Roundtable Discussion: Participants Analyze Different Classes of Drugs for Second-line Multiple Myeloma

James E. Hoffman, MD

Two years after being diagnosed with multiple myeloma and treated with daratumumab (Darzalrx), lenalidomide (Revlimid), and dexamethasone induction therapy, a 78-year-old patient presented with mild fatigue during routine follow-up. James E. Hoffman, MD, assistant professor of Clinical at the Sylvester Comprehensive Cancer Center at the University of Miami Health System discussed the case with a group of peers during a Targeted Oncology Case-Based Roundtable event.

HOFFMAN: Here you have a patient who’s on dual main-tenance therapy, high-risk MM by genetics, who’s now having some serologic progression. I have some questions I’d like to pose to the group: How would you handle this; a rising paraprotein, do you image these patients, do you repeat marrow, do we all do that as a matter of norm, and what is the trigger for this group to initiate second-line therapy? What kind of factors do you look at?

CARTWRIGHT: I think the first thing probably would be based on her symptoms. If she’s starting to feel fatigue, if that’s a new symptom, that would be certainly a trigger to consider into additional testing and possibly starting a change of therapy.

HOFFMAN: I agree. I think that when they’re starting to get sick, you’re getting right to the crux of the matter. Forget the numbers; if someone is starting to get sick, then that person needs treatment, so if the fatigue is new or progressive, and with rising paraprotein, it seems very reasonable that that would be a trigger to start therapy.

WANG: I would see [if she has] anemia, kidney dysfunc-tion, or any bone pain.

HOFFMAN: The hemoglobin was approaching 10.3 g/dL, so not severe, doesn’t really give you a baseline on the kidney function. If [creatine] had gone from 0.7 mg/dL to 1.3 mg/dL, that’s one thing. If it had always been 1.3 mg/dL, that’s another. What about standard imaging for a patient like this? What about a standard bone marrow biopsy? What do people feel? Do we always test bone marrow for these people, do we always scan them?

SANDOVAL SUS: Patients who don’t have any clear-cut symptoms or signs, especially high-risk patients who are doubling their light chains or their monoclonal proteins—I image them. I don’t use bone survey anymore, and I would encourage people not to do it in patients with active disease. I like PET scans, but MRI or low-dose “CT scans” can also work for detecting bone lesions. At least at first, I do [test bone] marrow in the patients; I think it’s important to know their clonal evolution, especially nowadays. I don’t think translocation 14 is a driving mutation, but I’ve seen some cases where they acquired it very rarely, and nowadays I think that’s the only predictor marker for treatment in MM.

HOFFMAN: A lot of good points there. The translocation (11;14) opens up the door for venetoclax (Venclexta)based therapy, so it’s nice to know. We live in an era where we have much more sensitive bone imaging than a skeletal survey, which the International Myeloma Working Group has marginalized now. Does anybody disagree with the idea that we should be [testing bone marrow for] a patient like this and getting some additional imaging? Anybody want to agree and build on that argument?

AZZI: I agree. I also use the time to retest [their bone] marrow too if I have not obtained an MRD [minimal residual disease] assay. There’s not a lot of utility yet for next-generation sequencing, but that might change in the future. [Testing bone] marrow opens up the possibility to analyze a whole ton of things. You cannot really do peripheral [blood testing] yet.

HOFFMAN: I think that’s reasonable; I don’t think anyone is going to disagree vehemently with the idea of a repeat bone marrow test on change of therapy, especially if initial assessment was limited, especially if you want the possibility of [seeing if] a translocation (11;14) is still there. A patient who had a different translocation is not going to now have translocation (11;14). Generally, they’re mutually exclusive, but in someone who you didn’t find one, maybe that’s helpful.

If you’re trying to convince yourself not to treat somebody, bone imaging makes sense. If you’re going to watch a patient like this, you want to make sure that they’re not building up some bone tumors. Dr Sandoval hinted at pace of increase in the number. If a number is rapidly rising vs gently rising, the fact that this patient had del(17p), the first relapses tend to be higher risk.

AZZI: They said she had been on 2 years of treatment. That seems unlikely that a lot of people were treating with daratumumab 3 years ago; I don’t think it was standard of care back then. I tend to use it, but I think not a lot of people use daratumumab, I found, for these patients.

SANDOVAL: It said it was a clinical trial in the case, right?

HOFFMAN: Yes, the case said it was a clinical trial, but it’s a good point.

AZZI: Oh, it did say clinical trial, OK.

HOFFMAN: Up-front treatment of MM is a hot topic. We’re really focusing on relapse here, but whether you’re using Dara-Rd, bortezomib [Velcade]/lenalidomide/dexamethasone [VRd], carfilzomib [Kyprolis]/lenalidomide/dexamethasone [KRd], whether you’re a quadruplet person—that’s probably a 3-hour thing we could haggle about.

Things that we might consider, we’ve already touched on; initial genetics, how frail is the patient, toxicities, do they have baseline neuropathy, baseline heart disease, etc. We’re now going to choose new treatment for this patient who was relapsing on daratumumab/lenalidomide maintenance.

Things that we might consider, we’ve already touched on; initial genetics, how frail is the patient, toxicities, do they have baseline neuropathy, baseline heart disease, etc. We’re now going to choose new treatment for this patient who was relapsing on daratumumab/lenalidomide maintenance.

PARAS: I don’t have a lot of experience with MM, and most of my patients [are] elderly, so I usually base the third-line treatment on their age, comorbidities, and copayments and cost to the patient. A lot of times, there are also issues of them having to come to the office, so it depends on what their initial treatment would be. A lot of them, I’ve treated with a single agent like lenalidomide.

HOFFMAN: For frail patients, people who need oral therapy, you might continue with immunomodulatory imide drugs [IMiDs]. This patient is relapsing on lenalidomide, so you might be thinking pomalidomide [Pomalyst] base as an alternative. I think that’s reasonable.

KAHN: This patient did not receive a proteasome inhibitor in the first line, [so I would] definitely want to put that in; [there’s] bortezomib, carfilzomib, those really are good, and if you switch lenalidomide to pomalidomide—the del(17p) makes it tough. They’ve already progressed on daratumumab, so I would like to see maybe a clinical trial if available, but a proteasome inhibitor definitely.

HOFFMAN: Good points; a class of medication that the patient has not relapsed on is a proteasome inhibitor, so that seems like a really good choice, and whether you partner that with the newer IMiD, pomalidomide, or maybe something else. Would you continue the daratumumab as part of this relapse, do you think? If we’re going to add a proteasome inhibitor, maybe an IMiD, would you stop or continue daratumumab?

S. SAWHNEY: I would stop daratumumab. There is no benefit and there are no data suggesting continuing daratumumab at this point…so without any data, once a patient has progressed, I would not continue CD38 antibodies.

A. SAWHNEY: I was thinking of KPd [carfilzomib, pomalidomide, dexamethasone]. The patient has been on daratumumab for 2 years, even though it was maintenance, and hasn’t had a proteasome inhibitor. Especially with the del(17p), I would go with something like KPd at this point.

AZZI: I would like to know more about the dynamics of this relapse, like how fast was it and how deep the response before was.

HOFFMAN: I agree with you. [For the patients with] del(17p), we definitely worry about rapid relapse. We’re talking theoretical here; there are definitely some issues that we would want to know a little bit more about in terms of comorbidity, adverse effects [AEs], etc, but let’s take it for face value that this was a real relapse and we knew we needed to do something.

HOFFMAN: It looks like Sawhney, you were compelling— you convinced everybody that carfilzomib and pomalidomide was the winner. Then some people felt that [they] might use bortezomib, pomalidomide, and dexamethasone [VPd]. Maybe they were influenced by some of the data recently that shows that maybe carfilzomib isn’t all that much better than bortezomib in certain circumstances, but either of the 2 drugs seems reasonable. Dr Cartwright, any thoughts? Which one did you vote for?

CARTWRIGHT: I picked KPd, but if there was another option, I would have probably considered just Kd [carfilzomib, dexamethasone]. The patient was 78 years old and a nontransplant candidate when she started; she’s now 80 [and] I wondered if she’s a candidate for 3 drugs or 2 drugs. I would say, assuming she wants aggressive treatment, [can] tolerate treatment, and aggressive treatment, [can] tolerate treatment, and 2 drugs would be an option in this patient, depending on stuff we don’t know.

HOFFMAN: I think that’s an excellent point that we didn’t really address—a doublet vs triplet on relapse, [considering] frailty and AEs, [which are both] important. Sometimes we start with 2 drugs and build up to 3, whereas if it’s a crisis we start with 3 and back off to 2.

Now, you may notice here, none of us kind of were eager to choose [selinexor (Xpovio) or elotuzumab (Empliciti)]. I voted VPd. We’re going to talk about selinexor coming up, and I’m interested to see where that takes us. Any thoughts on elotuzumab?

SANDOVAL SUS: There are a lot of good options in this list. I personally voted for VPd, but 2 medications, as second line with a del(17p), I would try not to do [is] ixazomib [Ninlaro]- and elotuzumab-based regimens, because of the aggressiveness of this disease. However, if the patient is now 80 years old, we need to take that into account.

HOFFMAN: Elotuzumab is tricky to find places for. It seems like it’s not a great drug in [patients who have progressed on] daratumumab, so none of us were keen on it.

HOFFMAN: [For selinexor, patients] need very close monitoring of laboratory results and nutritional status—weight loss and poor appetite are big problems. Then the concomitant treatments these patients often require are hydration, calorie counts, and a lot of prophylactic antiemetics, such as olanzapine…day of/day after in an effort to mitigate some of the gastrointestinal toxicity.

When I use it, I use all of these things. When I give bortezomib, I give fosaprepitant with it, and patients are on olanzapine day before, day of, but it’s tricky. When you think about costs, selinexor is an oral drug—that’s very exciting. When these patients are tethered to intravenous fluids, it removes some of the conveniences of the oral drug.

CARTWRIGHT: I think if I had an appropriate patient, I would refer them to a MM expert. With all these things, there are so many options, I don’t think I would really feel comfortable treating a patient in private practice. I’d probably refer it to somebody who sees MM every day and treats 5 or 6 of these patients a week or a month.

SANDOVAL: [Dr Hoffman], you were involved in one of the trials [for selinexor]; were there any patient-reported outcomes in this trial that were objectively evaluated [regarding] how the patients felt with this medication?

HOFFMAN: I did enroll on the STORM trial [NCT02336815], and patients had a very hard time, and the supportive care was very aggressive on the part of the company to try to keep people on drug.…I believe that using it at 80 mg or 100 mg once a week with bortezomib and supportive care, quality of life is definitely much better. The grade 3 and 4 fatigue, nausea, and vomiting are seen much less, and you can see dramatic benefit in a minority of patients. The only patients I use it for are patients who have failed the major classes of drugs, are not trial-eligible or interested, have good performance status, are [adherent], and [have] full awareness of the risks and benefits of proceeding. That’s a very tiny subset of my patient population, so I do use it, but in a very select group. I am not keen on moving it earlier, like they might have us do based on the BOSTON trial [NCT03110562].

There are all sorts of dose modifications based on hematologic and nonhematologic toxicity, the same as every other drug. [This] is difficult for people who might treat 1 or 2 patients a year with this drug, because it’s difficult for people who treat more than that, I can tell you for sure. There is very strict guidance as it relates to dose reductions and skipping doses.

HOFFMAN: Do you guys flip-flop in terms of mechanism of action, meaning if someone is relapsing on an IMiD, do you try to avoid IMiDs? What has changed in the last year or 2 in terms of how the group manages patients with relapse?

KAHN: I’ve been using a lot more daratumumab, especially now that we have the subcutaneous [option]; the previous all-day infusion was a real deterrence in the past, and so that’s increasingly becoming my backbone in the second line. Also in the first line, we use it in a handful of patients.

HOFFMAN: We live in a daratumumab world, and with subcutaneous, I agree. For people not exposed up front, we want to get patients on it when we can, on that first relapse.

AZZI: If you’re using quadruplet now, would you consider selinexor for your second line?

HOFFMAN: I think you’re bringing up a really good point, which is in a world where we’re testing daratumumab, bortezomib, lenalidomide, and dexamethasone—the quadruplets—up front, what is going to be there for those patients on their first relapse? So as a thought experiment, based on what Dr Azzi proposed, if someone is now relapsing on a quadruplet, let’s say daratumumab, bortezomib, lenalidomide, and dexamethasone, what [would we] put together for a young patient with some high-risk disease who’s now relapsing on quadruplet therapy?

S. SAWHNEY: Most patients who you start with quadruplets, you never continue quadruplets. You give them for a fixed period of time, and then you’ll put them on maintenance, so you still have an option to go to an IMiD or a proteasome inhibitor. I don’t think anybody is giving quadruplets forever, even if you treat to minimal residual disease [MRD]. Once you achieve MRD, you’re going to stop all the drugs, so I don’t think I would use selinexor in that situation.

HOFFMAN: So you’d go back to the drug that maybe you dropped?

S. SAWHNEY: Right.

HOFFMAN: What if you treated for 3 or 4 months and had primary refractory MM to a quadruplet, where do we go there? This would be a rare circumstance.

KAHN: That might be a case where you can consider elotuzumab. WANG: What about CAR [chimeric antigen receptor] T-cell therapy?

HOFFMAN: I think people that push quadruplets up front and then worry about Dr Azzi’s question of, what are you going to do if you waste all the good drugs? I think they’re hoping these patients are going to do so well, maybe their relapses are going to happen in a CAR T world.