Emerging Agents Offer Hope in Late Relapse Myeloma

Sandy W. Wong, MD

Patients in late relapse comprise one of the largest unmet needs in multiple myeloma, said Sandy Wong, MD, but added that monoclonal antibodies and antibody-drug conjugates (ADCs) are the biggest potentially practice-changing agents in this setting.

“There is good news for patients who are in late relapse. There are effective agents that we can use,” said Wong, an assistant professor at the University of California, San Francisco (UCSF) School of Medicine. Despite the fact that they are in late relapse, we can potentially achieve minimal residual disease (MRD) negativity in some of those patients.”

Monoclonal antibodies have shown consistent benefit in myeloma, specifically daratumumab (Darzalex) and elotuzumab (Empliciti). In June 2017, the FDA approved the third daratumumab triplet for patients who have received at least 2 prior treatments.

Elotuzumab, in combination with pomalidomide (Pomalyst) and low-dose dexamethasone, may be the next regimen to be approved for patients with relapsed/refractory disease. In August 2018, the FDA granted a priority review for the regimen for use following 2 or more prior therapies, based on the phase II ELOQUENT-3 trial. The triplet was associated with a 46% reduction in the risk of progression or death compared with pomalidomide and dexamethasone alone.¹

In addition to monoclonal antibodies, Wong explained that investigational ADCs, specifically those against BCMA and CD46, are showing early but impressive efficacy in heavily pretreated patients.

For example, data from the phase I DREAMM-1 trial presented at the 2017 ASH Annual Meeting indicated a 60% overall response rate in patients treated with the anti-BCMA ADC GSK2857916, leading to its breakthrough designation status in November 2017.²

OncLive: What are some of the agents being explored for patients in late relapse?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Wong discussed emerging agents being explored for the treatment of patients with multiple myeloma in late relapse.Wong: There are a lot of clinical trials being studied in that population right now. It is also the population of greatest unmet medical need. The first trial I went over was a daratumumab-based trial. Daratumumab has been used in multiple different combinations in both the newly diagnosed as well as in the relapsed setting.

Daratumumab has been combined with pomalidomide and dexamethasone. That was published by Dr Ajai Chari of Mount Sinai Hospital in 2017 in Blood. If you look at the percentage of patients who had prior treatment, many of them were heavily pretreated. They were refractory to both immunomodulatory drugs (IMiDs) and proteasome inhibitors. Despite that, the response rate was actually quite impressive at 60%. About one-third of patients who got a complete response or better met the criteria for MRD by next-generation sequencing. The regimen did have some toxicities, but they were pretty well tolerated. Most of the toxicities were hematologic in nature.

The second trial I presented was on elotuzumab in combination with pomalidomide and dexamethasone. This was recently presented at the 2018 European Hematology Association Congress. Elotuzumab is a monoclonal antibody against SLAMF7. It was studied in the ELOQUENT-2 trial where it was combined with lenalidomide (Revlimid) and dexamethasone compared with lenalidomide and dexamethasone. That led to its FDA approval for multiple myeloma.

What are some investigational agents moving through the pipeline?

In ELOQUENT-3, the drug was combined with pomalidomide/dexamethasone compared with pomalidomide/dexamethasone. The data are quite early at this point in time with a limited duration of follow-up. Thus far, this triplet combination looks to be better than the doublet. We await the final results of the trial for us to really see how that pans out.The last 2 agents I discussed are investigational. Both of these agents are ADCs. These are monoclonal antibodies conjugated to a toxin, which leads to cellular toxicity. The first agent is being developed by GlaxoSmithKline. It is a monoclonal antibody against BCMA conjugated to MMAF. This has been studied in a phase I, first-in-human trial that was presented at the 2017 ASH Annual meeting.

In the dose-escalation phase, there were no dose-limiting toxicities. In terms of expansion, the first cohort included relapsed/refractory patients with around 35 patients total. These patients were very heavily pretreated; many of them had 5 or more prior lines of therapy and were refractory to IMiDs, proteasome inhibitors, and daratumumab.

Despite that, the response rates were pretty impressive at around 60%. In terms of toxicities, there were some hematologic toxicities. Because of the MMAF, there were ocular toxicities as well—there were grade 3 dry eyes, corneal keratitis, and eye pain. That is one type of toxicity that needs to be closely monitored in patients who are receiving this type of agent. What really stood out to a lot of us was that the response rates looked very impressive. We'll await the final results of that trial for this disease.

The last agent that I discussed is a home-grown agent. This is a compound that was initially studied in the lab of Dr Abin Liu, who is an anesthesiologist at UCSF that was looking at this in prostate cancer. Dr Thomas Martin and Dr Jeffrey Wolf, both of UCSF, asked him to study it in myeloma. Low and behold, it seemed efficacious preclinically. The drug is an antibody against CD46 that is conjugated to the MMAE toxin. The drug attaches to surface CD46 internalized by the cell, causing cell death.

CD46 is highly expressed in patients with myeloma. Those who have gain 1q as a cytogenetic abnormality have an even higher expression of CD46. We think the reason is because the gene for CD46 is on the chromosome 1q. As a result, if patients have gain 1q, they have a higher protein expression of this targeted antigen.

How could the potential approval of elotuzumab, pomalidomide, and dexamethasone impact sequencing?

In preclinical studies, the antibody showed very little efficacy in mice given as a naked antibody. However, when it is given with an antibody that is conjugated to the toxin, it looks like the mice survive. We are really excited about this. We're planning a phase I first-in-human trial that we will hopefully have open at UCSF in the spring of 2019. It depends on the individual patient and what they have been exposed to. It makes it difficult to give a blanket statement because everybody has been treated differently during the disease course. Elotuzumab, pomalidomide, and dexamethasone look to be quite active—not surprisingly because we know the monoclonal antibodies have been very active agents. This opens up another possible combination for patients.

It's hard to talk about sequencing. In early relapse, we heard from Dr Michael Green of UCSF on carfilzomib- and daratumumab-based regimens. They are effective with very tolerable side effects. Elotuzumab with lenalidomide and dexamethasone in the earliest relapse setting is also efficacious. It’s nice to know that elotuzumab could have a place for patients who become more relapsed.

All patients who are in late relapse should be considered for clinical trials. Patients should be considered for clinical trials for us to expand the repertoire of agents available to them.

References

1. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide/dexamethasone (EPd) vs Pd for treatment of relapsed/refractory multiple myeloma (RRMM): results from the phase 2, randomized open-label ELOQUENT-3 study. In: Proceedings from the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract LB2606.
2. Trudel S, MD, Lendvai N, Popat R, et al. Deep and durable responses in patients (Pts) with relapsed/refractory multiple myeloma (MM) treated with monotherapy GSK2857916, an antibody drug conjugate against B-cell maturation antigen (BCMA): preliminary results from part 2 of study BMA117159. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 741.