Myriad Modalities Advance Multiple Myeloma Paradigm

Nina Shah, MD

Chimeric antigen receptor (CAR) T-cell therapy, bispecific T-cell engagers (BiTEs), and antibody-drug conjugates (ADCs) have all shown encouraging activity in patients with multiple myeloma, although investigators are still exploring the therapies to improve outcomes, explained Nina Shah, MD.

“Multiple myeloma is a really exciting place to be in treating patients, especially with the development of new therapies. I’m so happy that we’ve been able to work with academic and community centers to get so many clinical trials [running],” said Shah. “If your patient has myeloma, we’re always happy to see them and consider a clinical trial. The available options are increasing so that we can give patients back the time of life that they may have otherwise lost to this disease.”

In CAR T-cell therapy research, a phase I trial of bb2121 demonstrated an objective response rate of 95.5% in patients with relapsed/refractory multiple myeloma. Additionally, the median progression-free survival (PFS) was 11.8 months with a median duration of response of 10.8 months. The safety profi le is consistent with that of other CAR T-cell therapies.

In an interview with OncLive, Shah, an associate professor of medicine at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, discussed how CAR T-cell therapy, BiTEs, and ADCs are being used to treat patients with multiple myeloma and the importance of enrolling patients in investigational trials.

OncLive: What is the role of CAR T-cell therapy in the multiple myeloma treatment paradigm?

Shah: BCMA is a really good target for myeloma cells because it is spread exclusively on plasma cells and B cells that become plasma cells. It allows us to target the cell without getting in trouble with too many other cells that we still want to target.

CAR T cells are generally engineered autologous cells from the patient that are directed toward the BCMA protein. They are specifi c for the protein on the tumor cells, making it like an antibody, but the intracellular machinery is like T cells.

The CRB-401 trial looked at patients with refractory multiple myeloma who received CAR T-cell [therapy with bb2121], and results showed a median PFS of [11.8 months]. LCAR-B38M, which is another CAR T-cell drug candidate, has a little bit longer median PFS, at 15.0 months.

However, the studies [comparing bb2121 and LCAR-B38M] were a little different because bb2121 had patients who were more heavily pretreated with a median 7 lines of prior treatment versus a median 3 prior lines in the LCAR-B38M trial. In any case, results of both studies [demonstrate] promise for CAR T-cell therapy. However, a lot of work [still needs to be done] because it doesn’t look as if all patients are being cured, which is the ultimate goal.

What is your strategy for patients who do not respond to CAR T-cell therapy?

Some patients don’t respond to CAR T-cell therapy, although the response rate is greater than 80% to 90%. If they don’t respond, [we need to ask ourselves,] “Are the T cells that were engineered working correctly? Or is it that their cells do not have enough BCMA expression?” We have an idea that it is probably related to the T cells themselves. This situation makes us believe that we need these treatments in earlier lines instead of waiting for patients to experience multiple relapses and become very diffi cult to treat with less healthy T cells. Perhaps we would get better effi cacy out of this.

Some other emerging options in multiple myeloma include BiTEs and ADCs. Could you provide an overview of how these approaches are used to treat multiple myeloma?

In BiTE therapy, the only [available technology] is the Amgen BiTE [AMG 420], which has continuous infusion of anti-BCMA. Dose-related toxicities include cytokine release syndrome (CRS) and polyneuropathy. Ultimately, 10 patients were treated at this dose, and 7 patients responded, with a good number of them having a complete response.

In terms of toxicities [for the BiTE technology], there were a few interesting infections as well as CRS. This suggests that we have a potentially very effective therapy, but we need to know how to manage toxicities and anticipate potential infections with this type of drug.

For ADC therapy, results of the DREAMM-1 study showed that patients with a median 5 lines of treatment received the [ADC] for 16 cycles and had a median PFS of around 12 months, which is similar to [results seen with] CAR T-cell therapy. However, it is hard to compare 2 different studies because the patients may have been different. The patients [on the DREAMM-1 study] had some thrombocytopenia, but one of the major toxicities was ocular toxicity.

[Ocular toxicity] can [encompass] a variety of [issues], including blurry vision, irritations of the cornea, and more. [Ocular toxicity] is occurring in 60% to 70% of patients but seems to be manageable at mainly grade 1/2, for which steroid eye drops are prescribed. Investigators are going to continue to work on this therapy, potentially changing doses or dose schedules or using cooling eye masks. This therapy is promising because it’s very community friendly. For patients who cannot make it to a medical center to get a very intricate program of CAR T cells or BiTE, this might be something they can access.

In terms of research, what are the next steps for these treatment options?

For CAR T-cell therapy, we’re all waiting for the KarMMa trial, which is the pivotal phase II trial of bb2121. That is a really large trial that was carried out to determine the true efficacy of this therapy in patients with relapsed/ refractory myeloma.

The main goal of BiTEs is to try to get [patients] from receiving continuous diffusion to [make treatment] more like a scheduled chemotherapy because that is more user friendly.

For ADCs, we’re really looking forward to the DREAMM-2 data as well as understanding how to manage associated toxicities more proactively.

How do you decide which patients are eligible for each treatment?

Each of the clinical trials had its own inclusion and exclusion criteria, which varied between them. Generally, patients had to have at least 3 lines of prior therapy. These patients seem to be progressing and becoming more ill, which is hard to combat. When comparing candidacy for CAR T-cell therapy versus BiTE versus ADC, you have to make sure that the patient has good cardiovascular status to be able to tolerate CRS.

Additionally, CAR T-cell therapy has more intricate scheduling. You have to make sure you advise the patient similarly to transplant so they can get together their caregiving, housing, and other social planning in order to receive the therapy.

In the setting of BiTE, you want to ensure the patient is able to come for the continuous infusion, if that’s the product you’re using. In the setting of the ADCs, patients with preexisting corneal abrasion or something similar may not be eligible.

What are your thoughts on the recent FDA approval of the frontline daratumumab (Darzalex) regimen for patients with transplant-eligible myeloma?

Daratumumab has really made a splash—not only in the relapsed/refractory setting, but now in the up-front setting. Several trials have proved that adding daratumumab to almost any regimen improves at least the depth of response, if not PFS. The ALCYONE trial, which was in a transplant-ineligible population, showed superiority of a quadruplet regimen of bortezomib (Velcade), melphalan, and prednisone plus daratumumab versus bortezomib, melphalan, and prednisone alone.

Results of the MAIA trial showed the superiority of lenalidomide (Revlimid) and dexamethasone plus daratumumab versus lenalidomide/dexamethasone. Both of these trials suggested transplant-ineligible patients are better off adding daratumumab to whatever was already being done, although no one has compared lenalidomide/ dexamethasone/daratumumab to standard lenalidomide/ dexamethasone/bortezomib.

For transplant-eligible patients, it’s always hard to know whether it makes sense to add an extra drug because you’re going to have patients undergo transplant. Recently, results of the CASSIOPEIA trial showed an improvement in outcomes for transplant-eligible patients who received bortezomib/thalidomide (Thalomid)/dexamethasone plus daratumumab.

The GRIFFIN data showed a better depth of response for transplant-eligible patients who received bortezomib/ lenalidomide/dexamethasone plus daratumumab versus bortezomib/lenalidomide/dexamethasone. For me, this is very important because this is more like the population we see in the United States.

However, with the recent approval of daratumumab in the frontline setting for transplant-eligible patients, more of us are going to consider it as something to be used in the up-front setting in combination with bortezomib/ lenalidomide/dexamethasone. We look forward to the GRIFFIN data, which will allow us to continue to consider using daratumumab with bortezomib/lenalidomide/ dexamethasone. Hopefully, that trial will be positive.

Raje NS, Berdeja JG, Lin Y, 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 15; abstr 8007). doi: 10.1200/JCO.2018.36.15_suppl.8007.