Belantamab mafodotin is emerging as a novel BCMA-targeted therapeutic option to treat patients with heavily relapsed/refractory multiple myeloma, a population that continues to be an unmet need, explained Sagar Lonial, MD, FACP.

The DREAMM-1 trial evaluated the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical activity of belantamab mafodotin in patients with relapsed/refractory myeloma and other advanced BCMA-expressing hematologic malignancies. These data elicited an overall response rate (ORR) of 60.0%, with 3 complete responses (CRs) and 2 stringent CRs.1 The median progression-free survival (PFS) was 12 months (95% CI, 3.1—not estimable), and the median duration of response was 14.3 months (95% CI, 10.6-NE).

The DREAMM-2 trial compared different doses of belantamab mafodotin in patients with relapsed/refractory myeloma. The agent showed an ORR of 31% (97.5% CI, 20.8-42.6) in patients receiving the recommended 2.5-mg/kg dose. In those who received belantamab mafodotin at 3.4 mg/kg, the ORR was 34% (97.5% CI, 23.9-46.0).

Based on the DREAMM-2 data, the FDA granted a priority review designation to belantamab mafodotin in January 2020 as a treatment for patients with relapsed/refractory multiple myeloma who received prior therapy with an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 agent.

“Having an off-the-shelf BCMA targeted therapy is a really easy and simple way to talk about treating [patients] when you don't have a lot of other options,” said Lonial. “I suspect other [BCMA-targeted therapies] will start to move [into] the treatment paradigm as well.”

Data show that belantamab mafodotin is associated with ocular adverse events (AEs), which are typically manageable with supportive care and dose modifications. Monitoring and treating these AEs allows patients to continue with treatment, sometimes with a brief pause.

The next steps to take with belantamab mafodotin will involve searching for other agents to pair with the antibody-drug conjugate (ADC).

, Lonial, professor and Anne and Bernard Gray Family Chair in Cancer at Emory University School of Medicine, as well as chief medical officer at Winship Cancer Institute of Emory University, discussed the encouraging activity with the BCMA-targeted agent belantamab mafodotin in multiple myeloma.

: What novel therapies are being explored in multiple myeloma?

: The novel approaches involve the use of BCMA-targeted therapy, including ADCs—such as belantamab mafodotin&mdash;bispecific antibodies, or CAR T-cell therapy. [BCMA] is the next new big target in myeloma. We are trying to figure out the best approach, when to use [these BCMA-targeted therapies], and how to maximize their benefit to eventually discuss curing patients.

How will ADCs transform the myeloma landscape?

ADCs, particularly those targeting BCMA, have the ability to come off the shelf, meaning you don't have to wait for [the ADCs] to be available. They don't necessarily have the inpatient hospitalization that you might see with bispecific T-cell engagers (BiTEs) in terms of cytokine release syndrome (CRS) or other potential complications. As we're learning from early-phase studies, [ADCs] are able to be combined with other standard anti-myeloma drugs. Figuring out how to use [ADCs] and position them in a way that is effective immediately and can translate into long-term immunity is an exciting part of ADCs.

Could you discuss the DREAMM-1 and DREAMM-2 trials and their impact on the paradigm?

What we know about belantamab mafodotin comes from 2 trials: DREAMM-1 and DREAMM-2. The first was the DREAMM-1 study, which was a phase I trial designed to identify the dose that should go forward in trials. We saw that the ORR was around 60%. The median PFS was somewhere between 11 and 12 months. In that same trial, if you look at a penta-refractory patient population, these numbers are much smaller [compared with the overall DREAMM-1 population]. We demonstrated that the response rate was somewhere around 35% to 40% and the median PFS was around 4 months.

In DREAMM-2, we tested 2 different doses of belantamab mafodotin. One dose was 2.5 mg/kg and the other was 3.4 mg/kg; we tried to identify which was the safer dose to move forward. The ORR was relatively similar, at about 30% in both cohorts, which is similar to what we have seen for every other approved drug in the refractory myeloma setting. The median PFS is somewhere around 3 months. It looks like the duration of response is going to be much longer, suggesting that the responses patients get are durable.

If you begin to look at AEs, there were 2 big categories that came up. One was ocular toxicity, which can be managed with dose modifications and adjustments. The second was hematologic toxicity, which was not unexpected, given that it's an ADC. The hematologic toxicity is easily manageable by most hematologists and belantamab mafodotin hopefully will be a very active drug for us. The ability to combine belantamab mafodotin with other drugs is what we're looking at in current trials.

You want to partner with an ophthalmologist who can give you some early clues as to what's going on in the cornea, and then make decisions based on symptoms and AEs—regarding whether you want to hold the dose, give the dose, make dose adjustments, or dose modifications. Those are probably the biggest issues. Much of the other toxicity is infusion related, which is standard for most of us in hematology. There is also thrombocytopenia or hematologic toxicity, which most of us are used to dealing with in this disease.

If belantamab mafodotin receives FDA approval, what impact will it have on the myeloma landscape?

As good as we've gotten in myeloma, unfortunately, there still are a lot of patients who run out of available treatment options. Having something for those heavily relapsed and refractory patients will be a huge step forward.

What are the next steps of this research with belantamab mafodotin?

Beyond FDA approval, the next steps include combining belantamab mafodotin with standard drugs, such as bortezomib (Velcade), lenalidomide (Revlimid), pomalidomide (Pomalyst), and carfilzomib (Kyprolis). There are also other studies combining belantamab mafodotin with checkpoint inhibitors to see whether or not you can take that immunogenic cell death and use that to spur on an immune response that may last longer than the time that you're giving the drug. That is an exciting concept if we can prove that it works.

Trudel S, Lendvai N, Popat R, et al. Antibody—drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. 

. 2019;9(37). doi: 10.1038/s41408-019-0196-6           

Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. 

 2020;21(2):207-221. doi: 10.1016/S1470-2045(19)30788-0

Articles

Sagar Lonial, MD, FACP, discusses the encouraging activity with the BCMA-targeted agent belantamab mafodotin in multiple myeloma.

Belantamab Mafodotin Emerging as Novel Option for Relapsed/Refractory Myeloma

A significant uptick in investigational research regarding BCMA-directed therapies, specifically in the form of CAR T-cell therapies and antibody-drug conjugates (ADCs), has been underway to tailor therapies for patients with multiple myeloma and, in turn, enhance response rates, explained Jorge E. Cortes, MD.

"The advantage of BCMA is that it appears to be fairly selective for myeloma cells," said Cortes. "A lot of research is being directed toward using that factor to develop specific immunotherapies. We are starting to see some of that data emerge, and it is likely we will see approved agents for these indications in the next 2 to 3 years."

For example, the BCMA-directed antibody-drug conjugate (ADC) belantamab mafodotin demonstrated intriguing findings in the pivotal DREAMM-2 trial, in which the agent elicited an overall response rate (ORR) of 31% (97.5% CI, 20.8-42.6) in patients with relapsed/refractory myeloma who received the treatment at the recommended 2.5 mg/kg dose. In those who received belantamab mafodotin at 3.4 mg/kg, the ORR was 34% (97.5% CI, 23.9-46.0).

Based on these data, the FDA granted a priority review designation to the ADC in January 2020 as a treatment for patients with relapsed/refractory multiple myeloma who received prior therapy with an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody.

, Cortes, director of the Georgia Cancer Center at Augusta University, discussed the evolution of multiple myeloma treatment, the role of BCMA-directed therapies, and remaining questions that need to be addressed in this space.

: How has the treatment of patients with multiple myeloma transformed over recent years?

: The story with multiple myeloma has been dramatically changing in a relatively short period of time. When I started as a fellow, we were [exclusive giving patients] melphalan. Then the emergence of the vincristine, doxorubicin, and dexamethasone regimen was [revolutionary].

Now, we have all these remarkably effective drugs and, in particular, combination strategies. We are not using single-agent regimens, but rather we are combining proteasome inhibitors, CD30-directed monoclonal antibodies, and immunomodulatory agents, such as lenalidomide (Revlimid).

These combinations have given us remarkable responses to the point where we are getting a significantly higher rate of true complete remissions, with very little minimal residual disease in many patients. Our definition of responses may have evolved to emphasize how good the responses are.

While the role of transplant is not gone, we are thinking less about transplant; it is no longer a default for every patient.

Additionally, we are beginning to think about [implementing therapies] earlier in the course of disease. Should we start to treat patients with smoldering myeloma? In the past, we haven't because giving an alkylating agent to a patient with smoldering myeloma could create more problems. However, now we are starting to think that we should treat patients early because it may prevent progression to multiple myeloma.

What role does BCMA play as a target in multiple myeloma?

BCMA is an important target because it is very specific to myeloma cells. That opens the door to a lot of possibilities regarding the use of immunotherapy with monoclonal antibodies or CAR T-cell therapies, which may specifically direct toward this target.

The problem with developing these immune-based therapies is that, if you don't have a selective marker for the tumor, non-specific toxicities will be created. That is what happened in acute myeloid leukemia (AML), for example.

Potentially, that is going to represent a shift toward our use of stem cell transplant. Do we need to use stem cell transplant if we have a different modality of cellular therapy available?

Could you discuss the rationale for utilizing ADCs in multiple myeloma?

ADCs are going to help because they allow you to direct cytotoxic agents specifically to the malignant clone. However, the challenge here again is that you need a specific selective marker that can do that. Targeting a protein that is expressed in many other cells that you do not want to destroy will result in a lot of toxicity. If you instead have a marker that is selected for the malignant clone, you can [eliminate much of that toxicity risk].

ADCs require 3 main elements: an antibody directed at a good target, an effective toxin to kill the malignant clone while minimizing toxicity in the surrounding cells, and a linker that will remain stable while connecting the antibody and the toxin. That linker should only break once the drug is inside the targeted cell.

We are starting to see some of these drugs emerge in other malignancies. In AML and acute lymphoblastic leukemia, for example, we have gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin (Besponsa). We know the principle [behind ADCs] works, but now we need to expand it to other tumors, such as multiple myeloma, where we are starting to identify actionable markers.

What questions remain regarding some of these novel regimens or modalities in multiple myeloma?

We have gone from single agents, to doublets, to triplets, and now we are starting to see quadruplets. Combinations of standard triplet regimens, such as bortezomib (Velcade), lenalidomide, and dexamethasone, are now expanding to include daratumumab (Darzalex). Over the next few years, I anticipate that we are going to see a lot more of these quadruplets emerge.

The remaining question is, “Where do we use the quadruplets? Do we use them in every patient or only for high-risk patients?”

Additionally, if CAR T-cell therapy becomes a reality, will CAR T-cell therapy be used following transplant or replace transplant? How do we use CAR T-cell therapy? Right now, these are the key questions that will likely be answered over the next 2 to 3 years.

. 2020;21(2):207-221. doi: 10.1016/S1470-2045(19)30788-0.

Jorge E. Cortes, MD, discusses the evolution of multiple myeloma treatment, the role of BCMA-directed therapies, and remaining questions that need to be addressed in this space

Cortes Underscores Rationale for BCMA-Directed Therapy in Multiple Myeloma

Jorge E. Cortes, MD, director of the Georgia Cancer Center at Augusta University, discusses the advantage of BCMA-targeted therapy in multiple myeloma.

BCMA is a cell surface protein that is highly expressed on all myeloma cells and not normal cells. As such, BCMA has proven to be an effective target in multiple myeloma with treatments such as antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapy, says Cortes. Having a highly specific target is important in terms of efficacy and safety, explains Cortes. If the therapy is not highly specific to a target, it can lead to severe off-target toxicities.

A lot of research is moving toward developing more specific BCMA-directed immunotherapies, which may become available for commercial use in the next few years. Whether these agents will affect the use of stem cell transplant has yet to be determined, concludes Cortes.

Videos

Dr. Cortes on the Advantage of BCMA-Targeted Therapy in Multiple Myeloma

Noopur Raje, MD, director, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, and professor of medicine, Harvard Medical School, discusses data with AMG 420 in multiple myeloma.

Several novel bispecific T-cell engagers (BiTEs) are in development in multiple myeloma, says Raje. The drug that’s the furthest along in development is AMG 420, which is an off-the-shelf product. In vivo, the agent targets BCMA; it has a different linker which activates a patient’s T cells that then target the malignant myeloma cells and kills them.

The drug has shown remarkable responses in patients with heavily relapsed/refractory myeloma, leading to minimal residual disease (MRD) negativity. Additionally, some patients are on the drug for close to 1 year, says Raje. However, AMG 420 is a short-acting BiTE, so it has to be given continuously; this can make it challenging for patients because they have to wear a pump in order to receive the drug.

Another BiTE that is being developed by Celgene has been shown to lead to MRD negativity in patients. The difference between this BiTE and the Amgen BiTE is that it’s longer acting; therefore, it doesn’t have to be given as an infusion. Investigators are also working on developing a subcutaneous formulation that could make it easier to administer, concludes Raje.

Dr. Raje on Data With AMG 420 in Multiple Myeloma

Gareth J. Morgan, MD, PhD, a professor in the Department of Medicine and director of Multiple Myeloma Research, NYU Langone Health’s Perlmutter Cancer Center, discusses BCMA-targeted antibody-drug conjugates (ADCs) in multiple myeloma.

ADCs are designed to provide a direct means of killing malignant cells, explains Morgan. The drug that is the furthest along in development is belantamab mafodotin, where monomethyl auristatin F (MMAF) is linked to a BCMA antibody. The linker transports MMAF to the malignant cell, and kills it by inhibiting its spindle, explains Morgan.

Findings from the phase I DREAMM-1 trial and phase II DREAMM-2 trial are very encouraging, says Morgan. In the DREAMM-2 trial, more than 30% of patients experienced durable responses with belantamab mafodotin. Although there is concern for ocular toxicity that can lead to keratopathy, investigators are evaluating alternative dosing schedules to reduce this risk, concludes Morgan.

Dr. Morgan on BCMA-Targeted ADCs in Multiple Myeloma

Preliminary data with BCMA-directed antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and CAR T-cell therapy have demonstrated the importance of targeting BCMA in multiple myeloma, according to Noopur S. Raje, MD.

“BCMA is B-cell maturation antigen, which belongs to the tumor necrosis factor-α superfamily,” explained Raje. “BCMA is expressed on all multiple myeloma cells but not really on normal cells, so it tends to be a really good target [for treatment].”

Each modality has demonstrated high response rates in heavily pretreated patients. For example, in the phase II DREAMM-2 trial, the ADC belantamab mafodotin led to an overall response rate (ORR) of 31% in patients with relapsed/refractory disease who received the treatment at the recommended 2.5 mg/kg dose. Furthermore, the ORR was 34% in those who received belantamab mafodotin at 3.4 mg/kg.

 In January 2020, the FDA granted a priority review designation to a biologics license application for the agent as a treatment for patients who relapsed on prior therapy with an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and a CD38-directed antibody.

Additionally, data from a phase I trial showed that the BiTE AMG 420 elicited an ORR of 70% when administered at a maximum-tolerated dose of 400 µg/d in patients who received a median of 4 lines of prior therapy.

Among CAR T-cell therapies, bb2121 is the furthest in development, said Raje. In the phase II KarMMA trial, idecabtagene vicleucel (ide-cel; bb2121) led to an ORR of 73.4% in patients who received the product across the target dose levels of 150 to 450 x 10

 All treated patients had received ≥3 prior therapies, including an IMiD, a PI, and a CD38-directed antibody, and all were refractory to the last regimen that they received.

Additionally, treatment with the CAR T-cell product JNJ-4528 was shown to induce an ORR of 100% in patients who received a median of 5 lines of therapy.

 In December 2019, the FDA granted a breakthrough therapy designation to JNJ-4528 for the treatment of patients with relapsed/refractory myeloma.

 State of the Science Summit™ on Multiple Myeloma, Raje, director, Multiple Myeloma Program, Medical Oncology, Massachusetts General Hospital, and professor of medicine, Harvard Medical School, discussed the preliminary data with BCMA-directed treatment strategies in multiple myeloma.

: Could you discuss the success of BCMA-directed treatment approaches in myeloma?

: We know BCMA is a good target based on some of the clinical data we have. Many different BCMA-directed approaches are under investigation. [There is an] entire spectrum of BCMA-directed strategies, which include conjugated antibodies, BiTEs, and most excitingly, cellular therapies, such as CAR T-cell therapy.

Starting with ADCs, could you discuss the data that have been reported with belantamab mafodotin?

Belantamab mafodotin is the GlaxoSmithKline conjugated antibody; it has MFA as its toxin. We have seen some impressive single-agent data. In the DREAMM-1 trial, the ORR was about 60%. [Updated data] showed that the [median] progression-free survival with the agent was about [12] months, which is quite remarkable. To put this in content, single-agent daratumumab (Darzalex) had a 30% response rate when we first started using CD38-directed therapies; this is double that rate, further demonstrating the efficacy of targeting BCMA. One of the toxicities [associated with belantamab mafodotin] that we struggle with is the ocular toxicity; it’s more of a corneal toxicity. To this end, different dosing schedules and different strategies are being [investigated]. The hope is that we can mitigate some of these toxicities so that patients can stay on this drug.

What would the potential implications be if the drug is approved?

The good news is that it’s going to be an off-the-shelf antibody, so it's going to be easy to access. We don’t see a lot of toxicity outside of the ocular toxicity, so I believe that it’s going to be easy to combine with some of our backbone therapies. Ongoing trials are examining every potential combination with this drug, and I think it’s going to be used in combination going forward. Overall, we’re going to bring BCMA-directed strategies into earlier lines of therapy for patients with myeloma.

Are any other notable ADCs in the pipeline?

Some of the others are very early on in development. A few are in phase I clinical trials; for example, one ADC from MedImmune and AstraZeneca is currently in clinical development. No data have been presented with that agent yet, but it has the same target [as belantamab mafodotin]. We're looking forward to seeing those data.

BiTEs are also under investigation. Could you discuss the research being done with AMG-420? Do any challenges exist with this agent?

BiTEs are novel drugs in myeloma. We have several BiTEs that are in clinical trials. We saw data from the 2019 ASH Annual Meeting and 2019 ASCO Annual Meeting [on these drugs], some of which has been published. The drug that’s the furthest along in development is AMG 420. In vivo, it targets BCMA; it has a different link or arm, which activates a patient’s T cells and brings them to the myeloma cells and kills them. For such a strategy to work in myeloma is incredible. It’s an off-the-shelf approach.

However, AMG 420 is a short-acting BiTE, so it has to be given continuously; this can be a little cumbersome because patients have to wear a pump in order to receive the drug. Regardless, it’s remarkable that patients with heavily relapsed/refractory myeloma are achieving minimal residual disease (MRD) negativity. We’re seeing very deep responses. Most importantly, some patients are on the drug for close to 1 year. Even so, AMG 420 is still in early stages of development.

Data with a BiTE from Celgene were also presented at the 2019 ASH Annual Meeting. Again, we’re seeing MRD-negative responses in patients. The difference between this BiTE and the Amgen BiTE is that it’s longer acting; as such, it doesn't have to be given as an infusion. Investigators are trying to make a subcutaneous formulation. The results we saw were really encouraging.

We’re just [scratching the surface] with BiTEs. We are trying to figure out how best to deliver [these agents]. Most of us are [pushing for] subcutaneous dosing, which we’re already doing with [PF-06863135]. I presented data on the agent at the 2018 ASH Annual Meeting. Initially, we were giving the agent intravenously every week. Now, it's going to be given subcutaneously because it's a longer-acting bite. We're seeing similar responses with all of these BiTEs, so there is a lot of excitement in the space. Over time, we're going to figure out which of these BiTEs is best suited for which patients, as well as what the toxicity profiles are.

How do you foresee personalized strategies with BiTEs?

I don't know if we have the answer to that because we're in such early stages of clinical development. The exciting piece here is we're seeing deep and durable responses in very refractory patients. We have to figure out what the toxicities are with these agents as well as determine the most convenient route of giving these drugs to patients. Over time, can we decrease the frequency of these BiTEs? Ongoing clinical trials are going to be critical in answering some of those questions. The fact that we’re even asking them is exciting.

Could you speak to the rationale for CAR T-cell therapy in myeloma?

CAR T-cell therapy is our first foray into cellular therapy; this approach is a little bit different from [that of ADCs and BiTEs], but the target is the same. Most of the cellular therapy products are targeted against BCMA. CAR T cells have to be generated. The T cells are taken from a patient, genetically modified, and then given back to the patient. The idea is the same as with [BiTEs and ADCs] in that they kill cancer cells. [The approach comes with] certain events that we’re familiar with, such as cytokine release syndrome and neurotoxicity. The toxicities associated with CAR T-cell therapy in [patients with] myeloma have been very manageable. We have been pleasantly surprised by that. This may be because we've gotten better at managing these toxicities.

Again, we’re seeing deep and durable responses among patients who really didn’t have any other option. Given its efficacy, we’re studying this approach earlier on in the course of myeloma. We have national and international trials that are evaluating cellular therapy at first relapse or at initial diagnosis. It’s an exciting area of research.

Could you highlight some of the products under investigation?

Many different products are out there, but bb2121 is the furthest in development. The data from the phase I trial of that product have been published. The phase II trial has completed accrual. Hopefully, those data will be submitted to the FDA for approval of what would be the first cellular therapy in multiple myeloma. The Janssen product is not far behind. We saw the data from the CARTITUDE-1 trial [with JNJ-4528] at the 2019 ASH Annual Meeting. The results were very impressive with a very high response rate; the 6-month follow-up showed pretty durable responses. We’ll have to wait and see how long those responses last. That’s the same product that was studied in China in the LEGEND-2 trial. We’re seeing very similar results.

Other CAR T-cell products have used lentiviral-based transfection. Others have used different methods to create a more durable CAR with even better responses. Many different approaches are being examined. Going forward, we will be studying [allogeneic] CAR T-cell therapy, which are off-the-shelf products. You don't need to wait 3 to 4 weeks to generate the CAR. We’ll be opening some of those clinical trials in the next couple of months at Massachusetts General Hospital, as well as other institutions around the country.

Topp MS, Duell J, Zugmaier G, et al. Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: updated results of a first-in-human (FIH) phase I dose escalation study. 

. 2019;37(suppl 15; abstr 8007). doi: 10.1200/JCO.2019.37.15_suppl.8007.

Bristol-Meyers Squibb and bluebird bio announce positive top-line results from the pivotal phase 2 KarMMa study of ide-cel in relapsed and refractory multiple myeloma [news release]. Princeton, NJ, and Cambridge, MA: Bristol-Myers Squibb Company and bluebird bio, Inc; December 6, 2019. bit.ly/2DVej3e. Accessed February 25, 2020.

Madduri D, Usmani SZ, Jagannath S, et al. Results from CARTITUDE-1: a phase 1b/2 study of JNJ-4528, a CAR-T cell therapy directed against B-cell maturation antigen (BCMA), in patients with relapsed and/or refractory multiple myeloma (R/R MM). 

. 2019;134(suppl 1):577. doi: 10.1182/blood-2019-121731.

Noopur S. Raje, MD, discusses the preliminary data with BCMA-directed treatment strategies in multiple myeloma.

BCMA-Targeted Treatments Boost Responses in Relapsed/Refractory Myeloma

Sagar Lonial, MD, FACP, professor and chair, Department of Hematology and Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discusses data with belantamab mafodotin in multiple myeloma.

Belantamab mafodotin has shown promising responses in patients with heavily pretreated multiple myeloma as evidenced by data from the phase I DREAMM-1 and phase II DREAMM-2 trials. In the DREAMM-1 trial, the objective response rate (ORR) with the agent was 60% and the median progression-free survival (PFS) was 12 months. Notably, 14 of the 35 patients treated had received ≥5 prior lines of therapy. Additionally, among patients who were refractory to anti-CD38 therapy, the ORR was 31% and the median PFS was 3.4 months.

In the DREAMM-2 trial, investigators evaluated doses of 2.5mg/kg and 3.4mg/kg. Similar responses were seen across both dose levels, says Lonial. Notably, responses were durable. Ocular and hematologic toxicities were well managed with dose adjustments, says Lonial. Now that the safety and activity of the drug has been established, it will be evaluated in combination, concludes Lonial.

Dr. Lonial on Data With Belantamab Mafodotin in Multiple Myeloma

BCMA-targeted therapies, including CAR T-cell therapy, antibody-drug conjugates (ADCs), and bispecific T-cell engagers are shifting the multiple myeloma paradigm to create longer remission times and improve quality of life (QoL) for patients, explained Gareth J. Morgan, MD, PhD.

“The future for patients is really excellent,” said Morgan. “The introduction of therapies that target BCMA or target T cells to BCMA is going to change the whole arena as they come close to the upfront setting, and more and more people will benefit long term.”

For example, the BCMA-directed ADC belantamab mafodotin was granted a priority review designation by the FDA as a treatment for patients with relapsed/refractory myeloma who received prior therapy with an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. In the pivotal DREAMM-2 trial, the agent, when given at the recommended 2.5-mg/kg dose, elicited an overall response rate (ORR) of 31% (97.5% CI, 20.8-42.6). The ORR was 34% (97.5% CI, 23.9-46.0) in those who received belantamab mafodotin at 3.4 mg/kg.

In addition to BCMA-targeted therapy, venetoclax (Venclexta) has proven to be beneficial for patients with multiple myeloma who have t(11;14). In June 2019, the 

FDA lifted a partial clinical hold on venetoclax

 in multiple myeloma, specifying the phase III CANOVA trial (M13-494; NCT03539744), which is examining venetoclax in combination with pomalidomide (Pomalyst) and dexamethasone in patients with relapsed/refractory myeloma that harbors t(11;14), could continue.

“We are making a huge difference to outcomes in multiple myeloma. There is a proportion of patients that have very long-term remissions, and they are effectively cured,” said Morgan. “Now, we are trying to increase that percentage to get more people to spend more time with their family and have a greater QoL.”

 State of the Science Summit™ on Hematologic Malignancies, Morgan, a professor in the Department of Medicine and director of Multiple Myeloma Research, NYU Langone Health’s Perlmutter Cancer Center, discussed ongoing research of BCMA-targeted therapies, as well as the use of venetoclax in the myeloma treatment paradigm.

: What are the emerging novel approaches in multiple myeloma?

: In the last 20 years, we have seen [treatment for multiple myeloma] evolve from having 1 treatment to now a new therapeutic modality almost every 5 years. Until now, myeloma has been a disease that is treated, goes into remission, stays in remission, relapses, goes back into remission, and relapses again. That was about it. With the choices we have today, and the development of agents that target BCMA, we are able to get everybody into remission. We should aim to maximize the number of patients in remission, and have them be in long-term remission.

Myeloma is not a single disease. There are probably 6 different disease subtypes, all of which should be treated differently. This is going to be driven in the clinic by the introduction of venetoclax, which is largely active in the t(11;14) subset of myeloma, which makes up about 15% to 20% of the overall [population]. The responses in that subset are dramatic and remarkable, and therefore will change things around.

Another novel approach is agents that target BCMA on the surface of plasma samples, which can be considered as 3 different types. One is ADCs, in which you put a warhead on an antibody that targets BCMA. The classic example of that is belantamab mafodotin, which looks like a really good drug with excellent responses.

Then, there are CAR T cells, where the patient's own T cells are modified, given back to the patient, and they result in excellent responses. The third and final approach is bispecific antibodies, in which you have an antibody that recognizes the myeloma cell and T cells, bringing them closer together.

All of these agents are super effective. Even in heavily resistant disease, you can get patients into responses that last for as long as 1 year. If you move all of [these agents up front], they're going to give much better responses. At this time, it's hard to distinguish between them because the disease group is so diverse; cross comparing between trials shouldn't be done. We should be excited about the efficacy [these novel agents] are going to have.

ADCs target something that is toxic to the cancer cell—acting as the ideal silver bullet. The one that's closest to market is belantamab mafodotin, where monomethyl auristatin F (MMAF) is linked to a BCMA antibody. This takes MMAF to the target cell, kills it by inhibiting its spindle, and looks to be really effective.

There were 2 studies [with this agent]: DREAMM-1 and DREAMM-2. The activity looked somewhat greater in the DREAMM-1 study. The results in the DREAMM-2 study are more realistic, but it looks very exciting, with more than 30% of patients getting good responses that are durable. The downside is that we need to manage the ocular toxicity keratopathy, but that's being dealt with by adjusting the dose, and it's not becoming a problem in the clinic.

What is the research surrounding CAR T-cell therapy in multiple myeloma?

bb2121 is a CAR T-cell product that's being produced by Bristol-Myers Squibb [and bluebird bio]. The KarMMa study identified the optimum dose of bb2121, which is 150 to 450 x 10

. At [the highest] dose, people go into remission and [stay there] for approximately 11.3 months. It seems to be relatively safe, with only 3% of patients experiencing cytokine release syndrome. The product bb2121 is a significant advance because it is nontoxic and effective.

The other major CAR T-cell therapy, JNJ-4528, was recently studied in the CARTITUDE-1 study, which is the Janssen equivalent [of bb2121]. The data that were presented at the 2019 ASH Annual Meeting look somewhat similar to the data with bb2121, with remissions lasting for 1 year and perhaps slightly longer; however, cross-comparing between studies at this time is fraught with problems.

How is venetoclax being used in multiple myeloma?

Venetoclax is an anti-apoptotic drug, which targets BCL-2. Most myelomas aren't dependent upon BCL-2, but they are dependent on MCL1. In most cases, [venetoclax] does not work as effectively as it does in the t(11;14) subgroup, which comprises about 20% of patients with myeloma. The responses are outstanding, and when used in combination with other agents, the responses are even greater. There is a future for venetoclax as a therapy for the t(11;14) subset, and this will drive more molecular segmentation of myeloma in future.

How do you determine patient eligibility for each treatment?

We should be thinking about maximizing responses in terms of how we choose treatments. There are upfront treatments and relapse treatments. In the relapsed/refractory setting, it's about which drugs are available for patients. Selinexor (Xpovio) is a new drug that looks good. If they had t(11;14), the use of venetoclax would be [appropriate]. The differential use between CAR T-cell therapies and bispecific antibodies is difficult to judge, because they are only available in clinical trials. We are looking for slots in trials where we can enroll patients.

Gareth J. Morgan, MD, PhD, discusses ongoing research of BCMA-targeted therapies, as well as the use of venetoclax in the myeloma treatment paradigm.

Year in Review: Evolving Landscape in Multiple Myeloma | Supplements and Featured Publications