T-Cell Engagers and Combinations Push Myeloma Paradigm Forward

Sikander Ailawadhi, MD, of Mayo Clinic

Backed by a rich pipeline of novel agents, the future of treatment in relapsed/refractory multiple myeloma lies in implementing combination strategies that build upon established regimens and in working toward understanding sequencing and retreatment strategies, said Sikander Ailawadhi, MD, who added that T-cell engagers may reside in the center of new developments.

“Such a breadth of new data are coming out in the nonchimeric antigen receptor (CAR) T-cell therapy setting for relapsed disease,” said Ailawadhi. “The bottom line is that we are not going to be using drugs as single agents; that is not where the benefit [of these agents] lies in multiple myeloma. [Also,] although the initial CAR T-cell therapy data have given us extremely good signals, T-cell engagers may provide an alternative [option]. Immunotherapy for myeloma has finally arrived.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on multiple myeloma, Ailawadhi, a professor of medicine and consultant in the Division of Hematology/Oncology, Department of Internal Medicine, at Mayo Clinic, discussed the potential for retreatment with proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies and the promise of T-cell engagers in the field.

OncLive^®:What advances are on the horizon in relapsed/refractory multiple myeloma?

Ailawadhi: [We are evaluating] drugs that are already FDA approved, including selinexor [Xpovio] and belantamab mafodotin[-blmf; Blenrep], differently to see if they can be used more safely [and lead to] better efficacy for patients. At the 2020 American Society of Hematology [ASH] Annual Meeting and Exposition, we saw that both drugs are being used in combination instead of as single agents. [Also,] an alternate schedule is being explored [with selinexor] because the toxicity profile of the approved [indication] is quite significant. The question is how we can make [these drugs] safer, especially in combinations, because they may not be fully useful as single agents.

Also, drugs are on the horizon that may get approved in the near future. One such drug is melflufen [melphalan f lufenamide], which has been presented as a single agent. Data with melflufen[-based] combinations were also presented [during the 2020 ASH Annual Meeting and Exposition].

Other drugs are still a little further out but had interesting and promising data [presented]. One drug is iberdomide, which is an IMiD in the family of lenalidomide [Revlimid] and pomalidomide [Pomalyst]. Data with iberdomide as a single agent have been presented before, but my goal is to look more at combinations because that is where the true meat of practice is. Even if single agents get approved, we want to use them in combinations because they benefit the patient more.

How could combination strategies with selinexor and belantamab mafodotin improve the efficacy observed with these drugs as single agents?

Selinexor has been around for a little bit longer [than belantamab mafodotin]. It was approved in combination with dexamethasone; it’s given twice weekly. The toxicity profile [of the FDA-indicated formulation] was pretty significant and was very similar to what was noted in clinical trials. Based on prior data and the data presented at the 2020 ASH Annual Meeting and Exposition, we have transitioned to once- weekly selinexor. Although combinations are challenging because we don’t have approval for them, we have been using selinexor in combination with bortezomib [Velcade] and dexamethasone.

Belantamab mafodotin is not yet at the combination stage; we are still figuring out the [optimal] regimen and schedule [to use it in]. While patients are receiving the first and second doses of standard-of-care belantamab mafodotin, we are paying [a lot of attention] to their eye toxicity. If we notice changes appearing, we’re very [quick] to delay belantamab mafodotin or give it at a safer interval. Although the FDA approval is every 3 weeks, I’m OK with giving it every 6 weeks as long as the patient is benefiting. Based on emerging data, we are more comfortable implementing those changes before they become mainstream.

If a patient is eligible for selinexor or belantamab mafodotin, do you recommend they receive the FDA indication or participate in a clinical trial evaluating a combination strategy?

I always recommend enrolling in clinical trials that evaluate combinations because that is the way the field moves forward. I am a huge proponent of clinical trials, so as much as we can [enroll patients in these studies] would be great.

Where should the starting point be to evaluate combination regimens?

Most of these drugs get combined with [agents from] 3 different categories: PIs, such as bortezomib or carfilzomib [Kyprolis]; IMiDs, such as lenalidomide or pomalidomide; and monoclonal antibodies, such as daratumumab [Darzalex]. It is still to be seen which [types of combinations] will pan out; we don’t have a winner yet. [Evaluating] toxicity profiles will be extremely important with these drugs, in addition to clinical benefit.

What makes cereblon E3 ligase modulators (CELMoDs) like iberdomide unique and where do you see them fitting into the treatment paradigm?

We’ve noticed that we can use CELMoDs sequentially. In the immunomodulatory space, patients who progress on lenalidomide may still be captured by pomalidomide. Similarly, patients who have seen prior IMiDs can still be treated with iberdomide, based on the data. This is a category where a subsequent-generation drug seems to be more effective than a prior-generation drug.

It remains to be seen what would pan out if, hypothetically, we used iberdomide in the frontline setting. [Regardless], a subsequent-generation drug in the same family can be efficacious. That is the benefit [of CELMoDs]. Plus, we are not noticing new or concerning safety signals from the combination data, which is reassuring.

Where will T-cell engagers fall in terms of sequencing, especially as CAR T-cell therapy continues to show promise?

From my standpoint, the data with T-cell engagers are the most exciting that came out of the 2020 ASH Annual Meeting and Exposition. We are noticing excellent efficacy from bispecific antibodies, such as AMG 701, and antibody- drug conjugates, such as MEDI2228. If patients can get some amount of toxicity [out of the way] early [on, followed by] deep and sustained responses, that [would be encouraging].

Although we are waiting for data to mature, something that has been brought up [frequently] in myeloma is that responses with CAR T-cell therapy are not sustained. We’ve been seeing good, deep, and early responses with CAR T-cell therapy, but we have to figure out how to build upon them. That is where these T-cell engagers come in handy, because, frankly, not everyone will be candidates for CAR T-cell therapy. To have these T-cell engagers in our armamentarium and to know that they give deep, sustained responses with a manageable toxicity profile is extremely exciting.

Are current clinical trial protocols equipped to answer modern sequencing strategies?

[A lot of] the abstracts we’ve seen from the T-cell engager space were all BCMA-directed therapies. It is almost like a race to the finish line: Who gets to the market first? The first one is going to get approved, which sets the bar higher for all the subsequent ones.

We are noticing that patients are being sequenced with some of these therapies. Bispecifics are being studied in patients who have failed a prior bispecific antibody. A lot of clinical trials have at least 1 cohort or 1 arm asking whether [the therapy has utility] for BCMA-naïve patients or BCMAtreated patients. That is the need; we can’t tell patients that they get only 1 shot at BCMA[-directed therapy].

With IMiDs, PIs, and monoclonal antibodies established as backbones, is there potential to utilize BCMA-directed therapies as another backbone to increase the utility of these novel classes of agents?

The data are still being teased out as to whether retreatment with daratumumab is possible. The concept of retreatment with switching the backbones is a little bit different [when we talk about the potential] to use BCMA[-directed] antibodies as the backbone. Although the cell may not undergo PI exhaustion, it may undergo BCMA exhaustion or CD38 exhaustion. These drugs are in different categories.

For example, while we are trying to figure out the best utility of selinexor, the exportin 1 mechanism does not go away; it will stay. Whether we are able to recruit it or exploit it more depends on how we use the drugs. When we talk about these targeted agents, we don’t fully understand the response as it relates to baseline BCMA level. Some drugs seem to depend on it and others don’t.

What about BCMA exhaustion and retreating with the BCMA-targeted therapy after a certain period of time to allow for BCMA recovery? A lot of these data are very preliminary, but that is how the field has gone in the past with PIs, IMiDs, and monoclonal antibodies. That is how it is going to go with BCMA. Also, we will have to understand how to sequence, combine, and use [these therapies].

What sets melflufen apart as a promising agent in this space? Is there still a roll for cytotoxic chemotherapy in multiple myeloma?

Melflufen is more of an alkylating agent or a cytotoxic chemotherapy. I still think melflufen has a role because we use a lot of cyclophosphamide, VDT PACE [bortezomib, dexamethasone, thalidomide (Thalomid), cisplatin, doxorubicin, cyclophosphamide and etoposide], DT PACE [cisplatin, doxorubicin, cyclophosphamide, and etoposide], or DCEP [dexamethasone, cyclophosphamide, etoposide, and cisplatin]. We use those types of regimens when we need to.

The importance of melflufen will be to find out how useful it is in those settings where we are currently using an alkylator anyway. How can melflufen be used in combination? We never used to use melphalan. Although melflufen and melphalan are not the same drug, we’ve been shy of alkylator therapy in the United States. Can we somehow bring in melflufen and get more benefit than what we used to expect from melphalan?

Conventional cytotoxic therapy still has a role in multiple myeloma; that is not going to go away. If melflufen turns out to be a better partner [than other options], maybe that will be the [agent] that we use.

Editor’s note: This interview took place prior to the February 26, 2021, FDA approval of melphalan flufenamide for use in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma, who have received at least four prior lines of therapy and whose disease is refracto-ry to at least one proteasome inhibitor, one immunomodulato-ry agent, and one CD38-directed monoclonal antibody.