 The promising advances in triple-class multiple myeloma are in immunotherapy, with a focus on the BiTEs [bispecific T-cell engagers] and CAR [chimeric antigen receptor] T cells. We talked a lot about BCMA as a target. Right now, the BCMA CAR T cells are approved for multiple myeloma. There are many bispecific T-cell engagers and BCMA antibodies in clinical trials.

BiTEs bind BCMA on the surface of multiple myeloma cells. It also binds a T cell, and it brings the myeloma cell and the T cell into proximity so that the T-cell can directly kill the multiple myeloma cell. The T cells are also activated by the binding. It’s mimicking a natural immune response by activating the T cell and bringing the T cells together with a multiple myeloma cell in order to induce the T cell of the patient killing a tumor cell.

I’m also excited about the option to use other targets, and not only BCMA for CAR T cells and BiTEs. If you look into the future—the clinical trials are already ongoing—they use 2 targets to develop a CAR T cell, not only a BCMA but also a second antigen that you’re targeting with your CAR T cells. Those are very promising developments. The future in multiple myeloma, especially in triple-class refractory disease, is probably in immunotherapy, CAR T cells, and for older patients, BiTEs. There are also ongoing studies with allogenic CAR T cells, or with allogenic NK [natural killer] cells. Those trials are in the early stages, but also very promising in order to avoid the additional generation of stem cells and use off-the-shelf allogenic CAR T cells. We will see what those trials will bring. The immunotherapy, and especially the cellular therapy, is probably most exciting about the future in relapsed/refractory multiple myeloma.

 There are a lot of exciting things occurring for patients with triple-class refractory multiple myeloma. There was the KarMMa-2 trial, which is the phase 2 study looking at the BCMA-targeted CAR T-cell product, idecabtagene vicleucel, in patients with relapsed/refractory multiple myeloma. In that study, in the overwhelming majority of patients who had triple-class refractory disease, the overall response rate was a remarkable 73%. That’s clearly much higher than the response rates we saw with selinexor and dexamethasone, melphalan flufenamide and dexamethasone, as well as belantamab mafodotin in a similar patient population. The median duration of response was 10.7 months. The majority of patients relapse in this particular situation, but these are much better results than we’ve seen with other treatment strategies out there. Although that median duration of response is actually very similar to the other FDA-approved BCMA-targeted agent, belantamab mafodotin. So even though the overall response rate with belantamab mafodotin may be lower than it is with idecabtagene vicleucel, the median duration of response of both of the therapeutics is very similar.

A lot of us are excited about additional CAR T-cell therapies that are in development. For example, Janssen’s ciltacabtagene autoleucel product looks very promising. There are a large number of CAR T-cell products in development, targeting not just BCMA but other novel plasma cell–specific markers, such as GPRC5D. A lot of us are very interested in the bispecific antibodies, like those that are targeted against BCMA such a teclistamab, which is made by Janssen, but also other bispecific antibodies out there, including those targeted against the plasma cell–specific marker GPRC5D.

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Novel therapies in clinical development to improve outcomes for patients with triple-class refractory multiple myeloma.

Novel Therapies Under Study for Triple-Class Refractory Multiple Myeloma

 After receiving approval for selinexor, Blenrep [belantamab mafodotin], and melflufen, we have luckily also received approval for CAR [chimeric antigen receptor] T cells. Hopefully we’ll receive approval for BCMA BiTEs [bispecific T-cell engagers]. That will change the outlook of patients in the fourth and fifth relapses. Those therapies, especially when used earlier, can absolutely prolong the responses of patients with multiple myeloma. With CAR T cells, we have a very promising new tool available to us. If we are using those immunotherapies when patients still have active T cells, we might see much better response rates than we see right now. The progression-free survival with CAR T-cell therapy is currently around 2 to 11 months, so this is in a phase where patients already have an exhausted immune system based on multiple prior treatments. If we use those drugs much earlier, that would allow us to have a much longer progression-free survival in the third or fourth relapse.

 An unmet need in triple-class refractory myeloma is improving the durability of responses to these new therapies. That includes the BCMA-targeted strategies, belantamab mafodotin and idecabtagene vicleucel, melphalan flufenamide with dexamethasone, and selinexor-based regimens. In the BCMA-targeted space, looking at next-generation CAR constructs makes a lot of sense. As an example, we’ll see more combination therapies in that space incorporating other therapies that have an immunostimulatory effect with CAR T cells. Understanding mechanisms of resistance to these agents is going to be important. Similarly, understanding whether that resistance is conferred to other therapies in the same class is important. For example, if a patient relapses after idecabtagene vicleucel therapy, what’s the likelihood that they’re going to respond to belantamab mafodotin or the other way around? Looking at that is going to be incredibly important.

Understanding mechanisms of resistance for melphalan flufenamide and selinexor is also going to be incredibly important. You’re going to see more and more data emerging on combination therapies with selinexor. We already talked about the BOSTON trial, but there are numerous combinations being developed with selinexor that look very promising, including carfilzomib and daratumumab. With regard to melphalan flufenamide, there are very interesting early data with bortezomib-based therapy as well as daratumumab-based therapy. As far as those agents are concerned, you’re going to see more and more 3- and 4-drug combinations in earlier relapse.

Current unmet needs surrounding the management of patients with triple-class refractory multiple myeloma with newer novel therapies.

Addressing Unmet Needs for Triple-Class Refractory Multiple Myeloma

 Treatment of relapsed/refractory multiple myeloma, especially in triple-class refractory patients, is a challenge in contrast to initial treatment, which is relatively standardized. In initial treatment, there’s RVd [lenalidomide, bortezomib, dexamethasone] and also KRd [carfilzomib, lenalidomide, dexamethasone] for younger patients who are fit. The treatment in later relapse, especially in patients who are triple-class refractory, depends on the goal of the treatment, the adverse effects of prior treatments, and what we wish for in terms of quality of life. I’ll give some examples that might guide you on treatment, because we do not have any data that would offer guidance, like whether it’s better to use selinexor after Blenrep [belantamab mafodotin], or it’s better to use melflufen before selinexor. There are absolutely no data on the sequencing.

When you have a patient who is triple-class refractory, you should really look at the adverse-effect profile of the drug. For instance, with patients who already have very low blood counts and start with grade 3 thrombocytopenia and neutropenia, I’m not sure I would treat them with melflufen, where the main adverse effect is thrombocytopenia and neutropenia. In contrast, when a patient heavily depends on their eyesight—has to drive, needs to work on the computer—I’m not sure I would go with Blenrep, where 50% have a decreased vision and keratopathy that can last quite long. That might not allow those patients to use a computer or drive. Patients who already have a low body weight or struggle with low appetite might not be the best candidates for selinexor, because selinexor can decrease the appetite and lead to fatigue and a low oral intake. Those are things I would consider while deciding whether to use Blenrep, selinexor, or melflufen.

 As far as optimal treatment choices for patients with triple-class refractory disease and the various treatment strategies we’ve discussed, there are no data on optimal sequencing of therapy. I can’t tell you that it makes more sense to start with a selinexor-based regime followed by BCMA-targeted strategy or the other way around. Those data do not exist. It certainly is something we hope to have in the future.

Treatment needs to be based on what the patient brings to the table, particularly with regard to past medical history as well as past toxicities with treatments. For example, if you have a patient who has relapsed/refractory disease, has pretty fragile bone marrow reserves, and is predisposed to severe cytopenias in prior lines of therapy, they may not be the best patient for a melphalan flufenamide–based strategy. However, if you have a patient with triple-class refractory disease who hasn’t seen an alkylating agent since their transplant many years ago, and they’ve got robust counts—good neutrophil and platelet counts at the time of their relapse—they would be a very good candidate for melphalan flufenamide with dexamethasone.

For a frail patient who’s been prone to gastrointestinal adverse effects or significant constitutional effects of therapy in the past, selinexor is something you can use, but you have to use fairly cautiously. You should maybe be migrating toward the lower doses. Give it on a once-weekly basis as opposed to the twice-weekly 80-mg dose that’s FDA approved. That needs to be taken into consideration.

With regard to belantamab mafodotin, it’s important that the patient who has ready access to an eye care specialist who has some familiarity with the product and can help guide the hematologist-oncologist on whether it’s safe to continue dosing at the same interval. A patient who is being considered for belantamab mafodotin also needs a good social support network working in their favor. If you have a patient who lives alone and drives themselves back and forth to the doctor with no one available to help them in any meaningful way, and they develop severe reduction in visual acuity as a result of the drug, that’s going to obviously put them in a very bad spot.

All these things need to be considered when making choices. It’s really about the adverse effects of prior therapy and the agents you’re considering when you are making these choices. It’s a practical consideration with idecabtagene vicleucel, the BCMA-targeted CAR [chimeric antigen receptor] T-cell product that was just FDA approved. The patient has to be able to get to a center that can administer the therapy. Just as important, after the apheresis occurs for the manufacturing of the CAR T cells, the patient has to have a viable bridging therapy to keep their disease at bay while those CAR T cells are being manufactured. All those things need to be considered when you’re making choices.

The adverse effects of therapy and safety profile of a particular regimen are always important for patients with newly diagnosed disease as well as those with highly refractory, triple-class refractory disease. As the duration of response with subsequent lines of therapy shortens, quality of life becomes incredibly important. You have to be careful when you’re using these therapies. You have to have an in-depth discussion with the patient about the safety profile of the therapy and what the potential adverse effects are so they can make a good choice about the quantity of life that they may derive from a particular product and what effect that therapy might have on their quality of life.

Guidance regarding proper treatment selection and sequencing of therapies for triple-class refractory multiple myeloma.

Individualizing Therapy for Triple-Class Refractory Myeloma

 Another interesting drug was recently approved. Data from the DREAMM-2 study showed that Blenrep [belantamab mafodotin], a CD38 antibody that’s coupled with a cytotoxic agent, is very effective in patients who are triple-class refractory. Response rates were around 30%. The drug was relatively well tolerated. Unfortunately, there is 1 main adverse effect, keratopathy, which occurs in about 50% of the patients. That can really limit the use of Blenrep, despite it being well tolerated and successful at inducing high response rates, because patients who experience grade 3 keratopathy have to stop and hold the treatment until they have improvement of the keratopathy. That can take several weeks. Interruptions of that treatment are very likely. Nevertheless, it’s very well tolerated. It’s an additional potent drug in our armamentarium for patients with relapsed/refractory multiple myeloma.

 Another treatment option for patients with triple-class refractory disease is the antibody-drug conjugate belantamab mafodotin. This was the first FDA-approved BCMA-targeted therapeutic for these patients. BCMA is a cell surface receptor that’s unique to plasma cells. The way belantamab mafodotin works is that after infusion, it binds to BCMA-expressing plasma cells and, like any ordinary monoclonal antibody, can mediate antibody-dependent cellular cytotoxicity. In addition, just like brentuximab vedotin in Hodgkin lymphoma, the antibody-drug conjugate is taken up by the plasma cell, and the cytotoxic payload—which in this case is MMAF—is subsequently cleaved inside the myeloma cell, where it binds to microtubules and mediates cytotoxicity in that manner.

The DREAMM-2 study was a phase 2 trial that looked at 2 doses, 2.5 and 3.4 mg/kg of belantamab mafodotin infused once every 3 weeks, for patients with relapsed/refractory multiple myeloma. The vast majority of those patients had triple-class refractory disease. The study showed an overall response rate of 31%, with about half those patients achieving very good partial responses and complete responses. Importantly, the median duration of response was 11 months, which is very similar to the BCMA-targeted CAR [chimeric antigen receptor] T-cell therapy idecabtagene vicleucel, which was also recently FDA approved. Median overall survival for that study was 13.7 months. So belantamab mafodotin is another option.

In general, belantamab mafodotin is a well-tolerated agent. The rates of infusion reactions are quite low, despite the fact that a lot of patients did not get premedications prior to dosing in the phase 2 trial. We see some thrombocytopenia with this agent. But relative to a lot of the other therapeutics that we’ll use in this space, it’s very manageable. The most common toxicity associated with this agent is corneal toxicity. In the DREAMM-2 study, the rate of corneal events was around 70%. I tell patients that if they are going to get at least 2 doses or more and are responding to therapy, they are going to have corneal changes on physical exam at a minimum and may have symptoms related to that corneal involvement. That can include sensitivity to light, discomfort, and dryness in the eyes. In some cases, it can actually affect your vision, which can impact your ability to read, watch TV, and drive. For this reason, there’s a REMS [Risk Evaluation and Mitigation Strategies] program associated with this product. Patients need to be seen by an eye care specialist prior to each dose. It’s something that has to be monitored very carefully when you are administering this agent.

An overview of the DREAMM-2 study of belantamab mafodotin for triple-class refractory patients with multiple myeloma, with special considerations for managing treatment-related corneal events.

Single-Agent Belantamab Mafodotin for Triple-Class Refractory Multiple Myeloma

 Melphalan flufenamide is a novel peptide-drug conjugate. Basically, this is a peptide that is conjugated to an alkylator agent. This is a lipophilic product. Once it’s infused, it readily enters cells. Once inside a cell, aminopeptidases in the cell will cleave the peptide off, liberating the alkylating agent payload. In this case, that also includes melphalan. Melphalan is hydrophilic. In other words, it basically becomes trapped inside the cell where it can bind DNA, cause DNA damage, and mediate cell death. The reason we think melphalan flufenamide is a relatively targeted strategy is that aminopeptidases are upregulated in cancer cells, including multiple myeloma cells. In fact, there are data suggesting that in relapsed/refractory multiple myeloma, the levels of aminopeptidases are even higher. The idea is that you get more clipping of the peptide and release of the alkylating agent payload inside myeloma cells relative to normal tissues, which are then trapped inside the myeloma cell. That’s thought to be the basis for the relative specificity of the alkylating agent against the multiple myeloma.

The initial O-12-M1 study was the phase 1 study that established the optimal dose and schedule of melphalan flufenamide with dexamethasone. But it was the phase 2 HORIZON trial that led to its FDA accelerated approval. This was a single-arm study that looked at melphalan flufenamide given intravenously once every 4 weeks with a weekly dose of oral dexamethasone. Patients were allowed to stay on treatment until the emergence of unacceptable adverse effects or disease progression. Eligibility criteria were such that this group of patients was heavily pretreated and refractory to the majority of myeloma agents that are available. The majority of patients on this study were triple-class refractory.

In this study, the overall response rate was 29%. The majority of responses were very good partial responses and partial responses. The minimal responses, or what we call the clinical benefit rate, was 45%. Close to 50% of the patients achieved benefit and reduction of disease burden with this 2-drug combination. One of the other nice things we saw in this study was that response rates were very similar whether you had high-risk cytogenetics or not. The response rate was very similar whether you had extramedullary multiple myeloma or not. There was a fairly high percentage of patients in this trial who had extramedullary myeloma, which we know is a high-risk disease situation. That’s essentially what led to FDA approval of this combination.

 Melflufen is a peptidase-enhanced cytotoxic agent. I usually compare it with alkalines. It’s an important additional medication for the treatment of relapsed multiple myeloma, especially when patients failed antibody treatment, immunomodulatory drugs, and also proteasome inhibitors. We know that medications like Cytoxan, bendamustine, and melphalan are very potent in relapsed/refractory multiple myeloma. We use melphalan as treatment when patients receive high-dose chemotherapy and stem cell transplantation. Melflufen is a more potent, modified melphalan that has a high potency and can induce remissions in relapse/refractory multiple myeloma, which is important.

Don’t forget that if patients are resistant to all IMiDs [immunomodulatory imide drugs], proteasome inhibitors, and CD38 antibodies, the situation is pretty grim. Having a drug that can induce another remission is really important. Unfortunately, this is also associated with a high number of cytopenias, especially thrombocytopenias and neutropenias, which is a bit of a challenge because patients in that situation often start with lower blood counts. That might make it a little more challenging to treat patients in the relapse situation with melflufen.

 From the adverse-effect perspective, the combination of melphalan flufenamide and dexamethasone is good. The nonhematologic toxicity with the combination is fairly low. That speaks to the aminopeptidase-driven relative targeting of the agent to the multiple myeloma. But there was a very high rate of grade 3 and 4 neutropenia and thrombocytopenia with this agent, which is not all that surprising given that it is in the class of alkylating agents. Obviously, hematopoietic precursor cells in the bone marrow must make aminopeptidases as well, because we’re certainly seeing cytopenias as an adverse effect of this agent. That has to be managed carefully. Neutropenia can be managed with GCSF, for example. You must monitor counts closely to determine whether a patient needs red blood cell or platelet transfusion support. For now, melphalan flufenamide needs to be administered through a central venous catheter. There’s an ongoing study to determine whether it can safely be given through a peripheral line.

The rationale for adding melflufen to dexamethasone as treatment for patients with triple-class refractory multiple myeloma.

Melflufen and Dexamethasone for Triple-Class Refractory Multiple Myeloma

 Selinexor is a very interesting drug that was developed and designed based on extensive laboratory research. The mechanism is very interesting, because it inhibits a protein that shuttles other proteins from the nucleus into the cytosol. By doing this, it basically stops cell cycle. Without having any proteins going from the nucleus to the cell cycle, the cell cannot grow or produce more proteins. It’s a very elegant mechanism of action. Interestingly, high-risk cytogenetic multiple myeloma seems to be especially sensitive to selinexor; for instance, patients with 17p deletion. We saw on the BOSTON trial that patients benefited very well and to a higher extent from the selinexor-bortezomib combination in comparison with other patients who had normal-risk cytogenetics. I found that mechanism very interesting.

 Selinexor and dexamethasone were approved for use in patients with relapsed/refractory multiple myeloma who had gone through the 5 primary drugs, specifically CD38 antibodies; the 2 IMiDs [immunomodulatory imide drugs], lenalidomide and pomalidomide; as well as 2 proteasome inhibitors. The way that it was initially FDA approved, selinexor 80 mg was given twice weekly with dexamethasone concurrently. The idea behind including dexamethasone with selinexor, even though the overwhelming majority of the patients treated with this regimen have dexamethasone-refractory disease, has to do with the mechanism of action of selinexor. Selinexor basically blocks exportin-1, which is a shuttle that moves proteins out from the cell nucleus into the cytoplasm. One of those proteins happens to be the glucocorticoid receptor that dexamethasone binds to in the nucleus. The idea behind the combination of selinexor and dexamethasone is that the selinexor can trap a glucocorticoid receptor–bound dexamethasone in the nucleus, where it mediates its action.

What we have learned, and we knew this from early on in the STOMP study, is that the adverse-effect profile of selinexor is challenging when it’s given at 80 mg twice weekly. In particular, significant cytopenias and platelets are problematic. There are also nonhematologic adverse effects that are challenging at that dose and schedule. There are constitutional adverse effects, such as fatigue. There are gastrointestinal adverse effects, such as loss of appetite; nausea, sometimes with vomiting; and diarrhea. We’ve learned as time has gone on that the once-weekly dosing strategy of selinexor—particularly in the combination strategies—has performed very well, not only from an efficacy perspective but from an adverse effect perspective as well.

Selinexor and dexamethasone got its initial accelerated approval for the relapsed/refractory patient population, but the phase 3 BOSTON trial was done in patients with earlier-relapsed myeloma. This was a study looking at bortezomib and dexamethasone with or without selinexor for patients with relapsed multiple myeloma who had 1 to 3 prior lines of therapy. To make a long story short, the addition of selinexor to the regimen decreased the risk of myeloma progression and death by approximately 30%. Importantly, in that particular study, they used selinexor on a once-weekly basis. When you look at the rates of constitutional and gastrointestinal adverse effects in the BOSTON trial in the selinexor arm compared with the selinexor-dexamethasone treatment in the STOMP trial, it’s much better tolerated. These days, a lot of us are using selinexor and dexamethasone with other agents.

 Selinexor is being tested in the STOMP trial in different combinations. The trial has multiple arms. Selinexor is being tested in combination with pomalidomide, ixazomib, daratumumab, inotuzumab, and in quadruplets. This is very promising, because we know that selinexor, as a single agent, has a response rate of around 23%. It has substantial adverse effects. Combining a medication that has an excellent and very interesting mechanism of action, and is potentially very potent, with other drugs, is very promising because it will also allow us to reduce the dose of selinexor and combine it with other drugs that have fewer adverse effects, like elotuzumab and pomalidomide. We found that selinexor used in a lower dose, like 60 mg, and only once a week is much better tolerated than when we use it twice a week or in higher doses, such as 80 mg. We learned that lesson from the initial single-drug study, and we continue to as we use selinexor in a lower frequency and lower concentration in combination with other drugs. The data from the BOSTON trial are especially promising, where selinexor is used in combination with bortezomib, and showed superiority in a randomized trial over bortezomib and dexamethasone.

Considerations for adding selinexor to backbone treatments for triple-class refractory multiple myeloma based on data revealed by the STOMP trial.

Selinexor With Backbone Therapy for Triple-Class Refractory Multiple Myeloma

 At the time of first relapse, the majority of patients, at least in the United States, will have lenalidomide-refractory disease again by virtue of the fact that they’ve been on lenalidomide maintenance until disease progression. A lot of patients will fit in that category. The majority of patients in first relapse won’t have triple-class refractory disease. Typically, patients who have had 2 prior lines of therapy and then subsequently progressed will often be double refractory. But once you’ve gone through 3 prior lines of therapy and that third line of therapy has stopped working, the majority of patients are then becoming triple refractory.

There was a nice study, the MAMMOTH trial, that was spearheaded by Luciano Costa at the University of Alabama at Birmingham School of Medicine. They looked at this question specifically in patients with CD38-antibody refractory disease. It’s a little different. It’s not taking everybody with relapsed and relapsed/refractory disease. But for those who were CD38-antibody refractory, only 21% of them were not triple refractory. Everybody else was at least triple refractory. In fact, 25% of the patients were what we call penta-refractory, which basically means a disease that’s refractory to a CD38 antibody, lenalidomide, pomalidomide, and 2 proteasome inhibitors. Time is the biggest risk factor for developing triple-class refractory disease. The longer you have disease and have been on these therapies, the more time for the disease to find a workaround and develop resistance to those treatments. Most of us would agree that patients with high-risk multiple myeloma will develop triple-class refractory disease faster than patients with standard-risk disease.

 Patients with triple-class refractory multiple myeloma pose a challenge for treatment. Those patients are usually resistant to pomalidomide, lenalidomide, ixazomib, bortezomib, daratumumab, and isatuximab. We know those patients have remissions that last much shorter. Nevertheless, we thankfully had a couple of new approvals over the last year, which makes it much easier to treat patients with triple-class refractory multiple myeloma. Those drugs include selinexor, melflufen, and Blenrep. The options of those patients have broadened significantly.

We know that multiple myeloma is a disease that is relapsing. All patients experience multiple relapses before they become resistant. We know that the goal of the treatment is to postpone the relapses and use the best-available regimen. It is important to point out that in patients who are triple-class refractory, we need to switch the class and go to a new class. Options include Blenrep [belantamab mafodotin], selinexor, melflufen, and elotuzumab, which is also a good option, especially for patients who are older. Those new options have different toxicity profiles. It is important to discuss with the patient what the most suitable regimen would be for them and what is most appropriate based on prior cytotoxicities.

Triple-class refractory patients usually have a shorter duration of response. You can expect a duration of response of progression-free survival in patients to last several years—a median of 5 years—when they are initially treated and receive the transplant. This may be many more years with CD38 antibodies. The progression-free survival in patients with triple-class refractory multiple myeloma is much shorter. We know that can it last from 4 months, when they receive melflufen, to 6 months, when they receive selinexor. The difference is not too significant. It reflects that triple-class refractory multiple myeloma is a challenge for treatment and characterized by a much shorter duration of progression-free survival.

Sometimes you can see that there’s a change in biological behavior. Patients tend to have a much faster proliferation of the multiple myeloma cells. There’s also a higher tumor burden. They can have many more lytic lesions. Because of the multiple treatments patients receive, it is challenging to find the optimal doses of the treatment. They might start a fourth- and fifth-line treatment already with thrombocytopenia or neutropenia, which poses a further challenge to treat and find optimal doses for patients who are refractory.

It’s very difficult to tell a patient in their third, fourth, or fifth relapse what their prognosis is. What would be more honest is to say, “We know from clinical trials in which selinexor was used as a single agent that the median progression-free survival is 4.2 months.” When I discuss with my patients their prognosis, I usually discuss it based on the treatment I suggest. It’s very difficult to know what the options are after the treatment. For instance, a patient might change their prognosis by getting a BCMA BiTE [bispecific T-cell engager] or a CAR [chimeric antigen receptor] T-cell treatment. I would be hesitant to give a prognosis for patients who received their third- or fourth-line treatment. I would stick more to certain drug combinations I’m giving and rely on data that were obtained in clinical trials.

 The goal of therapy is obviously to get the disease under control, and this is particularly relevant for patients who are in clinical relapse and suffering from symptoms related to their disease progression. As I mentioned previously, durability of remission does shorten over the course of time. We always need to be cognizant of quality-of-life issues, but we need to be particularly cognizant of quality-of-life issues in this circumstance. Aside from navigating benefit as far as response to therapy and durability of that response, we have to be very careful about mitigating any adverse effects related to that treatment.

Insight regarding the risk of development of triple-class refractory disease in multiple myeloma and recommendations for working with patients to establish an appropriate treatment plan and counsel on goals of therapy.

Establishing a Treatment Plan for Triple-Class Refractory Myeloma

 It is important that when we initially start treatment for patients with multiple myeloma, we have all the information that guides us later. We need our serum protein electrophoresis, the free light chains, and also a bone marrow test that gives us good information about cytogenetics and FISH [fluorescence in situ hybridization]. This is very important because it provides a baseline for future decisions and for deciding whether the patient has high-risk or standard-risk multiple myeloma. I also want to point out that patients need sufficient imaging. A skeleton survey is not sufficient. In most parts of the world, especially in Europe, instead of a low-dose whole-body CT scan used in the United States, most of the patients get a PET-CT to visualize lytic lesions.

Especially in earlier relapses, it’s standard that patients receive imaging for the bones—best case, a PET [positron emission tomography] or CT also—to follow up on development and activity of lytic lesions. Is there productivity? In relapse situations, I usually also do a bone marrow biopsy, but the importance of the bone marrow biopsy varies. In very old patients, when you see a relapse and the development of new lytic lesions, and you have your cytogenetics and they are not high risk, you might not do a bone marrow biopsy. It changes in younger and older patients. In earlier relapses, you need information on the side of genetics; especially in younger patients. In older patients, where you focus more on the quality of life, you might omit a bone marrow biopsy if you have clear evidence of a relapse.

Patients in early relapse have a lot of options. It’s very difficult to pinpoint what we recommend for the first, second, and third relapses. A lot depends on the initial treatment. A lot also depends on the age and performance status of the patient. For instance, if a patient relapses or has a first relapse, I usually look at their initial response to the initial treatment. What was the duration of the response? Is there any resistance? For instance, patients who developed relapsed multiple myeloma and had prior RVd [lenalidomide, bortezomib, dexamethasone] and relapsed under Revlimid [lenalidomide] would now be good candidates for a CD38 antibody in combination with carfilzomib. I can’t give you a strict recipe. The treatment of relapse patients depends on what the patients had before and if there is any cross-resistance. We usually try to treat patients with a new drug class. For instance, if a patient never had a CD38 antibody initially, that would be the time in the first relapse to initiate a CD38 antibody. If a patient had Revlimid [lenalidomide] before, that patient would be a good candidate for pomalidomide. In the first and second relapses, we are still in a good situation to have treatment options like pomalidomide, carfilzomib, and daratumumab, to manage that situation very well.

 One of the most important considerations is to ask: What is the disease refractory to at the time of relapse? In first relapse, at least in the United States, lenalidomide maintenance therapy is often used until disease progression, provided the patient is tolerating it. At first relapse, a lot of patients will have lenalidomide-refractory disease. In that case, we’ll often go to a non-cross-resistant regimen as opposed to a lenalidomide-based regimen. That’s 1 thing that we look at. Past medical history is very important. For example, if you have a patient who has significant coronary artery disease, had a terrible myocardial infarction, and is now suffering from systolic congestive heart failure, that patient might not be the best candidate for a carfilzomib-based regimen. You might have a patient with a long history of suboptimally controlled diabetes mellitus who has painful neuropathy as a result. They may not be a good candidate for a bortezomib-based regimen. That’s important. It’s also important to recognize past toxicities of therapy that they’ve had. If someone had terrible bortezomib-related neuropathy with their initial induction therapy with lenalidomide, bortezomib, and dexamethasone, you may want to avoid a bortezomib-based strategy in the relapse space.

It’s important to look at whether the patient is in clinical relapse vs biochemical relapse. Biochemical relapse is a scenario where the numbers are getting worse, but the patient feels no different and is not experiencing any adverse sequelae of their myeloma progression. Whereas the patient in clinical relapse has new bone pain, for example. They might have renal failure, elevation in their calcium level, or become progressively anemic. With clinical relapse, you need to make sure you choose a regimen that’s going to get their disease under control very quickly. Whereas with patients with biochemical relapse, depending on the pace, you have a lot of different options available to you. You may be able to monitor the situation for a while without necessarily changing therapy. You may be able to tweak therapy a bit rather than completely moving to non-cross-resistant therapy.

We also like to look at standard vs high-risk cytogenetics. For patients with high-risk cytogenetics, we’re going to want to choose regimens that have performed well in that scenario. A good example is deletion 17p. We know that proteasome inhibitor–based therapy has performed well in patients who have deletion 17p. We also know that pomalidomide-based therapy has also worked very well in that setting. We now have emerging data that suggest selinexor is performing well in patients with deletion 17p. There are lots of factors to consider when choosing optimal therapy for a patient with relapsed myeloma.

As far as sequencing therapies, in general, it’s important to move to non-cross-resistant therapies at the time of progression. One of the things that we are often challenged with is a patient in first relapse who’s progressing in the face of lenalidomide maintenance therapy and technically has lenalidomide-refractory disease. The treatment strategies that are most commonly used would be a CD38 antibody, either daratumumab or isatuximab with pomalidomide and dexamethasone, or isatuximab or daratumumab with carfilzomib and dexamethasone. It remains to be seen which of those regimens is best.

Drug-resistance profile is important in the sequencing question. It’s also important that you use the regimens that are available for patients in the right space. As long as you’re doing that and making wise decisions about your treatment regimen based on the factors that I’ve already mentioned, the exact sequence might not make a big difference. For example, if you use a pomalidomide-based strategy in first relapse and a carfilzomib-based strategy in second relapse or vice versa, I don’t know that it’s going to make a big difference for the patients. They’re going to do well under both circumstances.

Strategies for patient assessment and treatment selection in patients with relapsed/refractory multiple myeloma.

Assessing and Managing Relapsed/Refractory Myeloma

 When we refer to relapsed multiple myeloma, we’re talking about multiple myeloma that has previously responded to therapy and has subsequently progressed. Typically, we want to see at least a minimal response for a 25% reduction in M [monoclonal] protein followed by subsequent progression. That would constitute relapse. Refractory is different. 

 essentially means that a patient’s disease is resistant to a particular therapy. That typically means the disease has progressed in the face of that therapy or has progressed within 60 days of stopping that therapy. There are also patients who have primary refractory disease, which has not responded to any initial treatment. Then there’s the relapsed and refractory, which means the patient has responded to therapy in the past, they’ve relapsed, and now the disease has become refractory to treatment.

 The number of patients refractory to treatment varies according to the stage of the disease. Almost all patients usually respond when they start the initial treatment. We have tested RVd [lenalidomide, bortezomib, dexamethasone], for instance, for newly diagnosed patients, or KRd [carfilzomib, lenalidomide, dexamethasone], and saw response rates over 90%. That rate of response decreases the number of relapses. We know that patients who have the third, fourth, or fifth relapse have a response rate of 30%. We recently saw that on trials using Blenrep [belantamab mafodotin], melflufen, and selinexor. In principle, you can say that the rate of responses decreases with the number of relapses, from initially over 90% of the overall response to fourth or fifth relapse to less than 30% of the response. That brings a huge challenge to the treatment of our patients. We know that the response rate decreases, but at the same time, patients do not tolerate the treatment very well. In addition to the decreased response rate, we see that the response duration decreases from initially 5 years after the first treatment with transplant to up to 6 months, or 4 months, for instance, which we saw in the melflufen trial.

It’s very important to point out that the initial response really matters. The goal of the treatment in multiple myeloma is to induce a long and deep response. We know that when patients receive MRD [minimal residual disease] negativity with the first treatment, the response can last much longer in comparison with patients who receive only a VGPR [very good partial response]. My goal with treatment is it to induce a deep response and MRD negativity initially.

I also want to point out that the goal of the treatment and response changes according to the age of the patient. In younger patients, the goal is to have a response over many years and to postpone the relapse by many years so that we first have an initial progression-free survival of 5, 6, or 7 years. That changes completely with the age of the patient. The goal of treatment in a 50-year-old patient is completely different from the goal of treatment in a patient who is 90 years old. In general, I’m more aggressive in transplant-eligible patients. In patients who are over 80 or 90 years old, the goal of the treatment is to maintain the quality of life, but control the disease at the same time. It’s important to point out that the quadruplet we are using in a 50-year-old patient may only be a doublet in a 90-year-old patient.

 The biggest challenge is keeping the disease under control once you’ve achieved a response to a particular therapy. The general paradigm has been that with each relapse, the likelihood of responding to therapy begins to drop. Even for those patients who do respond to therapy, the durability of the remission tends to decrease over time, to the point where the disease becomes relapsed and refractory to essentially all available therapy. That’s the biggest challenge. The other challenge, which is probably more relevant to patients who have had multiple prior lines of therapy, is management of adverse effects of treatment. These patients are often suffering from significant adverse effects of their disease, but also significant adverse effects of prior therapy, some of which may not have fully resolved. They may be more sensitive to low count issues related to treatment. Those are the biggest challenges as far as managing a patient who has relapsed/refractory myeloma.

Criteria for diagnosis and risk stratification in patients with relapsed/refractory multiple myeloma.

Peter Voorhees, MD, Atrium Health Levine Cancer Institute

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