s really important to, actually even some patients with SMM who come to you, you should do a full evaluation because you don’t want to miss something. If you find any of those 7 criteria, then it’s worth considering that you should have to treat the patient. There are some other criteria we’ve had in the past, for example, maybe the patient has amyloidosis, other things that you have to think about such as neuropathy, there’s some sort of POEMS [Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes] syndrome, and all these other things that you can think about, but this is sort of the garden variety, bread and butter.

Now, when you’re making the decision of how to treat these patients, it really is an individualized approach, even more so now than ever, because we have so many options. We think about the patient as a person. What do they want? Some patients want to go to work; some patients want the most aggressive therapy possible. Some patients only want to live at least 5 years because their kid is getting married, for example. You must know what the patient’s goals are and what the patient can handle.

For this, we do have tools. I really like the IMWG [International Myeloma Working Group] frailty calculator to help us assess where the patient is, especially when you’re making decisions about transplant eligibility. Gordon Cook MBChB, PhD, FRCP, had a nice EMN [European Myeloma Network] overview paper in June of 2020, looking at this and how these things were calculated and how you should use them, and how people progress being not frail to frail both in life and as they are patients with MM having undergone therapy. I think it’s good for us to remember those factors for patients with MM.

Once you’ve decided that a patient is transplant-ineligible, for example; of course, I am a recovering “transplanter” as everybody knows, so I think everybody is transplant-eligible. However, there are a few patients who may not want to go to transplant or aren’t transplant-eligible, and you can think about that with these frailty calculators, or other circumstances where they can’t be going to transplant. Now we have options for these people. We used to say VRd [bortezomib, lenalidomide, dexamethasone], VRd-lite. I think that’s a great regimen if you choose VRd [bortezomib, lenalidomide, dexamethasone]-lite. It’s well tolerated, many of our transplant-ineligible patients tend to be older, and this is well tolerated in that patient population. As you know, at Massachusetts General Hospital, they have a nice, long, extended VRd [bortezomib, lenalidomide, dexamethasone]-lite regimen that does very well.

But now we have other options. I have been impressed with the MAIA trial data, which compared DRd [daratumumab, lenalidomide, dexamethasone], to lenalidomide and dexamethasone, which has consistently shown increased PFS [progression-free survival] for the triple versus double regimen. One of the great things about this trial is it allows us to have another option, which does not necessarily have to include bortezomib, which some patients don’t want to get for various reasons. For example, they may have diabetes and peripheral neuropathy, or they just can’t handle it. Generally, I find that daratumumab is a very well-tolerated drug, so if I was going to think about daratumumab or bortezomib in these transplant-ineligible patients, I am comfortable giving DRd [daratumumab, lenalidomide, dexamethasone] as an induction regimen.

We also know from the European data that you can also consider a quadruplet regimen. I was actually very impressed that they did this study and they enrolled very quickly, the ALCYONE trial, which looked at DARA-VMP [daratumumab, bortezomib, melphalan, prednisone] versus VMP [bortezomib, melphalan, prednisone], and showed consistently that the quad regimen was better.

When you think about quads, and we’ll talk about them in a minute for transplant-eligible patients, we think about quads as being very toxic. All these patients were transplant-ineligible by European criteria, which generally was more of an age-related criterion. But these patients did very well, and they had an overall survival advantage, which was demonstrated at ASH [the American Society of Hematology annual meeting]. I think there is a role for adding daratumumab up front, and now we’re getting more and more data for the transplant-ineligible patients.

For those patients in the MAIA trial, LEN [lenalidomide] is 25 mg, and you’re supposed to continue that indefinitely. Do we really do that all the time with our transplant-ineligible patients? Probably not. That’s not an easy thing to take forever. I suspect that a lot of people had dose reductions, and in the real world they probably will. Therefore, if you’re thinking about how those data in the publication are going to compare to your patients, you should keep that in mind.

Moving on to the people you think are transplant-eligible, and we’re going to talk about transplant versus not I think a little later, so I don’t want to necessarily go into that right now. But there are a bunch of regimens. Our standard for a long time, was what I would say is the “Honda Accord” of induction therapies, was VRd [bortezomib, lenalidomide, dexamethasone] to give to these patients. But now we know there are other regimens that are possible.

Now, just a brief word about the ENDURANCE trial, which looked at KRd [carfilzomib, lenalidomide, dexamethasone] versus VRd [bortezomib, lenalidomide, dexamethasone] and was presented by Shaji Kumar, MD, at ASCO [the American Society of Clinical Oncology annual meeting], that didn’t show any PFS difference. I want to point out that that trial did not have transplant included in it. We really can’t say for transplant-eligible patients, whether KRd [carfilzomib, lenalidomide, dexamethasone] or VRd [bortezomib, lenalidomide, dexamethasone] is better. However, an interesting thing I noted in that data was that patients got to their response quicker with KRd [carfilzomib, lenalidomide, dexamethasone], and I thought about that a lot because sometimes you are on a schedule when you have a transplant-eligible patient, to consider where they’re going to go next. You want to keep them at their schedule, and you want to make sure they get into their remission as fast as possible. Regarding transplant-eligible patients, I think VRd [bortezomib, lenalidomide, dexamethasone], and KRd [carfilzomib, lenalidomide, dexamethasone] can be considered.

What I think has really made a splash recently are the DARA-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] data in the United States, and I’m just speaking for the US population now because the GRIFFIN trial was a US-based population that was enrolled. These patients were randomized to receive DARA-VRd [daratumumab, bortezomib, lenalidomide, dexamethasone] versus VRd [bortezomib, lenalidomide, dexamethasone]. The end point here was achievement of stringent complete response at the end of consolidation—a very specific end point—not a PFS end point, and it’s a phase 2 randomized trial. Right now, their MRD [minimal residual disease]-negativity data, as Jonathan Kaufman, MD, just talked about, is very good. We’ll talk about what those things are a little bit later in our discussion here, but those are options as well.

All these things are options for how you approach the patient with newly diagnosed MM and when to treat. When you think about transplant eligibility or not, you can use these calculators. I think the most important thing is to talk to the patients to see if they want to go for the transplant, if they have the support, and if you think that they are a good transplant candidate, something we think we’re good at, maybe we’re not as good as we should be, and we think about looking at bortezomib or other drugs for high-risk therapy.

I’ll just point very briefly to the FORTE trial, which showed some very nice data in the high-risk group using KRd [carfilzomib, lenalidomide, dexamethasone]. That was not a bortezomib/carfilzomib comparison, but I have been impressed by those data. So that’s the overview of treating and where we start about ineligible or eligible. We’ll talk a little bit more about the specifics of each of those trials, but that’s how we start our approach when we treat our patients with myeloma.

: Yes, and I think that’s beautifully put, Nina. I think the important point about the FORTE trial was exactly what you described, which was so interesting, the MRD data was similar, but PFS stands out as a gold standard. I was struck that clearly in that high-risk group, that ability to target the proverbial stemness of disease with high-dose melphalan clinically translated into PFS benefit, and that was very real.

I think what was an important confounder in that analysis, not a confounder, but something we’re going to learn about, is what kind of maintenance did folks get, carfilzomib, lenalidomide or lenalidomide alone, which we would all agree is an inferior maintenance strategy for high-risk disease now. That will be an important caveat. However, I do agree with you. I think the FORTE data tell us that there clearly is a role for targeting this stemness and eradicating it, because in high risk in particular, it generates a reservoir of disease biology that can be very adverse in the longer term, and we certainly all see that. I think it’s beautifully summarized, Nina, and thank you because you captured so nicely not only induction therapies in terms of how you approach a patient, but also what we learned at ASH.

I would concur with you about the GRIFFIN data. Jonathan Kaufman did a really nice job of showing not only that continued benefit from the quad, but what was so interesting was the benefit of the quad in consolidation. We’re going to come back to that in a minute, and we’ll ask David to take that on, about what did the GRIFFIN data tell us about consolidation, because that’s an important question.

Individualized Induction Therapy for NDMM

: Saad, there was a nice abstract from Dickran Kazandjian, MD. The work is by Ola Landgren, MD, PhD, and Dickran from the NIH [National Institutes of Health] group looking at an aggressive approach for KRd [carfilzomib, lenalidomide, dexamethasone]. Nonetheless, the data were quite compelling. What did you think?

: The key elements that I took away from that experience, it was a good data set. I believe there were 52 patients treated with this approach. Initially, I think Ola had started this trial when he was still at the NIH and carried it over to Memorial Sloan Kettering Cancer Center. They have over 7 years of follow-up now. They treated patients with 8 cycles of KRd [carfilzomib, lenalidomide, dexamethasone], specifically the 20/36 mg dose of the K [carfilzomib] given twice weekly, and then continued patients on LEN [lenalidomide] maintenance. He showed that at that 7-plus year follow-up, only around 20% of the patients had progressed to active disease. I believe it was 6 or 7 patients who progressed within the first 5 years, demonstrating that you can get good, deep responses in these patients. There was a high percentage of MRD [minimal residual disease]-negative CRs [complete responses] on this study.

Regarding the age range, there were younger patients on that study as well as older patients in their early 80s. I think this approach obviously needs to be validated compared to the standard of care where we are right now, but it’s compelling. If you can identify those high-risk patients early, it would be a reasonable approach to offer to patients in a clinical trial setting.

: I completely agree. In fact, I follow a patient who participated in that study and she’s doing extremely well. We harvested or collected the cells, she’s on lenalidomide maintenance alone and she’s in CR. To your point, Saad, the MRD-negative rate was 70%, and what Dickran did was a cross-trial comparison with GEM-CESAR, that’s Maria-Victoria Mateos, MD, PhD’s abstract from a year ago. In that study, her MRD rate was around 56%, and in Ola and Dickran’s work, it’s 70% with all the caveats of cross-trial comparison. I think it’s a fascinating new area.

I really like the point that was made by David and suggested by Nina, that observation is key and manipulating the microenvironment makes sense. For example, I’m very comfortable offering periodic infusion of bisphosphonate if there’s bone mineral density loss or a clue that might help with the microenvironment. From a protocol point of view, which is where we tend to go, we do not tend to treat patients with smoldering multiple myeloma [SMM] outside of the protocol at this stage. We’re looking at immune strategies, be they antibody, vaccine-based, something that addresses the milieu question that David just mentioned. Saad, is that your approach at your center, Levine Cancer Institute?

: I think we must be good clinicians first, and these criteria are only serving as a guideline and they’re giving us a snapshot answer. They do not tell us what to do with our patients who were diagnosed 5 years ago, who had at that time met the 2/20/20 [International Myeloma Working Group risk stratification]criteria, but instead of treating them, we continued to observe them, and they have yet to progress to active disease. So, these criteria don’t apply to that. I think the clinical gestalt stays. However, if you see the kinetics of those numbers moving as we follow patients, then you can make a very good case about treating them early. You have data now that support it. Observation is always OK, but I think enrolling them on a clinical trial or at least discussing treating them with lenalidomide is not an unreasonable thing.

: Regarding lenalidomide use, that I think is the only caution I have because obviously there’s a price tag to that. As you know, in the pivotal trial that was led by Sagar Lonial, MD, FACP, there was a high rate of discontinuation, there was this second primary signal and so forth. Does that influence your thinking in that regard?

: It certainly does, especially as many patients with MM are Medicare-age patients, so they have that 20% co-pay that they have to give every month with lenalidomide, and that would also influence that decision-making. But you’re right, that is going to be an important part of the discussion. I know David is itching to get into this debate about early treatment, and I would welcome his thoughts and ideas here, too.

: I find it very surprising that you couch this in terms of, “This is reasonable.” Yes, we can prevent a certain percentage, but in the large randomized lenalidomide trial, we treated 80 patients with no advantage, to prevent progression of disease in 10% of patients. The reality is, we would never take a real patient with MM today and just treat them with lenalidomide. You’re using a suboptimal, extremely expensive therapy to prevent an end point that may not need to be prevented in most of those patients. Moreover, even if that end point was to evolve, we’re treating them suboptimally.

If you go back to the Memorial Sloan Kettering/NCI [National Cancer Institute] data, it’s even more complicated. Once again, they treated a lot of patients who probably didn’t need to be treated. Whether long-term KRd [carfilzomib, lenalidomide, dexamethasone] is an optimal therapy or not, you’re committing a population of patients to long-term therapy, some of whom will never need to be treated, and you’re committing them to a strategy that is today’s strategy.

We are evolving as a community incredibly quickly. We just talked about Irene Ghobrial, MD’s data. Nina is publishing constantly about very sophisticated molecular tools that are going to lead us to CAR [chimeric antigen receptor] T cells and other kinds of therapeutics that may be curative. And if there’s an advantage to treating those patients early, once we start to gain those kinds of tools, and to say, “OK, let’s treat patients who are likely to have MM early with those kinds of things,” then I find this is reasonable. But the idea that I have to treat a patient today because they might progress over the next 2 to 5 years to MM; they might also not. I think it is, I don’t want to use the word irresponsible, but I will nonetheless. Why treat patients with suboptimal therapies that are toxic and very expensive when Nina may cure them a couple years from now with treatments that we haven’t thought about today?

: I just want to make sure we’re talking about the same thing, because I thought we were talking about high-risk SMM, not active myeloma requiring treatment. No one is saying to treat patients with active MM with lenalidomide. The discussion that we’ve had is about analyzing the data, we are preventing these patients from progressing to active MM and having that discussion with your patients or put patients on clinical trials. I made that statement very clear. I’m not a Sagar surrogate, so maybe you can have this debate with him later?

But the data are the data, and we must enroll on clinical trials to see it. I didn’t say treat them…the Spanish myeloma way either. But all those questions are important questions to ask in clinical trials.

: But I think we must remember who the audience is now. I think it’s a very dangerous message to leave with the general population of oncologists, that it is a reasonable approach to take their patients with SMM and treat them. It has another pitfall that is a very important one, that when they relapse, they have never met the diagnostic criteria for MM, they’re not going to be eligible for certain kinds of clinical trials, and they may not be eligible for payment for other strategies later on because they never met the diagnostic criteria. They won’t get CAR T cells; they won’t get a lot of things.

: I think to bring this together as we move on to the next phase, it’s a perfect segue to how do we diagnose newly diagnosed disease. I think the construct of participation in clinical trials, careful observation, the use of nontoxic approaches, targeting microenvironment, and the reality to your point, Saad, the data are the data from the ECOG study. But the huge caveats that are raised are so well put by David, I think our audience can appreciate that this is an area in evolution, and as we said at the very beginning, ask 4 myeloma specialists about smoldering disease and you’ll get 5 opinions is being beautifully captured. My comment would simply be for our audience, think clinical trials and recognize high-risk SMM, I would predict in a few years, is going to be defined as active MM, and we can think of it in those terms. But there may be viable strategies that we can use much earlier in the precursor setting that may not burn any bridges later, and at the same time, generate meaningful clinical benefit, but this is an area of very active research.

I do think it is worth saying one thing about eligibility for trials, because it’s a great point David made. We’re very careful that any of our patients who participate in a SMM trial are clearly defined as that, so it doesn’t in any way prejudice them for participation later. I think that’s a very important point, and thank you, David, for raising it. Saad, thank you for taking on a challenging area so nicely.

Approaching Early Treatment of High-Risk SMM

: As we think about treatment approaches, David, what do you do, and what did you think of some of the data presented on actual therapeutic intervention?

: I would point out that I am much in the same camp as Nina. The notion that we need to make decisions about treatment the first time we meet a patient is contrary to my experiences with multiple myeloma [MM]. Certainly, understanding who is more likely to progress should drive how we monitor those patients.

However, until we have an intervention that is either with curative intent that seems to be more advantageous, such as when patients have lower burdens of disease, or we’re making an intervention that is specifically targeted at either the disease, specifically more or less likely the microenvironment of that disease, or some other host factor. I will acknowledge that the most interesting work that I’ve seen regarding this comes from your institution, Dana-Farber Cancer Institute, and that is Irene Ghobrial, MD’s work. Irene’s work has been published, and it is not just something presented at ASH [the American Society of Hematology annual meeting]. Irene’s work is very exciting because it was exhaustive evaluation that identified several variables that were host variables as much as disease-related variables that are also potentially targetable.

If early during the disease, before patients start to clearly identify themselves as, “This is just a patient with MM who we hadn’t identified yet.” Specifically, this is what the 2/20/20 [International Myeloma Working Group risk stratification model] is, to try to identify the people who genuinely have MM, who haven’t hit those markers yet. Irene’s work is exploring the biology in a much more comprehensive way. Until we have therapies that are directed at altering the milieu or very uniquely going to be effective, meaning curative, in those patients early on, I don’t see the compelling need to change our strategies. If I know a patient really has myeloma, then I’m going to treat them in the fashion I think is the best way to treat patients with myeloma. My approach is going to be different than your approach.

However, I don’t think that’s the take-home point for the community oncologist. The take-home point is you don’t need to decide about committing a patient to therapy just because you saw them for the first time.

: Patients who have MM are going to progress. If the next time you see the patient a couple of months later and the M spike has doubled, you can make that decision then. However, very rarely is something horrible going to happen in those first few months of monitoring.

: That’s an excellent point, David. I think that whole point about observation is exactly that—observation and monitoring is an integral part of risk assessment and getting that trajectory of disease is fundamental. I’m so grateful that you emphasized it, David.

Role of Therapeutic Intervention in SMM

 titled, “Multiple Myeloma Management in 2021.” My name is Dr Paul Richardson, and I am from the Dana-Farber Cancer Institute in Boston, Massachusetts. It is my pleasure to introduce to you and to welcome in this virtual discussion my colleagues, Dr Nina Shah from the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco; Dr David Siegel from the Hackensack Meridian John Theurer Cancer Center in Hackensack, New Jersey; and Dr Saad Usmani from the Atrium Health Levine Cancer Institute in Charlotte, North Carolina. Today we’ll discuss modern approaches to management of multiple myeloma [MM], and we’ll reflect on the latest data, including some very exciting new information from the ASH [American Society of Hematology] 2020 virtual meeting. Let’s get started on our first topic.

It’s my pleasure to ask Saad to lead our first segment on smoldering multiple myeloma [SMM] and newly diagnosed MM. Saad, should patients with SMM receive treatment?

:Thank you so much, Paul, for having me as part of this esteemed group for discussion. Despite the challenges from what we’ve observed in 2020, many of these important questions, such as whether SMM should be treated, the work that we were doing in our respective institutions and as a collective has been coming to the fore. This debate started when our colleague, Maria-Victoria Mateos, MD, PhD, published the initial QuiRedex trial, demonstrating that you can delay the progression to active MM by treating patients with lenalidomide and dexamethasone. Notably, even though it was a small and underpowered study, they did see an overall survival [OS] benefit.

As of last year, Sagar Lonial, MD, FACP, presented the ECOG trial, which had compared LEN [lenalidomide]-only treatment versus observation in high-risk smoldering MM patients, demonstrating a delay in progression to active MM, specifically for the high-risk SMM, even by the newer criteria. As such, the debate is certainly heating up, and we are seeing more data emerge.

The focus of the debate is, if we are going to treat smoldering myeloma patients, what is the goal? Is the goal to delay the next line of therapy or active disease? Or, are we looking for long-term remissions and potentially even curing a proportion of them? There have been several different approaches to treating SMM. Specifically, there has been an active MM approach where you’re using a triplet or quadruplet therapy with or without stem cell transplant, and then extended maintenance for 2 years, which Maria-Victoria, has reported on. Additionally, there is the C. Ola Landgren, MD, PhD, approach of treating with a 3-drug combination, utilizing KRd [carfilzomib, lenalidomide, dexamethasone] for 8 cycles, and then moving on to maintenance.

Each of these strategies is showing that you can get good responses in these patients and delay the progression to active disease. However, what we do not understand is which patients benefit from the less intensive approach versus the more intensive approach. This is where I think you must marry the disease biology with the immune status of the patient. I think we can have a very nice discussion with the group. I simply wanted to lay out the entire debate and discussion considering everything that’s been going on in the field.

:I think we’ve all become very comfortable with the IMWG [International Myeloma Working Group] 2/20/20 risk stratification model and the IMWG position that Maria-Victoria has led with a number of investigators, in that it simplifies things and it helps us think very rationally for patients at the bedside about what we can offer in terms of “the patient with high-risk SMM.” I would love comments from Nina. How do you approach “a high-risk patient,” what do you consider them to be, and how do you think about them in terms of follow-up?

:Thank you so much for having me. I’m so sad that we couldn’t all be together in person, but this is almost the next best thing, and I really enjoy getting together with all of you to talk about what we’ve learned. SMM is ironically one of the most controversial topics in MM because it seems like you get 4 myeloma doctors and you get 4 different opinions.

One of the things I think is so hard about SMM is regarding all the trials, similar to the rest of MM, they start out one way, and then our field goes beyond that very quickly before results are apparent. One of the places that’s been true for me is even in defining high-risk SMM. I think this 2/20/20 model is easy and is something you can do right away, the first time you meet the patient, and you don’t have to go through all the data, it’s very easy to go through these things that they have. When I find somebody who has 2 or 3 of these characteristics, I do talk to them about their likelihood of progressing to MM.

I’m still in the camp that I don’t treat these people yet, but I do change my follow-up. I traditionally, in general with SMM, particularly if they have 2 or 3 of these criteria of the 2/20/20, I would elect for annual imaging and annual bone marrow as these are things that I might miss on a simple laboratory examination. I think it’s important to catch these things early because that’s what we want to do for these people that know they have something going on, but maybe don’t want to have chemotherapy right away.

As Saad said, there are so many factors that go into that, because if a patient is older and never wants to have chemotherapy again, then this is a good option for them to just watch and wait. Other patients who are younger may want to be as aggressive as possible, which is a different discussion.

:I completely agree, Nina. For our audience, the 2 grams per dL is the “2.” Traditionally, we say 2/20/20. The second figure “20” is the free light-chain ratio greater than 20, and the degree of plasmacytosis is the last piece, at 20%. Regarding the ASH meeting, Saad, what did you make of the paper where they examined whole-genome sequencing? Overall, might whole-genome sequencing data inform clinical identification of patients with progressive versus indolent myeloma based on that data?

:I thought that was a very interesting paper. If I remember correctly, the study consisted of a smaller number or patients. I recall there were around 30 patients in that group. I believe it was close to 150X depth of the whole-genome sequencing done in the groups, where they identified indolent versus early progressive and focusing in on disease biology. I think they came up with 2 targetable gene mutations; one was 

. While I do not recall the other, they did identify distinct clinical behaviors and were able to link them to specific gene mutations that have not been previously reported.

:I couldn’t agree more. Your memory, Saad, is excellent. It’s the 

which was detectable and characterized by a higher ratio, and that was associated with greater mutational activity. Essentially, in the 

-translocated patients, this is something that’s particularly important. Obviously, they were then able to identify features from the whole-genome sequencing that might point to a more indolent picture and so take us to the next step. I think you’re right, it symbolizes a more tailored approach.

Nina Shah, MD, UCSF Helen Diller Family Comprehensive Cancer Center

Articles

Using PI-based Combinations in RRMM

Role of IMiD-based Strategies for RRMM

Approaching Treatment of RRMM

Future of MRD Assessment in NDMM

ASH Updates on Transplant in NDMM

Individualized Induction Therapy for NDMM

Approaching Early Treatment of High-Risk SMM

Role of Therapeutic Intervention in SMM

Overview of Smoldering Multiple Myeloma

Nina Shah, MD, UCSF Helen Diller Family Comprehensive Cancer Center

Articles

Using PI-based Combinations in RRMM

Role of IMiD-based Strategies for RRMM

Approaching Treatment of RRMM

Future of MRD Assessment in NDMM

ASH Updates on Transplant in NDMM

Individualized Induction Therapy for NDMM

Approaching Early Treatment of High-Risk SMM

Role of Therapeutic Intervention in SMM

Overview of Smoldering Multiple Myeloma

Role of IMiD-based Strategies for RRMM