Emerging Agents Spur Optimism in Myeloma

Saurabh Chhabra, MD, MS

The addition of elotuzumab (Empliciti) to the treatment arsenal for relapsed/refractory myeloma is arguably the biggest advance made in the space within the past year, according to Saurabh Chhabra, MD, MS. However, antibody-drug conjugates and CAR T-cell therapies are also making headway within the paradigm.

In November 2018, the FDA approved elotuzumab for use in combination with pomalidomide (Pomalyst) and low-dose dexamethasone for the treatment of patients with relapsed/refractory myeloma who had received ≥2 prior lines of therapy, including lenalidomide (Revlimid) and a proteasome inhibitor (PI).

The regulatory decision was based on findings from the pivotal phase III ELOQUENT-3 trial, which showed a 46% reduction in the risk of progression or death with the addition of the monoclonal antibody. Median progression-free survival was 10.3 months for patients treated with the elotuzumab regimen versus 4.7 months for those on pomalidomide/dexamethasone alone. Objective response rates also significantly favored the elotuzumab arm at 53% versus 26% in the control arm.

Although the data from ELOQUENT-3 have been the most practice-changing, said Chhabra, who is an assistant professor at the Medical College of Wisconsin, ongoing trials with the antibody-drug conjugate (ADC) GSK2857916 and the XPO1 inhibitor selinexor could further shake up the paradigm.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Chhabra highlighted emerging agents in the field of relapsed/refractory myeloma that have oncologists optimistic for the future.

OncLive: What advancement in relapsed/refractory myeloma has been the most practice-changing?

Chhabra: I would have to say the ELOQUENT-3 trial has impacted practice the most. This [trial evaluated] the combination of elotuzumab with pomalidomide and dexamethasone, which was thought to be a great combination with immense efficacy, but it was never completed in a clinical trial. The drug combination has been [FDA] approved already; we can use it in practice. ADCs, which are in early phases at this point, will also have a lot of impact [on the space]. We have to see how these clinical trials play out, but we are definitely very excited, particularly with the GSK2857916 compound.

Are there other monoclonal antibodies that are moving through the pipeline?

There was a phase III trial recently completed and presented which showed that the combination of isatuximab plus pomalidomide and dexamethasone had significant efficacy compared with pomalidomide and dexamethasone alone. The question is, how beneficial would it be as a combination after patients have received daratumumab-based regimens? They are both CD38-directed monoclonal antibodies. Therefore, again, we will need more data to figure this out, but it's definitely a possibility.

In terms of ADCs, what are the data to date with GSK2857916?

We have [data from] a first in-human phase I study, which included only 43 patients, but was [conducted] in 2 parts: the dose-escalation part and the dose expansion part. We know what dose we should use; there was concern about toxicity, especially the corneal adverse events. [However, these events] were reversible in most patients at a median of 35 days. Only 2 patients discontinued treatment in the dose-escalation part [of the trial], and none discontinued in the dose-expansion part. It's still a concern, but if we consider the risk versus benefit, I think we can live with this drug.

If this agent were to receive FDA approval, where do you see it fitting into the paradigm?

That's the million-dollar question. We have so many drug combinations approved, it's almost impossible to predict where we would use it. I would imagine that it would be placed in either the third- or fourth-line setting to begin with, and as more clinical data are presented, then maybe it will move up the ladder to the second-line setting. However, it's too early to predict that.

Has GSK2857916 opened the door for more ADCs to be studied in this space?

This is the first one, but there are many in the pipeline. However, the results for GSK2857916 were the best that we have seen thus far. It’s a leader in the group [of ADCs] and these other drugs have some catching up to do. Time will tell where we go with this.

Has any progress been made with CAR T-cell therapies?

We very excited about the CAR T-cell therapies. In fact, we already have 1 trial open and we're about to open a second one with bb2121. This is a global trial called KarMMa-2 (NCT03601078). For this trial, there are 2 cohorts. [The first one will have] patients who have failed 3 lines of therapy, which is understandable. Many of the new drugs are heading in that area, patients who have failed a PI, an immunomodulatory agent, and daratumumab (Darzalex). The [second] cohort in this study for patients who are just starting treatment. That's a clear unmet need—patients who are progressing less than 1 year after an autologous stem cell transplant, for example. There are very few treatments that can help those patients, so having CAR T cells as an available option would be great. Community oncologists should be looking out for such patients.

Are there any other exciting agents under investigation that you would like to highlight?

Selinexor is another drug that is oral and has efficacy in patients who are penta-refractory. We were a little disappointed when we found out that the FDA’s Oncologic Drugs Advisory Committee recommended not to give it a full approval, but we will be very interested in seeing if the results of the phase III BOSTON study—which is comparing selinexor, bortezomib (Velcade), and dexamethasone versus bortezomib plus dexamethasone—shows efficacy. The trial should be completed by the end of 2019 or the beginning of 2020. We'll have to wait for the data from that.

What is your take-home message to community oncologists working in the field?

The treatment of myeloma is getting very complicated, especially relapsed/refractory myeloma. Having an academic institution with 4 or 5 myeloma experts can be an asset for our community oncologists. I would request them to get us involved more often. We do get many patients from the community, but it might be helpful for patients if we can figure out a way to collaborate with them without interrupting patients' treatment.

Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Eng J Med. 2018;379(19):1811-1822. doi: 10.1056/NEHMoa1805762.