Delivering Deep, Durable Remissions Remains Primary Focus in Multiple Myeloma

Thomas G. Martin, MD, a clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program at the University of California, San Francisco

Thomas G. Martin, MD

With the number of effective combinations and novel agents that have surfaced in recent years, patients with multiple myeloma should be treated as aggressively as possible, whether in the frontline setting or early relapse setting, to provide lasting remission durations, explained Thomas G. Martin, MD.

“I don’t believe that we should save something for the future, especially in cancer medicine,” said Martin, clinical professor of medicine, Adult Leukemia and Bone Marrow Transplantation Program, and associate director of the Myeloma Program at the University of California, San Francisco (UCSF). “I try to treat everyone’s disease—whether frontline, early relapse, or late relapse—with the best combination [available].”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Martin, who is also the co-leader of the Hematopoietic Malignancies Program, UCSF Helen Diller Family Comprehensive Cancer Center, discussed the current treatment approaches in multiple myeloma, as well as the agents that are generating excitement in relapsed/refractory patient populations.

OncLive: Should the most potent drugs be used in the frontline setting or saved for later lines of treatment?

Martin: People always ask me whether we really want to put our most potent drugs up front. Do we want to use quadruplets? Do we want to use daratumumab (Darzalex), lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone—or daratumumab, carfilzomib (Kyprolis), lenalidomide, and dexamethasone (D-KRd)? My answer to that is a resounding “Yes.” I always take it back to basketball: I want to put my best team on the court right from the start. We want to get ahead of the game and potentially win by [unleashing] our best group first. I don’t believe that we should save options for future use. [After I] treat with the best combination, I go to whatever my next drug is.

Today, if we start D-KRd, we suspect that the progression-free survival (PFS) of a patient with standard-risk, newly diagnosed disease is going to be 5, 6, or more years. Five or 6 years after today, I don't know what we're going to give patients at first relapse. The drug may not have been discovered yet, or it might be a combination of a CAR T-cell therapy plus maintenance therapy. It might be a bispecific T-cell engager (BiTE) antibody plus maintenance therapy or it might be an antibody-drug conjugate (ADC). [Regardless], it's certainly going to be different than what we're doing now for patients in first relapse.

Could you discuss the current management of patients in first relapse?

We have had good fortune in myeloma to have many agents available, so we have several choices. Many of our patients receive frontline therapy and then continuous maintenance therapy. Most of the time, lenalidomide is given as maintenance therapy. When patients have their first relapse, the biggest question is whether they’re still on lenalidomide. If they are still on lenalidomide, we have to choose regimens that favor lenalidomide-refractory patients. If they're not on lenalidomide, we can use a regimen that contains lenalidomide.

When patients experience first relapse, I believe we should treat them as aggressively as possible. Those patients are still able to achieve deep second remissions, and hopefully, very prolonged PFS. There has always been controversy regarding patients who have a slow relapse, an intermediate-to-fast relapse, and those who are doing really well at relapse whether we should treat them with a “light” regimen. My response to that is “No.” I like to treat all patients in first relapse very aggressively and with our best agents. We have many different types of agents, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies. We also have second-generation IMiDs and PIs.

Typically, we administer triplet therapy. In early relapse, we have found that the anti-CD38 monoclonal antibody daratumumab is a very potent agent. Patients have a fairly [strong] immune system at that time, can really take advantage of the monoclonal antibody, and use antibody-dependent, cell-mediated, and complement-dependent cytotoxicity to provide a fairly robust antimyeloma effect.

Many good agents can be partnered with daratumumab. If patients are sensitive to lenalidomide, we’ll combine daratumumab with lenalidomide and dexamethasone. That regimen provides an overall response rate (ORR) of more than 90% and deep remissions. If patients are refractory to lenalidomide, our choices are either daratumumab with pomalidomide (Pomalyst) and dexamethasone, or daratumumab, carfilzomib, and dexamethasone (KdD).

Could you highlight some of the exciting data in this space that were presented at the 2019 ASH Annual Meeting?

At the 2019 ASH Annual Meeting, the CANDOR trial results were presented. The randomized phase III trial compared KdD with Kd alone in patients who had received 1 to 3 prior lines of therapy. We saw an improvement in ORR in the triplet arm versus the doublet arm as well as an improvement in PFS. [Now we know that] KdD is also a really good regimen. About one-third of the patients were refractory to lenalidomide, so we now have data showing that the regimen works really well in that subset.

Prior to the phase III trial, Ajai Chari, MD, of Mount Sinai Hospital, led a phase II study looking at KdD. In that study, carfilzomib was given at a dose of 70 mg weekly. In lenalidomide-refractory patients, [the median PFS was very impressive], which is pretty remarkable. We always thought that [daratumumab] would work better with IMiDs, but in fact, it works very well with PIs as well. We also have the oral PI, ixazomib (Ninlaro), which has been combined with lenalidomide and dexamethasone in patients who received 1 to 3 prior lines of therapy. Ixazomib also works well in combination with pomalidomide and dexamethasone in patients who received 1 to 3 prior lines of therapy.

We also saw data with venetoclax (Venclexta), which is a BCL-2 inhibitor. Venetoclax has shown single-agent activity in patients with relapsed/refractory myeloma, particularly in those who have an 11;14 translocation [t(11;14)]. Specifically, an ORR of 40% [was observed with the agent], which is pretty amazing. Philippe Moreau, MD, of Nantes University Hospital, and colleagues combined venetoclax with bortezomib and dexamethasone in a phase I dose-expansion study in patients with relapsed/refractory disease. In bortezomib-sensitive patients who received 1 to 3 prior lines of therapy, the ORR exceeded 95% [with venetoclax]. That led to the phase III trial, now known as the BELLINI trial.

The BELLINI trial evaluated venetoclax, bortezomib, and dexamethasone versus bortezomib/dexamethasone in patients who received 1 to 3 prior lines of therapy. At the first [interim] analysis, the investigators reported that the triplet showed superior response rates and PFS versus the combination. However, decreased overall survival (OS) in patients who received the triplet were also reported. We saw almost a 20% mortality rate in the triplet arm, which was mostly due to infection. A small number of patients had cardiac toxicity. We don't truly understand the cause of the toxicity, especially the mortality. [The question of] how we’re going to mitigate [those toxicities] going forward still needs to be ironed out.

Notably, if we look only at the subset of 40 patients who had t(11;14), a marked advantage was observed with the triplet. The hazard ratio was about 0.10. That is the lowest hazard ratio that I've ever seen in a study; it's pretty amazing. This shows us that venetoclax is a very potent agent in patients with t(11;14). Notably, these patients overexpress BCL-2. If you can expand the [known] population of patients who express BCL-2 by doing a polymerase chain reaction test, you can double the population that may be sensitive to venetoclax. BCL-2—high patients also have a dramatic increase in ORR and PFS with the triplet.

In the general relapsed/refractory population, venetoclax needs to be investigated further before we get too excited about it. However, we’re seeing dramatic responses in the subset of patients who have BCL-2 [overexpression] or t(11;14). I believe that it’s going to be one of the best therapies for them in the relapsed setting, but I also think we’re going to move [the triplet] into the frontline setting because it works so well.

How are you navigating patient selection when it comes to treatment?

We’re going to come to an era of biomarker-driven therapeutics. Right now, [the utility of venetoclax] is limited to patients with t(11;14). We may expand its use to include those with BCL-2 overexpression. For the majority of patients, there isn’t a biomarker [that drives treatment decisions] yet. However, we’re going to look for more biomarkers. I always tell my patients about the triplets that are associated with the longest PFS.

I also go through more convenient options, such as all-oral options compared with subcutaneous and intravenous (IV) options. One of the things that is going to make a big difference is [subcutaneous daratumumab]. In a randomized phase III trial, investigators compared the subcutaneous administration of daratumumab over 5 minutes with the IV administration of daratumumab, of which the first dose can take 7 to 8 hours. Subsequent doses can [take] 4 hours. If you do the rapid infusion, it can take 90 minutes. Still, 5 minutes versus 90 minutes makes a big difference. Once daratumumab becomes available subcutaneously, it’s going to have even more widespread use in the early relapse setting.

In terms of treatment selection, most patients respond well to our available triplets. [We have the luxury of] picking our triplet of choice. [For example], if I gave daratumumab, pomalidomide, and dexamethasone for first relapse, I would move to a carfilzomib-based regimen for second relapse—perhaps carfilzomib, cyclophosphamide, and dexamethasone, or carfilzomib, panobinostat (Farydak), and dexamethasone.

What are some exciting emerging approaches?

[First, there is] CAR T-cell therapy, which is here to stay. Some of the new CAR T-cell products that are being tested in the United States include JNJ-4528; [this has the same CAR construct as] LCAR-B38M, which came out of China [and was studied in] the LEGEND[-2 trial]. It’s an exciting product because it has a dual epitope binder to BCMA as the binding protein and a 4-1BB costimulatory domain. In the phase I study that was done in the United States, 29 of 29 patients [with relapsed or refractory disease] responded to the therapy, which is pretty amazing. The data are still quite early. Unlike in lymphoma, we’re seeing patients relapse at 3, 6, 12, and even 24 months out. We don’t see a flattening of the curve as we do in lymphoma. Typically, in lymphoma, if patients are still in remission at 6 months, they maintain that remission. In myeloma, relapses keep occurring. We have room for improvement.

I’m also excited about a couple of off-the-shelf products. One is the BiTE antibodies. In a presentation on a novel [BiTE] from Celgene, which has a binding domain to BCMA and CD3, the investigators reported data from the first-in-human dose-escalation trial. They showed that patients who received 6 mg [of the agent], what they believe is the optimal dose, had an ORR of approximately 90%. This is a really relapsed/refractory population, and thus far, the responses appear to be deep and durable. A majority of those patients are able to achieve minimal residual disease (MRD) negativity in their bone marrow. However, [the agent is] not without toxicity. Patients still develop cytokine release syndrome and there's concern that they could potentially develop neurotoxicity. Patients do have to be hospitalized for the first 72 hours after their first infusion as well as for any dose escalation. After those first couple of hospitalizations, patients can continue to receive the medication as outpatient therapy. These are single agents that are leading to outpatient treatment with fairly little toxicity and no steroids.

The other drug that we heard a lot about was belantamab mafodotin, which is a BCMA-targeted ADC from GlaxoSmithKline. Over the past 12 to 24 months, we saw data emerge from a dose-expansion trial. Among 35 patients with relapsed/refractory disease [treated with belantamab mafodotin] the ORR was 60%. Patients who were exposed to daratumumab had an ORR of 38.5%, again suggesting the difficulty of treating patients with triple-class refractory disease. However, a 38.5% ORR without steroids is quite respectable. We also saw other abstracts on other aspects of belantamab mafodotin [at the 2019 ASH Annual Meeting] that I believe are going to bode well for the agent in the future. We're looking forward to future studies with the agent in combination with PIs, IMiDs, and daratumumab. This is a drug we’re going to see more frequently in the next 6 to 12 months.

How has the approval of selinexor impacted the relapsed/refractory setting, and what are some of the strategies in place to mitigate associated toxicities?

The unmet medical need in myeloma at the current time is the group of patients who are triple refractory; they are refractory to an IMiD, a PI, and a monoclonal antibody. These patients typically have an OS of less than 1 year. We don't have many exciting therapeutics that are approved for use at the current time, but we do have options. One of these options is selinexor, which was approved for use in combination with dexamethasone last year. Selinexor is part of a novel class of drugs called selective inhibitors of nuclear export; these drugs block the exportin 1 protein. The agent turns the cancer cell into a normal cell, so that it can undergo apoptosis when given in combination with other medications such as dexamethasone. With the combination, we saw an ORR of 26% in this triple-class refractory population. No other combination of agents—short of very intensive chemotherapy, which many patients aren't candidates for—has that kind of ORR.

Toxicities are associated with selinexor, so we have to watch patients closely for them. It's an agent we can all use, but we have to use it in the right way. We can't tell patients to take selinexor and dexamethasone twice a week and come back in 4 weeks; that is not the way to use the regimen in a population that already has blood count suppression. Patients may not be very robust. Patients need weekly, if not twice-weekly, blood counts, and weekly monitoring of their electrolytes. Patients can become hyponatremic; they can also experience nausea, loose stools, and become hypovolemic. Typically, we have patients come [into clinic] once or twice a week for IV fluids, to get their serum sodium checked, and to [receive] salt tablets, as needed. We have patients on double antinausea medications, potentially some antidiarrheal medications, and occasionally a stimulus like methylphenidate (Ritalin) or some other medication that will give them more energy and make them feel a little bit better.

It's not a drug for everyone. I do believe that patients can try it for a few weeks. They know right away whether they're tolerating it or not. If they're not tolerating the medication, then you stop. If they’re tolerating it, and you see some [decrease] in their [counts], they can continue to take it. We use selinexor as a bridge between when they're triple-class refractory to when we can hopefully get them on a clinical trial. In that circumstance, we can use the agent to hold their disease, so that they don't progress in that period of time.

What does the future of multiple myeloma treatment look like with all of these effective agents?

Because the agents are so potent, our goal in the future is going to be to achieve an MRD-negative state, and I believe that may have been an end point in one of the frontline trials with D+KRd. We’re going to have to be able to use MRD for treatment decisions. One of the studies that was presented at the 2019 ASH Annual Meeting by Luciano J. Costa, MD, PhD, of the University of Alabama, showed that when patients received D-KRd as induction followed by autologous transplant, followed by D-KRd for consolidation, you can look at MRD at each time point. When patients achieved sustained MRD negativity, the patients were taken off therapy. Those patients have continued in remission, which is amazing.

In the future, I think we're going to have studies that will show that MRD is the goal of treatment—especially sustained MRD. We’ll have to define what that means. Is [sustained MRD] 6 months, or 1 year? Additionally, at what time point can we take patients off therapy? The goal moving forward will be to achieve deepest remission, sustain it, and then take patients off therapy and see how they do. Hopefully, patients can spend more time off therapy than on therapy in the future.