Monoclonal Antibodies, ADCs, and CAR T Cells Invigorate the Myeloma Paradigm

Supplements And Featured Publications, My Treatment Approach: Multiple Myeloma, Volume 1, Issue 1

David H. Vesole, MD, PhD, discusses the evolution of multiple myeloma treatment, and explained how other BCMA-therapies are poised to impact clinical practice.

BCMA-directed therapies, such as bispecific monoclonal antibodies, CAR T-cell therapy, and antibody-drug conjugates (ADCs), are in the midst of transforming the treatment paradigm of relapsed/refractory multiple myeloma to get closer to a cure for patients, said David H. Vesole, MD, PhD.

“We keep striving for a cure. Right now, we have the option to make this a chronic disease in the same way high blood pressure or diabetes [are chronic diseases]. We didn’t have that option when I started. We can control a patient’s disease for an unbelievably extended period of time. Even if we don’t cure patients, we can make it a chronic disease,” said Vesole. “This is exciting for patients and their families. most of these therapies can be given with the prolongation of life, without negatively impacting QOL a great deal.”

In an interview with OncLive®, Vesole, director of the Myeloma Program at MedStar Georgetown University Hospital, professor of medicine at Georgetown University, co-director of the Myeloma Division and director of Myeloma Research at John Theurer Cancer Center at Hackensack University Medical Center, discussed the evolution of multiple myeloma treatment, and explained how other BCMA-therapies are poised to impact clinical practice.

OncLive®: What makes BCMA a logical target in multiple myeloma?

Vesole: All patients with multiple myeloma are BCMA positive. BCMA stands for B-cell maturation agent, and all myeloma cells have some expression of BCMA on their cell surface. The extent of BCMA positivity may be higher or lower for individual patients, but because they are all positive, BCMA serves as a very efficient target for BCMA-directed therapies.

How has the treatment of multiple myeloma evolved?

I’ve been caring for patients with multiple myeloma for over 30 years, and treatments have evolved tremendously over the years. Back in the day, all of our drugs were chemotherapies, which have a lot of bystander effects and can cause nausea and vomiting.

It wasn’t until proteasome inhibitors (PIs), which were enzyme-specific pathway inhibitors that were first approved in 2003, that we started [using] targeted therapies for specific pathways and cells. These [agents] had significantly fewer bystander effects on normal cells. Therefore, since 2003, [multiple drugs have been] approved for the treatment of myeloma. Most of the [newer treatments] are more sensitive and specific to myeloma cells with much less bystander effect. They are tolerated better and their efficacy is better than conventional chemotherapy.

Over the course of the past few years, we found that giving combination therapies with multiple mechanisms of action results in superior activity, such that triplets appear to be the standard of care for newly diagnosed patients. [These triplets] are based on different categories of drugs such as PIs, immunomodulatory drugs (IMiDs), and corticosteroids. Many trials have looked at triplets versus doublets, and essentially all of them show that triplets are superior to doublets in the frontline and relapsed/refractory settings.

Currently, triplet therapy seems to be the standard of care, but what is evolving is whether we should give quadruplet regimens with monoclonal antibodies in addition to those same 3 classes of drugs I mentioned. Emerging data indicate that [quadruplets] are even more efficacious without a significant increase in toxicity. Although they are not currently the standard of care, I anticipate within the next 5 years that they will become the standard of care potentially up front, as well as in the relapsed/refractory settings for patients with multiple myeloma.

It is exciting to know that we have these monoclonal antibodies, which target specific surface components of myeloma cells. They [cause] very few bystander effects on other cells in the body. Although [these agents] are not completely devoid of other toxicities, they focus predominantly on myeloma cells.

[Historically], we would see, at most, a 20% likelihood of achieving a complete remission (CR). Now, we are approaching potentially achieving CRs in 80% or more of patients depending on the regimen that we utilize. Overall survival (OS) [rates] have improved as well [compared with] when I first started more than 30 years ago. Currently, patients with stage I disease have a life expectancy that exceeds 10 to 15 years versus 2.5 years [when I first started].

What challenges remain with regard to treatment in multiple myeloma?

The biggest hurdle that we still have in multiple myeloma is [treating] patients with high-risk disease based on [their] cytogenetics and staging. We’ve certainly made major headway, but their OS remains in the 4- to 6-year range, which is much lower than what we see with those patients who do not have adverse cytogenetic features.

Belantamab mafodotin-blmf (Blenrep) received regulatory approval in August 2020. How does this agent compare with others in the space?

The first BCMA-directed therapy that has been FDA approved is belantamab mafodotin. It is an ADC where the antibody is directed against BCMA and is conjugated to a chemotherapy drug. Biologically, the monoclonal antibody attaches to the myeloma cell, which is endocytosed into the cell. Then, lysozymes break down the link between the chemotherapy drug and the antibody, which allows the chemotherapy drug to kill the cell [from within]. Other diseases have ADCs as well, but [belantamab mafodotin] is the first approved in multiple myeloma.

For patients who respond [to belantamab mafodotin], the duration of response exceeds 11 months. This is quite impressive for a group of patients whose lifespan would be shorter than patients who have not received 4 prior lines of therapy. This opens up a wide avenue of patients with multiple myeloma who may have exhausted all other potential treatments.

The drug does not [elicit] an overly robust response rate as a single agent. [The rates are] about 30% to 35% depending on which DREAMM study you look at. As a single agent, belantamab mafodotin is currently approved for patients who have been heavily pretreated with 4 or more prior lines of therapy—which is a lot of chemotherapy.

Could you describe the unique safety profile of belantamab mafodotin?

Yes, there are some bystander effects with [belantamab mafodotin]. From a hematologic standpoint, it can lower white [blood cell] counts and platelet counts, but that is usually not a major consequence.

However, for reasons that we do not know, [belantamab mafodotin] can cause problems with the eye, [namely] keratopathy. In the vast majority of patients, this is very minor and presents as blurred vision or dry, scratchy eyes. Although this occurs in about 80% of patients treated with the drug, severe reactions occur in about 10% of patients. To the best of my knowledge, most of these abnormalities are completely reversible with time. The time sequence of the reversibility depends on how severe [the toxicity] is. There is a grading system from 1 to 4 with regard to how involved the ophthalmologic abnormalities are.

Before each dose of [belantamab mafodotin], which is administered every 3 weeks, patients have to be seen by an ophthalmologist or optometrist to be cleared before receiving the next dose of therapy. If a patient meets certain grades of severity, the drug is either dose reduced or held.

Although this is the first approved [BCMA-directed] drug, there are a lot of other therapies directed against BCMA that have different toxicity profiles than belantamab mafodotin.

Selinexor (Xpovio) is another drug that was recently approved for patients who have had 4 prior lines of therapy. Selinexor is an [oral] pill given once or twice a week, depending on the schedule. It is not a BCMA-directed agent. Instead, selinexor is directed against a specific mechanism in the nucleus of the myeloma cells [called XPO1]. Selinexor has a completely different toxicity profile; gastrointestinal toxicities are mainly seen with this agent.

The FDA approval of belantamab mafodotin was based on data from the DREAMM-2 trial. How has the DREAMM series evolved since the approval?

The DREAMM-1 study essentially [evaluated whether] belantamab mafodotin had any activity [in patients with relapsed/refractory multiple myeloma]. DREAMM-2 is the phase 2 trial that led to the FDA approval for the drug. DREAMM-3 through DREAMM-16 [are trials] that are evaluating a variety of other agents to be added to belantamab mafodotin. Additionally, DREAMM-12 and DREAMM-13 are evaluating belantamab mafodotin in patients with renal failure and liver abnormalities, [respectively].

Essentially, [the trials] are taking all the known drugs that we currently use to treat patients with multiple myeloma and adding them to belantamab mafodotin in some form. The DREAMM series is an ongoing effort to improve the outcome of single-agent belantamab mafodotin. DREAMM-6 was presented at [the 2020 ASCO Virtual Scientific Program] in June, showing response rates north of 30% with the addition of bortezomib (Velcade), [which is] far superior [than what we’ve seen with belantamab mafodotin alone]. When we combine belantamab mafodotin with other active agents with different mechanisms of action, we can see superior response rates and remission durations.

How do you approach sequencing in your own practice? Where does belantamab mafodotin fit into the paradigm?

Although quadruplets are quite effective up front, they are not FDA approved at this point in time. We are not sure if they will be covered by third-party carriers. Therefore, we generally use triplet regimens for initial therapy.

Our group is heavily biased toward stem cell transplants, which is considered standard of care throughout the world. For patients who have multiple myeloma and adequate physiologic organ function, and agree to [undergo] transplant, transplant is considered standard. We would give a triplet regimen, followed by transplant. Our group is a bit unique because we are not particularly in favor of maintenance therapy. On average, patients stay in remission for 2.5 to 5 years. Then we come back with salvage therapy, usually with triplet regimens, of which there are a number approved by the FDA for patients who have had 1 to 3 prior lines of therapy.

Belantamab mafodotin was approved in kind of a niche sense in that it is approved for patients who had 4 prior lines of therapy. [The FDA] doesn’t specify lines of therapies, so it is an interpretation of what that means. The agent was only tested in patients who had 4 or more lines of therapy. It is a little bit confusing because, in theory, we could use [belantamab mafodotin] in the second- or third-line settings.

There will likely be a lot of competing options for BCMA-directed therapy. CAR T-cell therapy is likely going to be approved sometime in the first quarter of 2021. Two companies are neck-and-neck with the FDA submission for CAR T-cell therapy approval. [Both] are BCMA-directed therapies.

Bispecific antibodies are a little bit further away from receiving regulatory approval, but are also BCMA-directed therapies.

There will certainly be a lot of competition for belantamab mafodotin in this niche [setting of patients who received at least 4 prior therapies]. These other agents have different toxicities profiles and different response rates. Similar to the DREAMM studies, these agents are being combined with many of the standard therapies that we currently use. We are going to have a whole list of additional options with these BCMA-directed therapies in the very near future.

Where would you like to see future research efforts focused?

Right now, belantamab mafodotin is being given as a single agent. We are not going to control multiple myeloma with single agents. We need combination therapies that have different mechanisms of action. That is ultimately going to be the goal of treatment.

The future is going to have personalized medicine. There is a trial by the Multiple Myeloma Research Consortium that is using standard therapies and then doing next-generation sequencing to find out if there are specific gene mutations for which specific drugs can be directed toward. The investigators are giving individual drugs, based on the patient’s DNA sequencing, that will attack specific abnormalities.

Ultimately, this is what is going to happen. We are going to be individualizing precision medicine and treating patients’ specific DNA abnormalities in their myeloma cells.

Yes, we could have a BCMA-directed target, but if we add that with a targeted agent against some specific enzyme deficiency or genetic abnormality, it [will be a valuable] addition to these other mechanisms. I imagine that in the future, patients are going to get 4 or 5 different drugs, some specific to enzyme pathways, others specific to their individual DNA sequencing. That is, in addition to targets that are widely expressed on the myeloma cells themselves such as BCMA.

How do you see CAR T-cell therapy impacting the landscape of multiple myeloma?

CAR T-cell therapy is an exciting area now. CAR T cells are patients’ own lymphocytes that are genetically modified to improve their activity in targeting their own myeloma cells. Unlike belantamab mafodotin, which, as we mentioned, needs to be combined with other agents to improve efficacy, CAR T-cell therapy alone has a response rate of 75% to 100%.

Further, CAR T-cell therapy is [a] one-and-done [approach]. Patients get CAR T cells on day 1 and they may not need therapy for 1 or 2 years, perhaps longer. All the other BCMA-directed therapies require continuous and indefinite therapy until they no longer work. With CAR T cells, patients get their therapy, get their response, and may not require treatment for an extended period of time. Ultimately, this will result in superior quality of life (QOL) for those patients who are going to get continuous therapy.

The CAR T-cell technology continues to improve. There are probably over 30 different companies that are trying to [manufacture] CAR T cells in multiple myeloma. The vast majority of them are using BCMA as the target, but that is not the only target that is available.

Right now, CAR T cells are predominantly made using a patient’s own cells, which takes 2 to 4 weeks to generate, genetically modified, and engineered before being returned to the patient. In the future, there will also be what we call off-the-shelf CAR T cells that are made in a laboratory and can be given the day after ordering them. Studies evaluating these allogeneic

CAR T cells are just beginning, but they could save a lot of time. Some patients cannot generate good CAR T cells if they have been heavily pretreated or if they don’t generate the number of cells needed for the infusion. Allogeneic CAR T-cell therapy opens [the option] up for those patients, as well as for the patients who need treatment sooner rather than later; some patients cannot wait 2 to 4 weeks for the cells to be generated.

To me, this is the most exciting area because it is a one-and-done [approach] versus continued therapy. CAR T-cell therapy can cause toxicities, but in contrast to lymphoma and leukemia, most of them are minor in multiple myeloma. [Moreover,] there is at most a 10-day window in which these abnormalities occur, after which patients are essentially home free for the duration of time the cells are effective.