Sandy W. Wong, MD, discusses treatments in the pipeline for multiple myeloma.
Sandy W. Wong, MD
Updated data on several emerging treatment modalities in multiple myeloma were presented at the 2019 ASH Annual Meeting, 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 in patients with heavily pretreated relapsed/refractory multiple myeloma, a 150 x 106 dose of the CAR T-cell product bb21217 elicited an objective response rate (ORR) of 83%, composed of a 33% complete response (CR) or stringent CR rate and a 50% very good partial response rate.1 All patients in this group were minimal residual disease (MRD) negative, and the median duration of response was 11.1 months.
Selinexor is currently approved for use 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.2
In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, 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 are 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 agent that is probably next furthest along in development is [JNJ-4528], and there has been a lot of excitement about this. [Its data were] 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 evaluated [LCAR-B38M, which has the same CAR construct as JNJ-4528]; the product [came out of China and was examined] 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 2 [CAR T-cell products] are the most interesting right now.
Other CAR T-cell therapies 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 it, 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 were 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, infections, such as adenovirus, or astrogliosis.
At the 17th International Myeloma Workshop, we were told that [AMG 420] had been put on hold and [that the research team is] 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 those who were enrolled onto the CAR T-cell therapy trials, but the response rate [of the BiTE] 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, CC-93269 looks very promising because it is an off-the-shelf product, as opposed to CAR T cells that have to be [produced] 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] 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. Some toxicities are associated with it, as with every drug. For this particular drug, there are corneal toxicities, but it seems that [those events] are reversible with supportive care and by 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. This agent has some toxicities, but they can be mitigated. For fatigue, you can prescribe methylphenidate (Ritalin). Patients also very commonly experience nausea with selinexor, and I use olanzapine to prevent it. Patients [on olanzapine] need to be followed closely in the infusion center. Sometimes they can develop hypernatremia; that can be treated with salt tabs and intravenous fluids.
Selinexor is not an easy drug to give. You need to closely monitor the patient to make sure that they're getting through it OK. That agent 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 moved up into earlier lines of treatment. We will be seeing data on that in the future.
At the 2019 ASH Annual Meeting, data on selinexor in combination with pomalidomide and dexamethasone were presented. It was not a randomized phase III trial, but the ORR in patients who aweree 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 are vigilant [in tracking] how patients are experiencing the drug.