Adriana Rossi, MD

 I think it is challenging for those of us who do nothing but myeloma to keep up with the volume of data, the new agents, the combinations, the new therapeutic approaches. I can only imagine in a community setting, when you still need to know how to care for so many different things, it is not possible to keep track of everything. I would hope that most community physicians are able to partner with someone at an academic institution, or someone who devotes most of their time to myeloma, and have that shared—one of my patients calls it shared custody. Where you have someone who is keeping up to date and hopefully participating in clinical trials to keep a running tally. And you’d have a local oncologist to give the hands-on care to the patient. Maybe that would be one of the silver linings of COVID-19 and all the telemedicine we’ve developed, a little easier access to the academic institutions. If we can help in any way to educate and to facilitate, and to run through cases, it’s one of my favorite things.

This was a great case that offers us a lot of reminders on best practices. This was considered a patient with transplant-ineligible multiple myeloma. She received highly active triplets. Hopefully, again not detailed, but she was maintained on continuous therapy. Once you use a triplet regimen, you have a component of that triplet continued until progression or intolerable toxicity. We’ve talked about the bone health and making sure that patients, in addition to their chemotherapy regimen, have some sort of antiresorptive therapy, be it denosumab or zoledronic acid. Our practice is to dose monthly during active treatment and every 3 months during a maintenance treatment. We also want to make sure they’re being followed by dentists, specifically for that. And we want to be sure we’re monitoring patients, especially an active patient who’s on therapy should be monitored every month. This poor lady went 3 months and got herself into an awful lot of trouble. And selecting drugs; when a patient is relapsing, if it is a clinical relapse, you have to be sure you are picking a new regimen. But in the setting of a biochemical relapse, you could alter one or the other partner and try to gain more mileage out of each agent the patient receives.

Case: A 75-Year-Old Woman with Triple-Class Refractory Multiple Myeloma

A 75-year-old woman diagnosed with multiple myeloma 5 years ago returns to the clinic with complaints of extreme fatigue, increased muscle weakness and new bone pain in her right hip, right forearm and low back. She reports that she is currently taking antibiotics for a bacterial infection, her third in the last 12 months.

Initially treated with DRd; CR lasting 20 months

Switched to VRd, stable disease lasting 16 months

Subsequently switched to KPd, achieved a PR lasting 12 months

Started selinexor; follow up at 9 months showed M protein increase by 0.5 g/dl; patient continued to feel well 

Currently, 3 months after her last visit, she returns to the clinic for follow-up

PE: new bony tenderness appreciated on right hip, pelvis forearm and lumbar spine; bruising and mild bleeding of the gums

Labs: Hb 6.2 g/dL, calcium 8.4 mg/dL, LDH 160 U/L, creatinine 2.1 mg/dL, albumin 2.7 g/dL, b2 microgloblulin 4.9 mcg/mL, serum M-protein 4.2 g/dL, lambda free light chains 4.1 mg/dL

Skeletal survey and MRI revealed lytic bone lesions in the left hip, pelvis and L2 vertebrae and lytic lesions as well as a hairline fracture in the distal radius of the right arm

Bone marrow shows 62% plasma cells IgG k

FISH: t(11;14) at diagnosis; new del(17p)

Initiated treatment with belantamab mafodotin

Videos

Adriana Rossi, MD, provides clinical pearls on the management of triple-class refractory multiple myeloma.

Clinical Pearls for the Management of TCR MM

 This patient case highlights what is a recognized unmet need—patients with triple-class refractory who have had a number of lines of therapy, have been exposed to all of our strongest agents, and are now relapsing. It’s very exciting to see as the field evolves that we do have a number of drugs that have been studied specifically in this patient population. And even if the drugs have been used as single agents, we are getting responses, which is something that was unheard of 10 years ago. Having single-agent response is going to change that landscape. In general we tend to use combination therapies for myeloma to get deeper and more durable responses. And as we combine these agents, the effect this will have on survival will be palpable. We used to say, your first remission is your best and deepest. I think it’s still a concept. You try to get that deepest first remission and try to get it to last as long as possible. But we are now seeing unprecedented responses, even MRD [minimal residual disease] negativity, in heavily pretreated patients.

As data accumulate on some exciting new agents and new modalities, I think we will see even more changes. Namely, I think in addition to ADCs [antibody-drug conjugates], there are the bispecific T-cell engagers, as well as the CAR [chimeric antigen receptor] T-cell therapies, which are cellular therapies approved in other disease states, and hopefully soon to be approved in myeloma that will provide, again, a completely novel mechanism. Based on current data, we have reason to expect very deep responses, and we are learning how to make them durable responses for these patients.

We now have data for combination therapies, not only using 3 agents, but 4, which I think in the past we would say, 4 drugs offered way too much toxicity. But the addition of a monoclonal antibody to a triplet regimen seems to be not only well tolerated, but incredibly efficacious. Especially in a patient who would be transplant ineligible, using 4 drugs to get them into that deepest MRD-negative state is a very doable thing. Using combinations of, maybe, stem cell transplants with CAR T therapies, and how to sequence such therapies in patients who are eligible, will be another interesting challenge for the field. Also combination therapies; with belantamab, we have impressive data for a single agent, but we are now working toward getting combination data. DREAMM-8 is one such study, comparing pomalidomide, dexamethasone, and belantamab to pomalidomide, dexamethasone and bortezomib. What I would say, VPd [bortezomib, pomalidomide, dexamethasone] is a very good triple. So if BPd [belantamab, pomalidomide, dexamethasone] can do even better, that would be fantastic. I think we only have reason to believe it can. There are preclinical data supporting the combination of pomalidomide and enhancing the effects of belantamab. It seems in the clinic, we’re now starting to see that come to fruition as well.

I think one of the exciting things we are missing is a system of classification for myeloma and a biomarker-driven therapeutic approach. For now we do remarkably well, and most triplets will give you a 90% or higher response rate. But we don’t know which drug works for which patient. And while multiple myeloma is considered a single diagnosis, anyone in clinic knows there are very different patients. Cytogenetics and risk stratification go some of the way. I think it informs and alters how we maintain patients or how we pick their second, or third, or fourth line. But especially high-risk patients who are going to go through everything we have available and need something else in shorter and shorter intervals, it would be great to be able to predict and say, here is a patient who really needs an alkylator, or here is a patient who doesn’t need to go through that toxicity because it is not an effective regimen. For now it’s a lot of trial and error, but there is a lot of ongoing research and efforts to try to develop either a system or a biomarker, or identifying how we can better pick the right treatment for the right patient, especially as our selection is getting so big and vast, not a problem we used to have.

An expert in multiple myeloma shares her perspective on the significance of recent single-agent approvals for patients with triple-class refractory multiple myeloma and highlights promising combination regimens under investigation.

The Evolving Treatment Landscape for TCR MM

 In a patient who is triple-class refractory, their standard of care options are certainly limited. It’s important at every junction, once myeloma relapses, to take into consideration the patient. What comorbidities do they have? Was is their access to the clinic, their schedule, ability to sit in a chair, ability to tolerate oral medications? Also, it’s important to identify the relapse, so certainly, always having a bone marrow biopsy to identify potentially new cytogenetic changes, as was the case in this patient. And use disease characteristics, which could then influence drug selection. In addition to that, we have now their history. So, what drugs have they been exposed to? How well did they respond to them, but also, how well did they tolerate them? Knowing that this patient has renal compromise at this time makes a rapid response highly desirable. We don’t know her comorbidities, but those should play into it, and the prior toxicities.

We know which agents she’s had and the response she was able to get, but were any of those limited due to toxicity? Was she able to stay on continuous therapy for all of those lines? Were they interrupted? Were there relapses while she was off drug? These are all important considerations. Having a drug that has nonoverlapping toxicity to her previous medications, I think is important. Having a schedule that she can keep to, again, even if it is not the first plan, whatever the schedule is established to be. And again, always considering clinical trials. I think the ability to expand that menu of options is really valuable, especially in this population.

Dr Adrianna Rossi reviews considerations for treatment selection in the triple-class refractory setting in patients with multiple myeloma.

Considerations for Treatment Selection After Fourth-Line Therapy in TCR MM

 The approval of belantamab comes following the study called DREAMM-2, which was a single-agent monotherapy with belantamab in 2 different drug levels. The cohorts were either receiving 2.5 or 3.4 mg/m2 on a schedule of once every 3 weeks. There were a total of nearly 200 patients enrolled, split evenly between the 2 arms. Overall response was the primary end point. In the 2.5 mg, which was the chosen dose, the overall response rate was 30%. And as far as toxicity, again, it was mostly hematologic, so thrombocytopenia, anemia, and leukopenia were all noted at about 20%. But the ocular toxicity is the one that got the most attention. It was the most frequent grade 3/4 toxicity, and it occurred in up to 27% of patients, requiring dose reductions, dose modifications, and rarely, discontinuation. Over about 50% of patients required dose delays, and these were significant, usually longer than another cycle. One cycle is 21 days, and there were a number of patients who required over 3 cycles of delays. Dose reductions were required in about one-third of the patients, but discontinuations were rare.

In addition to overall response rate, we do have a presentation of PRO [patient-reported outcome], which was a very important addition examining the quality of life of patients while on therapy. And fatigue and pain, which are very difficult and challenging things to treat, improved over time. Even in patients who did have significant ocular toxicity, they’re functional role and their ability to continue to do the things they wished to do were unhindered. It was interesting to see that even though this is a significant toxicity, and it does require mitigation and a game plan, it really does not seem to affect the patient’s quality of life negatively.

In addition to the excellent overall response that we see in these heavily pretreated patients, as far as the toxicity profile, we’re all comfortable and well aware of the hematologic toxicity, and all 3 lines have been affected. Thrombocytopenia is the most commonly seen grade 3/4 of the hematologic toxicities. But also, the keratopathy. Sometimes patients are asymptomatic and require an ocular examination to identify the cysts, which can aggravate their vision and potentially become difficult to reverse. One of the most important things is to partner with an ophthalmologist or optometrist, which I think is something we forget sometimes. Optometrists are perfectly able to do these exams and make sure that patients are being followed and have an ocular exam before each dose. This has absolutely facilitated. There is a lot of education for our ophthalmologic partners, and it’s important to have the patient sent up late in the cycle, just before the next dose, because our experience has been that many times it’s in that third week that the ocular toxicity will show up. Some patients will have vision changes, or a dry eye feeling. However, many of them will have no symptoms and really require the testing.

The important thing is to focus on the response. Even though the approved schedule is once every 3 weeks, this is how the original study was done, there was an interesting presentation at SOHO [Society of Hematologic Oncology annual meeting] 2020 that showed that patients who had up to a 3- cycle delay, so 63 days or greater, did not lose their response. So 88% of those patients were able to maintain their clinical benefit. About one-third of them actually deepened their response, with another third maintaining, and only 2 patients going on to progress and lose their response due to the delay. So, in ongoing clinical trials, there are now new schedules, dosing once every 4 weeks, or even wider, which may allow patients to stay on therapy and not require a change, and not be allowed to progress. Adjusting it to the patient’s needs and making sure the dosing is done safely is absolutely in their greatest benefit.

Adriana Rossi, MD, describes key clinical trials and their implications for the management of triple-class refractory multiple myeloma.

Clinical Trial Data in the Setting of TCR MM

 Patients like this who’ve progressed on 4 prior lines of therapy have very limited options. Certainly consideration for a clinical trial would be advised. If they have access to either an academic center or otherwise are able to participate in clinical trials, that is always a good option. But especially given her age, and we don’t know about her comorbidities, I think the option of belantamab was a very good one, not only because this is exactly the population that we’ve studied, but it is a very tolerable and very effective therapy for this patient population.

Belantamab mafodotin is an antibody-drug conjugate that targets BCMA. It carries a toxic payload known as MAF, which is known to cause ocular toxicity. I think it’s the first antibody-drug conjugate, or ADC, that we have available in myeloma. It’s also the first BCMA-targeted therapy. Both of these make it a very exciting option. It does come with the unique ocular toxicity, which has gotten quite a bit of attention. But interestingly, I have a number of patients who have tolerated it. About half of patients will go on to develop ocular toxicity, but the vast majority will improve with dose delays or dose reductions. Just as in the clinical trials, my experience has also been that maybe the dosing was a little optimistic. And if we dose it less frequently or at a reduced dose, we can get patients to stay on therapy for much longer. The schedule, which is once every 3 weeks, is something patients really appreciate.

The current treatment the patient is on, selinexor, is another recent addition to our armamentarium. In this case, it is an XPO inhibitor, which is a nuclear transport. So, it’s a protein that the cells use to get rid of tumor suppressors and growth factors. And by inhibiting them, these accumulate in the nucleus and lead to cell death. The drug is oral, which I think is one of the big selling points, especially in this past year, with reducing visits to the office. It was a good time to have it added to our menu of options, but it does come with significant toxicity itself, namely central nausea. So, patients usually require a number of antiemetics. There again, I think approval on the studies started with maybe an optimistic dosing of twice a week. As we’ve moved through different studies and different combinations, I think we’ve learned that once-a-week dosing makes it much more tolerable, and dose reducing as necessary. Again, not all patients will be able to tolerate the full dose as approved.

Dr Adriana Rossi reviews the therapeutic options for patients with triple-class refractory multiple myeloma in terms of mechanism of action and safety profile.

Treatment Options After Fourth-Line Therapy in TCR MM

 Reviewing all of the findings for this case, I think a few important things show up. This patient has now been exposed to IMiDs [immunomodulatory drugs], proteasome inhibitors, and an anti-CD38 antibody, and is what is now called a patient with triple-class refractory multiple myeloma. It’s not an uncommon case, especially in the academic world where I am at a tertiary referral center. Many patients who come to me are exactly those patients who have had all of the easily accessible frontline medications and are now running out of standard options. I think it’s interesting to try to look at prognosis. We really don’t know at this point. The field is moving so fast; there are so many new agents coming up that are changing the landscape and changing the field. Last time we looked, I think back in 2017, and had data on proteasome inhibitor- and IMiD-refractory patients, we were expecting them to have an overall prognosis of about a year. But we now have a number of studies in these multiply refractory patients where we are getting deep and meaningful responses, not only CRs [complete responses], but MRD [minimal residual disease] negativity in the relapsed setting. I think that will absolutely translate to a survival difference. So we need more time to be able to see the effect this will have.

But it is challenging. This patient comes in with a significant clinical relapse. We often would monitor patients every month. Part of that is to not give time for the myeloma to get so unruly. If you are monitoring every month and you see signs of a biochemical relapse, where the M spike is going up but the end organ damage is not there, it gives you time to think and pick drugs, and hopefully prevent the damage. In this case, her anemia is quite severe, her renal function is impaired, and she has extensive bony disease. Part of what’s not addressed in the case is whether she has any antiresorptive therapy as part of her treatment plan. I would say any patient, not only those with lytic lesions, but all patients with myeloma, should have their chemotherapy complemented with either zoledronic acid or denosumab.

An expert in multiple myeloma provides insight on the treatment challenges for patients with triple-class refractory disease, particularly after fourth or later lines.

Adriana Rossi, MD | Authors

Articles

Clinical Pearls for the Management of TCR MM

The Evolving Treatment Landscape for TCR MM

Considerations for Treatment Selection After Fourth-Line Therapy in TCR MM

Clinical Trial Data in the Setting of TCR MM

Treatment Options After Fourth-Line Therapy in TCR MM

Management Challenges in TCR MM