 What do you see in the future? What do you see as a path to improved outcomes for patients with relapsed/refractory myeloma? I think that’s where we are now.

I do want to briefly mention 2 other therapeutics or drugs that I think are going forward. One is selinexor. As we know, selinexor is approved for use, and there were a couple of presentations at American Society of Clinical Oncology (ASCO) virtually. There was the BOSTON trial. It was randomized to selinexor/Velcade/dexamethasone (DEX) versus Velcade/DEX, and an improvement triplet over doublet. There was also a combination of selinexor with daratumumab and a combination of selinexor with carfilzomib. When they’re combined with another drug, it’s given weekly, and I think it’s better tolerated. I’m looking forward to seeing weekly dosing of selinexor with some of these other drugs, to hopefully improve the tolerability of that.

 Yes, and you do give a lot of premedications with the selinexor. We have a cocktail that we give patients.

 Yes. Then there’s the new cereblon E3 ligase modulators (CELMoDs), the CC-220 and CC-940. I think the CC-220 is iberdomide. Dr Sagar Lonial presented thatat the American Society of Hematology (ASH), showing upwards of a 30% response rate in pomalidomide (POM) failures. Paul Richardson presented data on the most recent CELMoD, what he called CC-940, which had a response rate that was over 50%, which is amazing.He showed some impressive results in the extra-medullary disease. A person had a big liver lesion that disappeared on this combination with dexamethasone.

Those drugs have to move forward, maybe together with some of these immunotherapies, together with bispecifics, together with ADCs (antibody-drug conjugates), maybe with a post-chimeric antigen receptor (CAR) maintenance. The drugs that we have now, 5 years from now… I don’t think we’re going to be using most of them. We’re going to have these novel drugs. That’s what I think we’re moving forward to.

 The CELMoDs—the iberdomide, CC-220—are very tolerable in the phase 1/2 trials. Alliance, now at Cancer Therapy Evaluation Program (CTEP), is looking at combinations in 2 or more prior lines of therapy. It’s really in patients with daratumumab (DARA); it was started also in DARA refractory and then the POM refractory. Which drug has a 30% response rate in DARA refractory patients? It’s nice to have these drugs in clinical trial. Again, after you’ve used all these drugs or in patients who have continued relapse and refractory, for the patients who relapse within 2 years… In all of these treatments, I’m going to put a plug in for allotransplant. These patients are going to relapse, and allotransplant is the only chance for a possible cure in myeloma. Twenty percent of patients may have a cure, but you have to use it early.

A meta-analysis was just published, looking at a 1083 patients that did autologous transplant (auto)-allotransplant (allo) versus auto-auto tandem transplant, and showed that after a median follow-up of 118.5 months, the median overall survival was 98.3 months for the auto-allo compared with 78 patients. The good thing about the allo, if they relapse and are given reinduction and retreatment, myeloma versus disease effect takes over, so the graft-versus-host disease effect also takes over. It showed that patients who relapse after auto-auto or auto-allo did better in terms of progression-free survival (PFS) post-relapse. It was 62.3 months compared with 41.4 months in the tandem transplant.

There’s a clinical trial through the BMT CTN 1302 that closed early because it was a slow accrual, and I think the reason for that is it was initially held off, closed for some toxicity, and then it reopened, which slowed the accrual. After it reopened, we had like 5 patients on that trial. The toxicity was very minimal. We’ve had a few patients who relapsed, and they go back into a complete response (CR) after reinduction of treatment. Allo is an option out there for the young patients, young and … patients who relapse early.

 Our portfolio of drugs and what we have coming down the pipeline is just tremendous for all of us. We need to devise strategies, a multiprong approach for the newly diagnosed patient, which can really induce a rapid and deep remission; hopefully, it will allow us to step back from the continuous therapy model and be able to take patients off therapy. Maybe there will be a percentage of patients, an increased number of patients, where the myeloma will never come back.

One of our goals should be not only to get to a limited timeframe of therapy—hit people hard and fast for a year, 18 months, or 24 months, and then give them a break—but also to try to get rid of some of our most toxic therapies. I do think that transplant, whether it’s auto or allo, are our most toxic for sure. If we could get rid of those as part of the envelope for frontline therapy and give people longer quality of life, potentially cure 20% or a third or more, that would be the holy grail. That’s what I think we should be going forward with.

 I’m excited about the way things are going in myeloma and to be a part of it. I try to enroll patients in clinical trials, even at first relapse, because that’s the only way we’re going to have more drugs and approve more drugs. Clinical trials are number one for anything. If there aren’t any, then you choose from the others that are available. It’s been a great discussion and I look forward to working with you in the future, Dr Martin. Thank you.

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The Future of Multiple Myeloma

 Is there anything else that has your interest in the relapse setting?

The toxicities of isatuximab (ISA) were really manageable. I agree with the NCCN (National Comprehensive Cancer Network) guideline, so we put isatuximab as category 1 because it was a larger study, well conducted, and did not have much toxicity either, apart from the pulmonary. No prophylactic regimen was given on that study. I know they had about 20% to 28% of pneumonia and bronchitis and upper respiratory infection. Do you give prophylactic treatment? That’s something that could be considered when we give patients this treatment. Otherwise, it was well tolerated.

The other drug, you know, targeted therapy, is chimeric antigen receptor T cells (CAR T). That’s the area of great research and discussion. In terms of relapse, I think that’s where we are heading to. Yesterday, the FDA gave unanimous approval to proceed for discussion regarding FDA approval for the antibody-drug conjugate (ADC), belantamab, as a single agent. That’s great.

The study that was published was a single agent, but the DREAMM-2 study looked at belantamab with bortezomib/dexamethasone, or belantamab with lenalidomide/dexamethasone. At ASCO (American Society of Clinical Oncology annual meeting), belantamab/Velcade/DEX (dexamethasone) was presented with 59 patients. On that, the overall response rate was 78% with a very good partial response (VGPR) of more than 50%. Clinical benefit—when you’ve had multiple relapses, you always look at stable or minimal response (MR) clinical benefit—was 83% for the dose of 2.5 mg/kg. It’s well tolerated and given every 3 weeks. The eye problems we saw in the DREAMM-2 study are not a big issue at all. It’s manageable by them seeing an ophthalmologist first or during, and some patients just use eye drops. I’m excited about belantamab.

Of course, the CARTITUDE and karMMa studies showed a 97% response or higher. The cytopenias in that were very high, 97%, so we are really scratching the surface of the CAR T. In CARTITUDE … to gratitude, right, patients who are having 3 or more prior lines. These are patients who have had up to 18 prior lines of therapy seeing some clinical benefit in those studies. The quality of life was also assessed, which was better with the studies.

Last, but not least, was the bispecifics antibody, teclistamab, that was also presented at ASCO. There were 66 patients, and it showed up to a 78% response at the highest dose of 270 mcg/kg. The cytokine release syndrome and newer toxicities are usually things that need to be discussed and managed with the patient. I’m curious to hear your thoughts about these new drugs.

 You beautifully described those 3 classes, the ADC the CARs, and the bispecifics that are now targeting B-cell maturation antigens (BCMA). There are going to be other targets and similar types of novel immunotherapies. We haven’t had a big problem with the ocular toxicity with belantamab mafodotin. We have a good relationship with our ophthalmologist. It hasn’t been problematic in terms of dosing. I’m very curious because they have a randomized trial where they are going to go head-to-head against a variety of different agents, including daratumumab (DARA)—belantamab/bortezomib (VEL)/DEX versus DARA/VEL/DEX. It will be interesting to see that. Then there’s lenalidomide, bortezomib, and dexamethasone (RVd) versus belantamab/RVd. I’m curious to see the results of that one, too. I do think we’ll have to figure out the dosing.

In terms of the CARs, we’re all excited, but at the end of the day, it’s not lymphoma where the CARs last for a tremendously long time, maybe forever.

 At some point, in myeloma, it seems like everybody is going to relapse, so I think the take-home point, in terms of the CARs for me, is that it’s not going to be; we’re hoping for a one-time dose of CARs, and then they don’t need any therapy. We have to figure out what maintenance to give afterwards, and also, if and when they relapse, what to give them as salvage therapy. I gave the review of teclistamab at ASCO virtual, and I was really impressed by the data. We have 3 bispecific T-cell engagers that have shown more than 50% for response rates. We have AMG 420, we have the BMS (Bristol Myers Squibb) CC-93269, and then we have teclistamab.

With the BMS therapeutic, and also with teclistamab, some of these patients are out more than a year in continuous remission, and they’re looking durable and continue to get therapy. There’s a little bit less cytokine release syndrome (CRS) with CARs; 80% or more have CRS, with a bi at 50% to 60% and less neurotoxicity. It could be that a monthly dose of a bispecific might be the best therapeutic out there. Single agent, no steroid… For me it’s amazing, and then at the end of the day, can’t we all get along? Maybe we use them all together. Maybe they get an ADC as front-line therapy and then a CAR as consolidation instead of a transplant, with a bi as maintenance after that.

 In fact, 1 of the things that the BMT CTN (Blood and Marrow Transplant Clinical Trials Network) is looking at is how do we incorporate CAR T? Just like in the lymphomas, there was a randomized trial looking at CAR T versus autologous transplant. That study was completed, and we’ll see what the results are. Can we incorporate CAR T in high risk as a consolidation after autologous transplant, or a patient post-autologous on maintenance and haven’t reached either partial response (PR) or less? Can they benefit from an addition of CAR T? It will be interesting to see. My only thing with the CAR T, even with the lymphoma, is the cytopenias. These patients can have cytopenias for up to 6 months and need transfusion. Again, it’s still early in the game. I’m sure they will be making changes in the constructs and making them better, less cytotoxic. It’s exciting that we have so many avenues and different things to look at for myeloma patients, improving their survival.

Targeted Treatment Options in Multiple Myeloma

 Agreed. Because we have a lot of tools at our disposal, it makes it better for patients. I think early relapse—1 to 3 prior lines of therapy—that’s a scenario where we still want to be aggressive. I will say at ASH (American Society of Hematology), Dr Saad Usmani presented the CANDOR study, which was daratumumab with carfilzomib and dexamethasone (DEX) versus carfilzomib and DEX, and that showed an improvement in progression-free survival (PFS). It was not reached after about 20 months of follow-up in the daratumumab (DARA)/carfilzomib and dexamethasone (Kd) arm versus 16 months in the Kd arm, with a hazard ratio of about 0.63. There were better response rates in the triple versus doublet. Just recently, Dr Philippe Moreau presented the data from the IKEMA study at the European Hematology Association virtual meetings. The IKEMA study was using isatuximab (ISA) again with carfilzomib and DEX, and the carfilzomib was given at 56 mg/m2 twice weekly. It showed an unreached PFS in the triplet arm versus 18 or 19 months in the Kd arm after over 20 months of follow-up. That hazard ratio was 0.53, which was a good hazard ratio. These data are statistically improved, and I like the regimen of ISA/Kd or DARA/Kd in the relapse setting.

They also combined ISA with pomalidomide (POM) in the same 1 to 3 prior lines of therapy; the PFS was 11.5 months versus 6.5 months in the POM/DEX. That’s a good regimen; it’s very well tolerated.

In terms of the CD38 antibodies, where does it fit for you with your therapy now, and what do you think in a year from now? Will it be front-line for everybody, and then you’ll banter between one or the other? What do you think?

 Daratumumab is already in the upfront—DARA/bortezomib, lenalidomide, and dexamethasone (VRd); DARA/lenalidomide and dexamethasone (Rd)—for the transplant-eligible and transplant-ineligible, respectively. I did like the study with the ISA/POM/DEX. In fact, that’s an area isatuximab has been studied in upfront with Kd and even carfilzomib, lenalidomide, and dexamethasone (KRd), the 4-drug study. I think that’s been done in Europe. Given the robust minimal residual disease (MRD) negativity and the dip in the response, with very good partial response (VGPR) or better with CD38, it’s probably going to be a standard in terms of front-line therapy.

What we’re going to be faced with is once you use those as induction and then transplant, or no transplant but induction, and then maintenance, how long do you use CD38 as maintenance in addition to lenalidomide? It’s only 2 years from the study, but we don’t know. From the trials for the non–transplant-eligible, DARA maintenance with lenalidomide (LEN) has been used continuously; I still have like 3 patients on that study with the monthly maintenance and lenalidomide. Even though it’s completed and published, my patients are still on it and getting DARA and lenalidomide monthly.

Does it apply to patients who undergo transplant? Can DARA be given continuously with LEN? The question, once those patients progress—hopefully after median of 7 months or later—is what do you give them when they’ve been exposed to CD38? That’s the challenge: Will a second class of CD38, like isatuximab, be able to overcome the refraction of daratumumab once patients progress? I know there are studies looking at that.

Patients exposed to DARA were excluded in the study that was published with ISA/POM/DEX. I think it was only 1 patient that was exposed. Refraction to daratumumab were excluded, and patients who were exposed to pomalidomide were also excluded in that study. It will be nice to see how DARA fits into the DARA refractory and how ISA fits into the DARA refractory line. I’m sure as time goes, they’re probably going to compete with each other as first-line, in addition to the IMiD (immunomodulatory imide drugs) and proteasome inhibitor. What do you see?

 findings. Isatuximab was able to do apoptosis without cross-linking, and that’s why it was selected. It was the best antibody that could induce apoptosis. I’m excited that it will be combined with carfilzomib because I think there’s synergy between the 2. We know from the ICARIA study that there’s also synergy with pomalidomide, for sure. Daratumumab was selected based on its ability to induce complement-dependent cytotoxicity (CDC). It’s a little different, and it doesn’t do apoptosis without cross-linking.

I do think there is a possibility that you can use 1 for front-line and another in the relapse setting. I do think that using 1 followed by the other within 3 months is probably not going to be successful. If you give a 6-month break and choose a different partner, I think that’s fine to go back to a CD38 antibody-based therapeutic. The nice thing with isatuximab, in terms of giving it, is the infusion-associated reaction rate is about 30% to 50%, and it’s typically grade 1/2. They don’t get a lot of pulmonary symptoms, which is great. We use acetaminophen and intravenous (IV) dexamethasone, either 20 or 40 mg or whatever the regimen calls for, an H1 and H2 blocker, and give that for at least the first 3 or 4 doses. On the package insert for ISA, on the third dose, you can give it over 75 minutes IV, which is actually pretty convenient. At 10 mg/kg, it’s a pretty effective dose. We’re just getting that up and running here at UCSF (University of California San Francisco); although we’ve used a ton of it in the research setting, we’re getting the standard-of-care drug up and going.

Trials in Relapsed/Refractory Multiple Myeloma

 Let’s talk about relapsed and refractory myeloma. When somebody has evidence of relapse, what do you look at to try to help you decide what treatment to give?

 The cytogenetics. I try to do a bone marrow biopsy. How long from the initial transplant, or diagnosis if they were transplant-ineligible, did they relapse? Time from initial diagnosis or time from transplant to relapse? Are they now on maintenance? Some patients may say, “I haven’t been on maintenance treatment.” Were they on maintenance, and what was the maintenance at the time of relapse? Did the cytogenetics change? Were they standard risk and then they become high risk? Of course, there are comorbidities; how well are they going to tolerate treatment, a 3-drug versus a 2-drug treatment based on their comorbidities? Those are some of the things I look at in terms of reusing initial induction treatment. If a patient had a good response, VGPR (very good partial response), CR (complete response), and had stayed on for 4 or 5 years and has been disease-free for 3 or more years, I can safely use the initial induction treatment. Will they be eligible for a second transplant? If they’ve gone 3 or more years from their first transplant, there are data out there for second autologous transplant if they have cells and are able to collect cells. Always think of a clinical trial for patients who are high risk and patients who relapse within a year from their transplant or even 2 years. Those are considered super high risk. I am a big fan of allotransplant. Those are things I also put in my equation. Are they eligible for an allotransplant? How about you?

 We have so many agents to choose from. We have the 3 major classes: we have the proteasome inhibitors (PI), the immunomodulatory drugs, and now the monoclonal antibodies. Typically, it is a ping-pong approach between those 3 classes of drugs. Which ones are you going to compare? I agree, refractoriness to an agent is the important thing in my mind when we’re starting off for the first therapy after their initial induction. A lot of our patients are on continuous lenalidomide. I will not bump up the dose of lenalidomide and add another agent. That is not a great regimen. I switch at that point. Typically, it’s a class switch. If they’re lenalidomide refractory, I either go to the next-generation—IMiD (immunomodulatory imide drug), such as pomalidomide—and typically add something to that. There are good combinations. Daratumumab/pomalidomide is one of my favorite ones, but sometimes I’ll also choose carfilzomib or pomalidomide. For whatever reason, if they’ve had toxicity to the IMiD and they’re lenalidomide refractory, I might switch completely and just give a PI plus daratumumab or a monoclonal antibody, even bortezomib if they haven’t had it for a while plus daratumumab. There are more recent data with using carfilzomib with the CD38 antibodies; some of those studies are quite convincing, that combination is really good in the lenalidomide refractory population. How about you?

 How did this patient relapse? Patients can have what they call biochemical progression where they’re totally asymptomatic. You’re looking at the numbers, and the time for progression is when the monoclonal protein is 500 above the nadir, or their light chains are at least 100 points above the nadir in terms of the units—mg per L or 10 mg per dL above their nadir. I’ve had patients who, just by a chemical progression, are totally asymptomatic and on lenalidomide maintenance, 5 mg. I increase the lenalidomide and add dexamethasone; I’ve had patients 2 years on that regimen without any progression. It all depends on the nature and symptom of the progression. If they’re not refractory to lenalidomide, I would do it.

Again, the timing from their initial treatment, VRd/DARA (bortezomib, lenalidomide, dexamethasone plus daratumumab) base, or DARA (dexamethasone) base is actually my most second-line choice, either DRd (daratumumab, lenalidomide, dexamethasone), DARA/POM/D (daratumumab, pomalidomide, dexamethasone). Some patients like all oral drugs, so IRd (ixazomib, lenalidomide, dexamethasone) is a good option for a patient who doesn’t want any IV and/or just likes the oral. If they’re refractory to lenalidomide, then KRd (carfilzomib, lenalidomide, dexamethasone) would be good. Of course, the daratumumab/Velcade, daratumumab/pomalidomide, carfilzomib/pomalidomide, elotuzumab/pomalidomide, CyBorD, daratumumab/carfilzomib/dexamethasone, isatuximab/pomalidomide/dexamethasone were approved for both PI and the IMiD refractory setting. It could be either second-line or third-line prior regimen.

As you go down the road, you have the panobinostat, Velcade/dexamethasone, selinexor, and VD PACE for the younger patient with really aggressive disease that you want to cytoreduce right away. Those are other options. There are so many options you can switch back and forth with. If we’ve used so many lines of therapy and they’ve progressed on 3 drugs, I can just remove 1 drug and add a different drug to the regimen. Say if they’re on carfilzomib/POM/DEX, I will just remove the carfilzomib and add daratumumab because POM is more tolerable, so we’ve done that. Again, it’s all patient-directed and depends on the tolerability by patient.

Treatment Options in Relapsed/Refractory Multiple Myeloma

 What do you think about transplant-ineligible patients?

 There are so many treatment options. Again, a combination of 3 drugs is always better than 2 drugs. That has been shown in several trials. There are some patients who may not initially tolerate the 3 drugs, so you start them on 2: RVd (lenalidomide, bortezomib, dexamethasone) again, or RVd-lite with the weekly Velcade that has been shown; and you had mentioned earlier with the RVd-Lite, given weekly with Velcade for 3 weeks and 1 week off and still the dose of Revlimid. The MAIA study (NCT04307667) with DRd (daratumumab, lenalidomide, dexamethasone) is a blockbuster for me. In fact, I’m switching between RVd and DRd. Those are such good outcomes. That study that compared DRd was also a large study, more than 360 patients; the median follow-up was 28 months and showed that at 30 months, 70.6% of patients in the daratumumab arm were disease-free versus 55.6%. The CR (complete response) was also high in the daratumumab arm, 47.6%, versus 20%.

Then the DARA VMP (daratumumab plus bortezomib, melphalan, prednisone) was also published as the European study, where they did VMP (bortezomib, melphalan, prednisone) as the backbone versus DARA VMP. That also had about 350 patients in each, with a median follow-up of 40 months that showed the median progression-free survival for DARA VMP was 36.4 months compared with VMP, which was 19.3 months. All of those are good options.

RVd and DRd are really my first go-to, based on the trials. Again, in patients who have renal insufficiency where lenalidomide initially may not be an option—also, lenalidomide cannot be given inpatient unless you write the script—it takes a week. For patients who really need treatment right away, CyBorD—Cytoxan, bortezomib, dexamethasone—are good agents for patients with acute renal failure. Cytoxan/bortezomib is a great agent. KRd (carfilzomib, lenalidomide, dexamethasone) is another option, and carfilzomib/Cytoxan/dexamethasone. Those are other good options. What’s your favorite?

 I completely agree. I use CyBorD or VCd (bortezomib, cyclophosphamide, dexamethasone) for the people who have renal insufficiency, but most everybody else gets RVd. It’s a triplet, like you said. I’m starting to use more DRd as induction. It’s extremely well tolerated, so we’ll see how that evolves. The last thing I’ll say about transplant ineligibility is maintenance therapy. I think we’ve shown in multiple settings, in multiple studies—including the first study, and Dr Polombo did a randomized study of no maintenance versus maintenance 10 years ago or more using lenalidomide as maintenance—that continuous therapy always wins out. I usually give people somewhere between 8 and 12 cycles of induction therapy, and then I switch them to maintenance.

The same thing with transplant ineligibility, with the guidelines in my mind, is that most people get lenalidomide unless they’re not tolerating it, and then I go to bortezomib every other week. Give them bortezomib every other week and watch them for neuropathy. That goes well.

 That’s another area of contention: How long is maintenance? The Europeans do 1 year, maybe because of the medical insurance that they have. I did a debate at NCCN (National Comprehensive Cancer Network) last year in September, and they gave me the role of fixed duration of maintenance versus continuation, even though I do continuation of maintenance. That’s a debate area: how long should maintenance be? It’s really all over the place. The BMT CTN 1702 (NCT03904134) was the 3-arm study that looked at single autologous transplant followed by maintenance as the standard versus tandem autologous-autologous transplant followed by maintenance, or autologous transplant with consolidation VRd (bortezomib, lenalidomide, dexamethasone), followed by maintenance. The initial length of maintenance therapy was 3 years; I’m proud to say that my patient was the first patient on this study, and he’s doing well even 10 years out now, still on maintenance lenalidomide. After 3 years, we decided to do the long-term follow-up and give patients the option to either continue maintenance versus stopping. Some patients decided to stop.

At ASCO (American Society of Clinical Oncology annual meeting) this year, they presented the long-term follow-up of BMT CTN 1702, and it showed that patients who continued beyond 3 years had an improved PFS (progression-free survival) compared with those who stopped. They were in remission or the disease was stable, VGPR (very good partial response), or PR (partial response). When they stopped, the disease progressed earlier than those who continued maintenance. That’s the first study that has shown that, beyond 3 years, there is a benefit for lenalidomide maintenance. Patients, too, they read and see this. I’ve had patients who say, “I want to continue. I’m doing very well on it. I don’t want to stop.” You talk to them about the risk of second primary malignancies, which is about 7% to 8% compared with 4% in the placebo group, but with a 67% increased benefit, patients say, “Look, I’m going to continue and take my chances.”

Options for Transplant Ineligible Patients in Multiple Myeloma

 What are your favorite maintenance strategies?

 Lenalidomide is the most studied, of course—the IFM (NCT01936532), the CALGB-100104 (NCT00114101), the GIMEMA (NCT01553357) studies. There was a meta-analysis published in 2017 that showed an improvement in PFS (progression-free survival) overall with lenalidomide maintenance, 53 months compared with 23 months for placebo. This was a median follow-up of 80 months. It’s amazing. The overall survival has not yet been reached for lenalidomide; it was 86 months for the observation. Patients with high risk were also shown to benefit from lenalidomide, but on that study, many patients did not have cytogenetic data. On the other hand, the study by Jackson, the UK study, had 1187 patients that they randomized to lenalidomide versus 834 to observation. The follow-up was a little shorter, 31 months, but the PFS was 39 months for lenalidomide maintenance compared with 20, and all patients in that group benefited from the high risk. In the transplant arm, the PFS was 57 months versus 30 months for observation compared with maintenance. It goes along with CALGB trial, 53 to 57 months.

For patients who were not transplant-eligible, the median PFS was 26 months compared with 11 months. That goes along with the previous trial that was done by the Italian group who looked at MPR (melphalan, prednisone, lenalidomide), followed by lenalidomide versus maintenance that showed a PFS of 30 months for the maintenance compared with 14 months. In all of these, the maintenance was until disease progression. In the UK study, it showed patients benefited even if they were high risk or regardless of stage, cytogenetic risk or age, or even CR (complete response) status. Bortezomib is another one. Patients with high risk will benefit from bortezomib, so I categorize. If the patient is standard risk, add lenalidomide alone; if a patient is high risk, I still like lenalidomide, but I will probably add bortezomib.

With these patients, you use bortezomib initially, and they have peripheral neuropathy; even though you’re giving it every 2 weeks as the standard maintenance, they can still have increased neuropathy. Adding that proteasome inhibitor to the high-risk patients has been shown to actually improve PFS more so, even overall survival. The HOVON trial (NCT01208766) by Sonneveld in 2012 showed there was an improvement in PFS from 13 months to 30 months and the overall survival from 21 months to 54 months. That trial, though, gave vincristine/Adriamycin to access the induction therapy. With most of these patients you talk to, it’s hard to tell, but I do those.

Ninlaro (ixazomib) was an option. I can combine that with lenalidomide. I don’t know where Ninlaro fits in your category in terms of doing it as maintenance, but the IRD study (NCT02253316) by the MMRC (Multiple Myeloma Research Consortium) showed that when they compared lenalidomide versus Ninlaro as maintenance, the interim analysis showed there was slightly more relapse in the Ninlaro arm than Revlimid (lenalidomide). Patients who were on the Ninlaro arm were informed and given the option to move to the lenalidomide arm.

 We were part of that trial, too, here at UCSF (University of California, San Francisco), and it wasn’t a statistically powered study that compared lenalidomide versus ixazomib. The statistics showed that ixazomib wasn’t going to be able to beat lenalidomide. That’s why we, as a group, said, “Alright, maybe everybody should just get lenalidomide since it’s the tried-and-true.” I totally agree with you; what we would use for standard risk is lenalidomide maintenance, 10 mg daily to start off, and then we try to increase it to 15 if the patient can tolerate it. You have to adjust the dose often over time.

I did like Dr Nooka’s study from Emory (University), even though it was a cohort study, where they looked at their high-risk patients and gave them RVd (lenalidomide, bortezomib, dexamethasone) for 3 years post-transplant. Those high-risk patients did quite well with a median PFS of over 30 months, better than what we expected. I do use RVd in the high-risk patients.

There are a couple of studies that are doing lenalidomide versus lenalidomide and daratumumab as maintenance, so that will be interesting. One is the FORTE trial (NCT02203643), which used KRd (carfilzomib, lenalidomide, dexamethasone) as induction. Some patients got a transplant, and some didn’t, but the maintenance is randomized of either lenalidomide alone or carfilzomib and lenalidomide for maintenance. There are some high-risk patients in that study, too, without dexamethasone, so that will be interesting.

Maintenance Therapy in Multiple Myeloma

 Yes, those were amazing. Now that we have all these good induction treatments, what is the best time for transplant? When do you do transplant? What is the optimal timing for transplant, early or later transplant? These are questions that we are still looking at. Only 1 study so far has published, the IFM study (NCT00430365) by Attal. This was a study that was going on in conjunction with the US study, the DETERMINATION trial (NCT01208662), where patients were induced with the 3-drug regimen, VRd (bortezomib, lenalidomide, dexamethasone), for about 4 cycles and then underwent Cytoxan mobilization with stem cells collected. Patients were randomized to transplant, followed by lenalidomide maintenance or continuation of VRd for a total of 8 cycles, and then maintenance. The difference between the 2 is that the IFM only did maintenance with lenalidomide for 1 year, whereas the US study is maintenance until disease progression.

Of course, there are over 300 patients in each arm. The French enrolled the 700 patients in 2 years. These Europeans enrolled so many patients in a very short period of time, and it took the United States about 5 to 6 years to finish enrollment. The goal was to publish both at the same time, but such a gap difference in time meant that the French published theirs in 2015. What it showed was that doing transplant early on, within 12 months from diagnosis, was better in terms of the progression-free survival. The median PFS (progression-free survival) was about 45 months compared with 33 months for patients who did not have transplant. The 3-year overall survival is about the same, about 80%. It’s still a short period of time to follow those patients. I’m sure they will be doing a long-term follow-up shortly.

The DETERMINATION study was completed almost 2 years ago, and we still haven’t reached an end point yet in terms of PFS. I am assuming that because the lenalidomide maintenance made such a huge difference, we may not see any difference between the 2. As it stands, early transplant is the way to go. Until the DETERMINATION trial comes through, or other trials that indefinitely incorporate maintenance, early transplant is preferable rather than delayed, except for patients who are not transplant-eligible. Anything to add to that?

 No. I have a question for you because I totally agree that early transplant is the way to go. The data all point to that. The 1 caveat that gets us in trouble… Because we follow MRD (minimal residual disease) all the time after induction, if I have a 70-year-old who is MRD-negative after 4 cycles of RVd (lenalidomide, bortezomib, dexamethasone), they ask me if they need a transplant. You can’t detect any protein in the blood or the urine, and there’s less than a million cells in the marrow. What do you do in that scenario? Would you take that person to transplant, or do you give them a delayed transplant option?

 Still, the data is not completely there yet. I don’t think there are any data looking at MRD negativity and going to transplant. I know MRD is being investigated the most with how long we should do maintenance. The SWOG 1803 trial (NCT04071457) is going to try to answer that. This is a study that’s going to go on for maybe 7 or 8 years, with over 1,000 or 1,200 patients who are being given maintenance post-transplant, to be randomized to daratumumab/lenalidomide versus lenalidomide. Daratumumab will be for 2 years; based on MRD negativity for at least 2 years, they will determine if lenalidomide will be continued versus observation. For now, MRD is something that we use to put in our analysis and say this patient is, but we don’t really know how to manage these patients. If they’re MRD-negative, do we give a transplant or do it later? I’m sure we’re going to be doing those studies. Also, how long should we do maintenance if patients are MRD-negative? The ALLIANCE trial (NCT03720041) is proposing a study on that, and it will be interesting to see.

The Role of Transplant in Multiple Myeloma

There are a couple of other interesting presentations at the virtual ASCO [the American Society of Clinical Oncology annual meeting]. I’m going to go back to ASH [the American Society of Hematology annual meeting] of 2019 and talk a little bit about the GRIFFIN study. Peter Voorhees, MD, presented the GRIFFIN study at ASH 2019, and we’ve all been waiting for this.

Yes, it discusses adding daratumumab to VRd [bortezomib, lenalidomide, dexamethasone]. It was a phase 2 randomized study, just over 200 patients involved. Half the patients were randomized to VRd, 4 cycles, a single autologous transplant, VRd, 2 cycles, consolidation, and then REV [Revlimid] maintenance. The other half had DARA [daratumumab] added in, so it was DARA/VRd for 4 cycles, single autologous transplant, DARA/VRd for 2 cycles, and then DARA/R [Revlimid] as maintenance-based therapy where the DARA is given. Initially it was given every 8 weeks, and then they changed it so a patient could get it every 4 weeks or every 8 weeks, so we’ll see if there’s a difference there. They gave it for 2 years. And then after that patients could continue on lenalidomide maintenance. 

The primary end point of the study was stringent complete remission. At ASH, the presentation was to show that the study met its primary end point where the stringent complete remission basically was 42.4% in the DARA/VRd arm versus 32% in the VRd arm. And then the overall response rate post-consolidation was actually 99% in the DARA/VRd. We put patients on the trial at UCSF [University of California, San Francisco]. We had about 10 patients on the trial, and we were all very impressed with the rapid reduction of the tumor burden from DARA/VRd as induction, and then their post-transplant had good, deep responses.

The 24 month PFS [progression-free survival] was 96% in DARA/VRd and it was about 90% in VRd. There’s no statistical difference in that just yet. The thought is that these patients are going to be in remission. The PFS may end up being 6 or 7 years. That is an amazing thing, that if we put a patient on the trial today or that therapy, they’re going to be in remission for 6 to 7 years. When they come out, and we’ll talk about relapse later, when they come out of remission and go into relapse, who knows what we’re going to give them 6 or 7 years from now. It’s going to be a whole new playing field, which is really kind of fun. And there was a higher number of MRD [minimal residual disease]-negative patients in the VRd.

The other abstracts from ASH I’ll mention briefly were some DARA/KRd [carfilzomib, lenalidomide, dexamethasone] abstracts. In this one it was the weekly carfilzomib. One was from Dr. Ola Landgren, MD, PhD, who did DARA/KRd. He did a 2-cohort study. One was weekly carfilzomib and the other was twice weekly carfilzomib. Between the 2—the weekly was 56 mg/m2, the twice weekly was 36 mg/m2—they did 8 cycles of this therapy, standard lenalidomide at 25 mg and dexamethasone, 40 mg weekly. The efficacy and the safety were similar between the weekly and the twice weekly, which was quite interesting and great. There were many fewer doses, the average being 20-some doses of carfilzomib in the weekly dosing, and over 50 doses of carfilzomib. So just in convenience, it was much better if you did weekly dosing.

And the goal of the study was interesting. It was to try to induce an MRD negativity rate of over 60%. And in fact, what Ola described is in 18 patients for whom they did MRD testing, of the weekly carfilzomib at 56 mg/m2, day 1, 8, and 15, with 25 mg of LEN [lenalidomide] and 40 mg of DEX [dexamethasone], they had 83%, or 15 out of 18, achieved MRD negativity. Pretty amazing actually, quite an amazing regimen.

The other interesting trial was the MASTER trial, which was presented by Luciano Costas MD, PhD,, who also used DARA/KRd and the K [carfilzomib] was 56 mg/m2 weekly. They gave 4 cycles of induction, and then they checked MRD. Then they did a single autologous transplant, and then they checked MRD. Then they did 4 more cycles of KRd/DARA and checked MRD, and another 4 cycles of KRD/DARA. But the goal with the checking of the MRD was once patients had 2 consecutive MRD-negative results, they could come off therapy. They were able to stop therapy.

Now, he just presented the initial data showing basically after 4 cycles of DARA/KRd, the VGPR [very good partial response] or better rate was over 90%. And then after consolidation, more than 80% of patients were MRD-negative. It was a pretty potent regimen. In terms of how many were able to come off therapy and be able to stay off therapy for a long period, again, trying to give intensive therapy over a short period, we’ll have to see how that works out. I suspect he’ll present it again virtually at ASH of this year. We’ll see.

Looking at GRIFFIN Trial Data

 The ENDURANCE trial—KRd [carfilzomib, lenalidomide, dexamethasone] versus VRd [bortezomib, lenalidomide, dexamethasone]—this was a plenary session at ASCO [the American Society of Clinical Oncology annual meeting] today. These were standard-risk patients where they included the translocation 4;14 and excluded the high-risk patient, plasma cell leukemia, the other high-risk translocation 14;20, 14;16, and deletion 17p. They even excluded patients with LDH [lactate dehydrogenase] that was greater than 2 times the upper limit of normal. It was a big study, over 500 patients in each arm. This was a 2-pronged study, first to randomize either to VRd versus KRd and then afterward, randomize each group to LEN [lenalidomide] maintenance for 2 years versus until disease progression or toxicity mandates them to stop maintenance.

This one was just based on the induction regimen. The median PFS [progression-free survival] for VRd was 34.4 months and for KRd it was 34.6 months. There was no difference seen in terms of age, absence or presence of the translocation 4;14 or ISS [International Staging System] stage. The 3-year overall survival was 84% for VRd and 86% for KRd. They did see more cardiac, pulmonary, and renal toxicity with 16.1% in KRd, versus 4.6% in VRd, and there was more neuropathy in the VRd, 53.5% compared with 24.4% in KRd. The majority of that was grade 1 to 2 because treatment was given as subq [subcutaneous].

Based on those data with the cardiac and pulmonary toxicity, I think the conclusion from that trial was that VRd was the first line or mainstay. This wasn’t studied in high risk, so you can make a case with the high-risk patients, using KRd or DARA [daratumumab]/VRd as an induction regimen.

I like that study also. I agree, I think the conclusion for me in that is—and this was, as you said, so many patients, more than a thousand patients on the trial—that in the standard-risk patients, because they did exclude all the high risk, VRd and KRd, we’re splitting hairs in terms of how well patients are going to do. What did you think on the toxicity of one versus the other? What was your take-home point on the toxicity?

 The cardiac toxicity was a major concern for the KRd. The dosing was 20 mg/m2 and then 56 mg/m2. Maybe if the dose was a little lower compared to what it was initially approved for, carfilzomib, the 20 and then 27 mg/m2, maybe you would not have seen that much toxicity. That was the deal breaker for me with the cardiac and renal toxicity, 16.1% compared to 4.6% in VRd. Even in the clinic, most of the neuropathy now from bortezomib is grade 1 to 2, and those are manageable, about 45.4% out of the 53% were grade 1 to 2. VRd is my go-to for induction and then adding DARA for the high-risk patients. But I’m still open to using KRd in some cases.

I agree, and the neuropathy is probably the biggest thing, right? More patients stop on the VRd arm versus the KRd arm because of neuropathy. The trade-off of toxicities was fairly similar but more people stopped because of neuropathy. At the IMW [International Myeloma Workshop] summit in Boston, there were probably 5 or 7 different abstracts looking at how to give VRd. Do we give it twice weekly, the bortezomib? Do we give it once weekly? At the end of the day, it really doesn’t matter.

I don’t know about you, but we use a 4-week schedule in general, and it’s REV [Revlimid] at the standard dose, 25 mg or adjusted by renal insufficiency, and then we use bortezomib on day 1, 8, and 15. So we do 3 doses of bortezomib per 4-week cycle rather than the twice weekly, 3-week cycle that’s been done in all these trials. There’s less neuropathy and it’s better tolerated.

A Look at the ENDURANCE Trial

 That brings us to the newly diagnosed. What are the triggers to initiate treatment? The CRAB [calcium elevated, renal insufficiency, anemia, bone lesions] has been mentioned before, are the symptoms, the myeloma-defining event. Initially, we label these patients with smoldering myeloma if they have a bone marrow biopsy showing a plasma cell percentage of 60% or the involved/uninvolved free light chain ratio of 100 mg/L and above.

We used to say these are patients with smoldering myeloma, let’s just watch them. Now these are true myeloma cases and starting treatment, even when they are asymptomatic, is beneficial. That includes the PET [positron emission tomography] and MRI scan that are part of initial testing. The skeletal survey and now PET, MRI, or CT scans can be used as initial assessment to see if they have 1 or more involved lesions, 5 mm or above. Those are the patients for whom you will start treatment.

When we see a patient who has newly diagnosed myeloma, we basically are assessing how well they’ll be able to tolerate whatever induction therapy we can administer. We try to assess the best regimen at that point. The first thing that comes into our mind is, is this person a transplant candidate or not? A lot of that has to do with their cardiovascular health. As long as they don’t have any significant cardiac comorbidities or pulmonary comorbidities or are not on any oxygen, then most patients—if they’re fit and they’re able to do all their activities of daily living and some exercise—are likely going to be a transplant candidate.

We recently published some ASCO [American Society of Clinical Oncology] guidelines with the premise that age is typically not a determinant of whether we’re going to take patients to transplant. That said, I don’t know what you do, Yvonne, but for us at UCSF [University of California, San Francisco], we typically look for patients less than age 75. There is the rare patient age 75 to 80 who might be fit enough to go to transplant. But the majority of patients are less than age 75, and honestly the majority are less than age 70.

For some patients who are older and have comorbidities like neuropathy, we might want to avoid agents that cause neuropathy. For some patients who have cardiac dysfunction or have congestive heart failure, we likely will go low on the steroids, less dexamethasone, and will have less problem with arrhythmias and with water gain. In some patients who have renal failure, we often have to adjust the doses of the medication. Sometimes a lenalidomide-containing regimen may not be our first choice for somebody with renal insufficient, and we may choose something like bortezomib/cyclophosphamide, and dexamethasone.

You already described very well the molecular risk status, and I agree that we tend to be very aggressive with the treatment of high-risk patients. We usually don’t have those data back when we initiate somebody with therapy. If we do, in somebody who has high-risk disease, typically it’s an immunomodulatory drug [IMid] plus a proteasome inhibitor [PI] plus a steroid, at least a triplet for people who have higher-risk disease. The stage in my mind doesn’t matter so much in terms of what therapy we’re going to do right out of the gate. But I do think we have to make a decision right out of the gate on whether we’re using a PI plus an IMiD, a PI plus cyclophosphamide, and then which PI are we going to use: bortezomib or carfilzomib.

I’m curious, Yvonne, to see what your favorite regimen is in pretransplant patients and in nontransplant patients. For me, in the pretransplant patients I’m still a fan of KRd [carfilzomib, lenalidomide, dexamethasone], trying to do 4 cycles of KRd as a pretransplant. That’s been my go-to, and that’s what I do. In the older population, the nontransplant eligible, I think almost everybody can get lenalidomide, bortezomib, and dexamethasone. But lately I’ve actually been giving a monoclonal antibody. I’ve been more interesting in giving daratumumab [DARA] with lenalidomide and dexamethasone, because I think it’s extremely well tolerated. How about you, Yvonne?

 Yes. We’ll come back to the timing of transplant, but for the induction regimen, I’m still a fan of bortezomib, lenalidomide, dexamethasone. And of course, in high-risk patients, maybe adding DARA/bortezomib, DARA to the triplet regimen based on the GRIFFIN trial.

Newly Diagnosed Multiple Myeloma

 Hi, I’m Dr Yvonne Efebera. I’m a professor at Ohio State University Comprehensive Cancer Center, focusing on multiple myeloma, amyloidosis, and transplant.

Hi there, I’m Tom Martin. I’m at the University of California, San Francisco. I’m interim chief of hematology, director of transplant, and codirector of the myeloma program. We’re here today to discuss a lot of things about multiple myeloma.

Let’s start. We’re going to have an overview of myeloma, the complexity of the way patients present, and biology, and prognosis. Let me start. When patients present with myeloma these days, it’s quite heterogeneous. With the new biomarkers for the diagnosis of myeloma, we can have patients be asymptomatic when we’re initiating those therapies. Those are the patients who have light chain ratios of greater than 100 mg/L, have a bone marrow biopsy showing greater than 60% plasma cells, or have more than 1 bone lesion seen on MRI with a monoclonal protein. We know that within a year, they’re going to develop symptomatic myeloma, so we get started right away.

We go from asymptomatic patients—it’s actually easier to treat those patients because they tolerate everything better—to more typically presenting patients who have anemia, symptoms of fatigue, and shortness of breath. The anemia, or the elevated total protein, prompts a bone marrow biopsy and then the myeloma diagnosis. We pick therapies based on their clinical scenario. We go from asymptomatic, to typically presenting, to very aggressively presenting patients, patients who may come in with cord compression, hypercalcemia, renal failure, or have sepsis and are very sick due to infection. Those aggressively presenting patients warrant very quick induction therapy, a guided work-up that goes much faster, so that you can initiate therapy sometimes within 72 hours of them presenting.

And those patients, in general, have had a worse prognosis when they present very aggressively like that. At ASCO [the American Society of Clinical Oncology annual meeting] this year, there was a poster about patients who presented in renal insufficiency. With the novel drugs that we have right now, we can turn around the renal insufficiency quite quickly. In fact, their long-term prognosis is probably as good as those who don’t present with renal insufficiency. What do you think, Yvonne?

 Yes, I agree. In addition to these patients and their presentation, one of the most important things is looking at their risk assessment and what the prognostic factors are. What we have looked at the most is the cytogenetics, which tells us a lot about whether they are high risk or standard risk. High-risk patients are those with 17p deletion or 

 deletion, translocation 4;14, 14;16, 14;20, LDH [lactate dehydrogenase] of greater than 2 times the institutional upper limit, and patients who have plasma cell leukemia. One area of contention is the gain of chromosome 1q. In some studies, those are listed as a high risk, and other studies don’t show that it may be a high risk.

Even in some clinical trials, like the BMT CTN Protocol 1401, which was completed a year ago, we excluded the gain of chromosome 1q as part of high risk. But in the allotransplant [allogeneic stem cell transplantation] trial, the BMT CTN Protocol 1302, we include those. It’s a gray area. Those high-risk features—the 

 deletion, or 17p, translocation 4;14, 14;16, and 14;20, and hypodiploidy— and then the standard risk—trisomies or hyperdiploidy, and translocation 11;14—are the other mutations that we see. The treatment, what you give them initially, the maintenance that you give, and incorporating the transplant, will vary.

Yvonne Efebera, MD, Ohio State University Comprehensive Cancer Center

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