Updated Data Unveiled With Emerging Treatments in Myeloma

Updated data on several emerging treatment modalities were presented at the 2019 ASH Annual Meeting in multiple myeloma, including CAR T-cell therapy, antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and a novel selinexor (Xpovio) combination, explained Sandy W. Wong, MD.

For example, data from the phase I CRB-402 trial showed that patients with heavily pretreated relapsed/refractory multiple myeloma receiving a 150 x 106 dose of the CAR T-cell product bb21217 elicited an objective response rate (ORR) of 83%, which comprised a 33% complete response (CR) or stringent CR rate and a 50% very good partial response rate.1 All patients in this group had minimal residual disease (MRD)-negative disease, and the median duration of response was 11.1 months.

Selinexor is currently approved in combination with dexamethasone for patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody. In a phase I/IIb trial examining the addition of pomalidomide (Pomalyst) to selinexor/dexamethasone, results showed that the triplet led to an ORR of 50% and, in all evaluable patients, a median progression-free survival (PFS) of 10.4 months.

In an interview with OncLive, a sister publication of Oncology Nursing News, Wong, an assistant clinical professor in the Division of Hematology/Oncology, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed treatments in the pipeline for multiple myeloma.

OncLive: How is CAR T-cell therapy currently being evaluated in multiple myeloma?

Wong: All of the CAR T-cell therapy data are from clinical trials; there are no FDA-approved CAR T-cell products currently, but hopefully that will change. The data for bb2121 is probably the furthest along in development. A press release during the 2019 ASH Annual Meeting showed that their dose level of 415 million cells had a very impressive ORR as well as a long PFS.

The other agent that is probably next furthest along in development is [JNJ-68284528], and there has been a lot of excitement about this. It was presented at the 2019 ASH Annual Meeting, and the response rate is unprecedented at 100%, which is very exciting. It's early, so we don't have any PFS data from that particular trial yet.

The LEGEND-2 trial is quite telling, because this is the same product, but is used in the Chinese setting, albeit in earlier lines of therapy. In that trial, the response rate was still pretty high. It wasn't 100%, but was more like 80%. The PFS was actually very long, which speaks to the fact that these agents should probably be used earlier in the course of myeloma treatment. Those are the 2 [CAR T-cell products] that are the most interesting right now and probably the farthest along in development.

There are other CAR T-cell therapies that are being developed, such as bb21217, which is essentially bb2121 but cultured with PI3K in order to improve the amount of T-cell memory. The results were [initially] presented at the 2018 ASH Annual Meeting with a really good ORR and a median PFS of around 11 months. JCARH125 is also in development; we are in the early days in terms of what we know about this product so far. We'll be excited to hear about more about this product, hopefully over the next year.

What data have been reported regarding BiTEs in multiple myeloma?

The BiTEs are really interesting. [Previously, there were] data on AMG 420, which was presented at the 2019 ASCO Annual Meeting. It's proof that this category of drugs can be effective in the relapsed/refractory setting. The response rate was great, but many patients suffered from neuropathy and infections, such as the astrogliosis and the adenovirus.

At the 17th International Myeloma Workshop, we were told that [AMG 420] had been put on hold and they're focusing their efforts on what seems like the same drug, but one with a longer half-life. We look forward to seeing data on that drug eventually, but that agent showed us that even in the very relapsed/refractory setting, you can still get responses with this modality of treatment.

That really set the stage for CC-93269, which was presented at the 2019 ASH Annual Meeting with a response rate of 88%. These patients are just as sick as the patients who were enrolled onto the CAR T-cell therapy trials, but the response rate [of the BCMA T-cell engager] rivals that of the CAR T-cell products. These are early days with limited numbers, and we don't have any PFS data. Thus far, it looks very promising because this is an off-the-shelf product, as opposed to CAR T cells that have to be manufactured and require a certain period of time for manufacturing purposes.

What are your thoughts on the investigations with ADCs in this space?

The [ADC] that is furthest along is belantamab mafodotin, which is directed against BCMA. [Data that are] actually now published from the phase I trial show that the drug, in a pretty heavily pretreated population, has an ORR of 60%, which is exciting. The PFS was close to 1 year, so this is a very active agent. There are some toxicities associated with it, as with every drug. For this particular drug, there are corneal toxicities, but it seems that those toxicities are reversible with supportive care and withholding the drug. That's another very exciting development in the myeloma field.

How has the approval of selinexor impacted clinical practice?

Selinexor is approved with dexamethasone for the treatment of patients with penta-refractory myeloma. There are some toxicities with this agent, but they can be mitigated. For fatigue, you can prescribe methylphenidate. Patients very commonly have nausea with this medication, and I use olanzapine to prevent [nausea]. Patients [on olanzapine] need to be followed closely in the infusion center. Sometimes they can develop hypernatremia that can be treated with salt tabs as well as intravenous fluids.

It's not an easy drug to give. It is a drug for which you need to closely monitor the patient to make sure that they're getting through it OK. It is an agent that has an ORR in the 20% to 30% range in a very heavily pretreated population. In the future, we want to see this agent being combined with other drugs, and move it up in earlier lines of treatment. We will be seeing data on that in the future.

At the 2019 ASH Annual Meeting, data of selinexor in combination with pomalidomide and dexamethasone was presented. It was not a randomized phase III trial, but ORR in patients who are pomalidomide-naïve was around 50%, which is not bad compared with patients who received pomalidomide/dexamethasone alone. Thus far, it seems there is clearly a benefit with the addition of selinexor. We will wait for the phase III trials to confirm that. [At this point], the combination [of selinexor plus pomalidomide/dexamethasone] is tolerable as long as we pay vigilance to how patients are experiencing the drug.

References

1. Berdeja JG, Alsina M, Shah N, et al. Updated results from an ongoing phase 1 clinical study of bb21217 anti-BCMA CAR T cell therapy. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 927.

2. Chen CI, Bahlis N, Gasparetto C, et al. Selinexor, pomalidomide, and dexamethasone (SPd) in patients with relapsed or refractory multiple myeloma. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 141. https://bit.ly/2GfPGQ2.

This article was originally published on OncLive as, "Updated Data Unveiled With Emerging Treatments in Myeloma."