Expert Highlights Ongoing Advances in Multiple Myeloma

Sarah Holstein, MD, PhD

There is a plethora of treatment options for patients with relapsed/refractory myeloma, but the challenge for physicians lies in defining an optimal treatment sequence, particularly when a patient becomes refractory to lenalidomide (Revlimid), said Sarah Holstein, MD, PhD.

In heavily pretreated patients, CAR T-cell therapy has emerged as a method to generate deep responses. At the 2018 ASH Annual Meeting, data from the next-generation CAR T product, bb21217, showed encouraging efficacy and promising safety. In the phase I CRB-402 trial, data showed an objective response rate of 83.3%, with a very good partial response or better rate of 75%.¹ Additionally, complete remissions were observed out to 10 months after infusion.

bb21217 follows bb2121, which garnered attention at the 2018 ASCO Annual Meeting due to its impressive progression-free survival (PFS) and response rates in a penta-refractory patient population.²

In addition, the OPTIMISMM study introduced a promising combination regimen specifically for patients who became refractory to lenalidomide. In data presented at the 2018 ASCO Annual Meeting, the median PFS was 11.2 months with the triplet regimen of pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone compared with 7.1 months with bortezomib and low-dose dexamethasone alone.³

Other novel agents, such as venetoclax (Venclexta) and selinexor, are also moving through the pipeline, added Holstein, who is an associate professor at the University of Nebraska Medical Center.

OncLive: What is the state of relapsed/refractory multiple myeloma?

Could you highlight the data with bb21217?

Could you discuss the role of melflufen?

In an interview during the 2019 OncLive State of the Science Summit™ on Hematologic Malignancies, Holstein highlighted the vast treatment paradigm of myeloma and shared some considerations for sequencing.Holstein: There were a few studies that have been published and presented in other forms that are relevant to triplet therapies that we could already begin using in daily practice, such as OPTIMISMM. I also highlighted what I thought was most exciting from the 2018 ASH Annual Meeting, focusing particularly on agents like venetoclax and selinexor, as well as the various modalities used to target BCMA. This has all been exciting.We have very little data on bb21217, but it is essentially taking the bb2121 construct that we already know has potential. [Investigators are] growing these CAR T cells in the company of a drug that is supposed to change the phenotype of the T cells so that they become more memory-like. The hypothesis is that these cells will then have a longer persistence when they are administered into a person; this [approach] could potentially improve potency as well. We are taking an active construct, bb2121, and then growing it in a special cocktail. The initial data with a small number of patients were presented and it looks promising. However, at this point, it is still a little early to know the durability of these responses.This is an interesting drug. At its heart, it is related to melphalan, which is a drug that we have been using for 50 years or so. We do not use it in the context of oral low-dose form anymore, but in a high-dose form in the context of stem cell transplant. Melflufen has taken advantage of some biology of malignant plasma cells; it is essentially a pro-drug form of melphalan, which has a lipophilic component to it. [Melflufen] gets readily taken up into cells, but for it to be active, it needs to be stimulated by enzymes called aminopeptidases. It turns out that myeloma cells express a lot of these aminopeptidases, in part just because it is part of a plasma cell that needs protein and then is able to degrade protein.

What have been some of the recent data with venetoclax?

Because these myeloma cells have such high levels of aminopeptidases, they then cleave the melflufen into the alkylating moiety, which then has a hard time leaving the cell. This is a very interesting way to more effectively deliver an active alkylating agent.The interest with venetoclax has been that it seems to have a signal in patients with t(11;14) disease; [data on] that have been presented. There were also data with venetoclax in combination with bortezomib; it doesn't seem like [patients] need t(11;14) to be able to respond [to that regimen].

What about the use of bi-specific T-cell engagers (BiTEs)?

How has the combination of selinexor and daratumumab (Darzalex) shape up in clinical trials?

What options are available for patients who are refractory to lenalidomide?

What are some considerations for sequencing?

Most recently, there were data [with venetoclax] in combination with carfilzomib (Kyprolis). Again, it was a relatively small study but there were interesting response rates. What was most interesting was that patients were responding to this combination at the same level, regardless of having high-risk or standard-risk cytogenetics. There was a small number of patients who had t(11;14), and all of them responded, so clearly there is a signal there.We are excited to have our first BiTE [candidate] in myeloma. Basically, the idea [of these engagers] is to take the antigen recognition part of an antibody that, in this case, is recognizing BCMA on the surface of myeloma cells and an antibody recognizing CD3 on a T cell. Therefore, they hook the 2 together, which allows the T cell to be brought to the myeloma cell. It is a way of bringing the cytotoxic T cells directly to the target cancer cell.These are interesting data. It has been a little bit disappointing, but a caveat of these trials is that it is a very small patient population. You need to be daratumumab-naïve to be responsive to this regimen. In this study, they did include some patients who were refractory to daratumumab and there were no responses to the combination in this group. Perhaps it is too early to make strong conclusions, but it seems from a mechanistic perspective that there may not be synergy with these 2 agents.There are still many options, such as pomalidomide- and carfilzomib-based regimens, in combination with several different drugs. I often use pomalidomide with daratumumab; but more recently, since its approval, I have been using pomalidomide with elotuzumab (Empliciti). Carfilzomib is great with cyclophosphamide, and even with pomalidomide. The difficulty is deciding when to use what.There are patient-specific factors to consider, such as whether or not they have high-risk cytogenetics. That would make me think more about combining an immunomodulatory drug with a proteasome inhibitor. Also, are there [other] patient-specific factors, such as comorbidities?

I also think about what my intent in that specific line of therapy is. For example, if I have someone who is relapsing 5 or 6 years after their first stem cell transplant and they are still young and healthy, I might think about transitioning them to a second transplant. Perhaps I would use something that is effective very quickly. This is a different approach than I would want to use [if I wanted] to keep someone on [the regimen] for many years.

How has the FDA approval of elotuzumab impacted the landscape?

There are also the logistical issues of a patient working full-time and not being able to come in for an infusion, and many [factors] like that. How many times do patients have to come into the clinic and how far do they have to travel? I always try to think about how a decision made in this line of therapy affects my choices after that.We have probably been underutilizing elotuzumab with lenalidomide just because, in this country, by the time patients reach the relapsed/refractory [stage], they are refractory to lenalidomide. The utility of adding elotuzumab is quite small.

The data with pomalidomide, on the other hand, is very interesting and represents another good combination. The safety signal is also excellent. [An area of] even more interest is [finding out] if we can use this regimen in a patient already exposed to pomalidomide or [who is] refractory to the drug.

References

1. Shah N, Alsina M, Siegel DS, et al. Initial results from a phase 1 clinical study of bb21217, a next—generation anti BCMA CAR T therapy. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 488. ash.confex.com/ash/2018/webprogram/Paper116953.html.
2. Raje NS, Berdeja JG, Lin BY, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).
3. Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide (POM), bortezomib, and low‐dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): phase 3 OPTIMISMM trial. J Clin Oncol. 2018;36(suppl; abstr 8001). doi: 10.1200/JCO.2018.36.15_suppl.8001.