Lonial Lays Out Optimal Sequence Strategies for Relapsed/Refractory Myeloma

Sagar Lonial, MD

When approaching treatment for a patient with relapsed/refractory multiple myeloma, it is important to have a clear plan and use the patient’s history of treatment as a guide, says Sagar Lonial, MD.

In a presentation during the 2018 Pan Pacific Lymphoma Conference, Lonial, professor and chair, Department of Hematology & Medical Oncology, Emory University School of Medicine, chief medical officer, Winship Cancer Institute of Emory University, discussed optimal sequencing techniques for patients with relapsed/refractory myeloma.

The “players” in the treatment of patients with relapsed/refractory myeloma are separated into 2 categories, Lonial explained—older agents and new novel agents. Older therapies include bortezomib (Velcade), lenalidomide (Revlimid), carfilzomib (Kyprolis), and pomalidomide (Pomalyst), while newer novel agents are ixazomib (Ninlaro), entinostat, elotuzumab (Empliciti), and daratumumab (Darzalex). There are many others that are on the heels of these new treatments, Lonial added.

An ongoing debate in the space has revolved around treatment at relapse. Lonial noted that while some experts theorize that biochemical relapse is sufficient evidence to initiate therapy, he prefers to wait and assess before rushing into treatment.

“There is a huge controversy on this issue, but I come down on the side of observation for patients with asymptomatic biochemical relapse. Just because a patient has a protein, doesn't mean you have to feel obligated to jump in and do something,” Lonial explained.

When considering treatment, Lonial said there are 3 factors that clinicians should look at: disease-related, treatment-related, and patient-related factors.

Disease-related factors include presentation of indolent or aggressive relapse, genetics of said relapse, level of tumor burden, and Multiple Myeloma International Staging System stage at diagnosis.

Treatment-related factors are prior agents used, progression on an immunomodulatory agent or proteasome inhibitor, maintenance, toxicities experienced, cardiac dysfunction after treatment, chronic obstructive pulmonary disease, and duration of prior therapy.

Lastly, patient-related factors can be prior illness, comorbidities, renal insufficiency, hepatic involvement, frailty, and patient preference, Lonial said.

"One of the things that we struggle with at our center is that patients come from 2 to 4 hours away, so if you have a choice between something oral versus something that is intravenous that needs weekly therapy, that may change your decision making when you have a choice," Lonial explained.

Once a treatment course is decided, clinicians must then assess the landscape. Lonial said that most of the action currently is in the randomized phase III trials, which are broken down into 2 groups. The first group are patients who received lenalidomide plus dexamethasone in the control arm. Such studies include the ASPIRE trial with carfilzomib, TOURMALINE-MM1 with ixazomib, ELOQUENT-2 with elotuzumab, and POLLUX with daratumumab.

In ASPIRE and TOURMALINE-MM1, lenalidomide and dexamethasone were partnered with proteasome inhibitors, while ELOQUENT-2 and POLLUX used immunotherapy. All 4 trials were identically designed, Lonial explained, but they were somewhat different in terms of size. Additionally, regarding progression-free survival (PFS), very few of these patients had prior lenalidomide with dexamethasone. Moreover, no patients were refractory to lenalidomide plus dexamethasone.

"That is important because many of our patients are progressing on lenalidomide maintenance," said Lonial. "How relevant are these trials to the patient you have sitting in your office who is progressing on lenalidomide maintenance?"

The second group is for those who received bortezomib and dexamethasone as the control arm. These trials were ENDEAVOR, PANORAMA, and CASTOR, as well as a trial of bortezomib plus dexamethasone with or without elotuzumab.

"Most of us have patients who are progressing on maintenance therapy in one form or another," Lonial said. "What you are going to do next may depend on what they are immediately coming off of."

The questions and challenges that remain are deciding what to do for patients progressing on lenalidomide, the limitations in proteasome inhibitor dosing, and data with pomalidomide-based treatments in early relapse, according to Lonial.

Considering some of the recent data that have been presented, Lonial explained how these regimens might fit into treatment for patients with relapsed/refractory disease.

Findings from the international, open-label, randomized, phase II ELOQUENT-3 trial (NCT02654132) showed that the addition of elotuzumab to pomalidomide and dexamethasone reduce the risk of disease progression or death by 46% compared with pomalidomide and dexamethasone alone.¹

The primary endpoint of this phase of the ELOQUENT-3 trial was investigator-assessed PFS. Investigators reported at the 2018 European Hematology Association Congress that the median PFS was 10.3 months (95% CI, 5.6-not evaluable) with the elotuzumab combination compared with 4.7 months (95% CI, 2.8-7.2) with pomalidomide plus dexamethasone (HR, 0.54; 95% CI, 0.34-0.86; P = .0078). The secondary endpoint objective response rate was 53% (95% CI, 40%-66%) with elotuzumab compared with 26% (95% CI, 16%-40%) in the control arm (odds ratio, 3.25; 95% CI, 1.49-7.11; P = .0029).

“The median PFS of elotuzumab plus pomalidomide and dexamethasone was on par with daratumumab plus pomalidomide and dexamethasone, suggesting that if they get daratumumab earlier, perhaps elotuzumab plus pomalidomide and dexamethasone could be a good salvage,” said Lonial during an interview with OncLive^®.

Findings from the phase III OPTIMISMM study presented at the 2018 ASCO Annual Meeting showed a median PFS of 11.20 months with pomalidomide, bortezomib, and dexamethasone compared with 7.10 months with bortezomib and low-dose dexamethasone alone (HR, 0.61; 95% CI, 0.49-0.77; P <.0001).² These findings suggest that the combination of pomalidomide, bortezomib, and dexamethasone may be a new standard of care in patients with relapsed/refractory multiple myeloma with prior exposure to lenalidomide.

New agents on the horizon include venetoclax (Venclexta), selinexor, and BCMA-directed chimeric antigen receptor (CAR) T cells, such as bb2121. These therapies hold great opportunities for durable responses, Lonial said.

Overall, Lonial advised taking a standard approach to the management of early relapse, and to have a plan for how to subsequently manage first and second relapse.

“It is important to have a plan in terms of how you approach relapse. Make sure you know what patients are progressing on and use that information to guide where you are going next. If a patient is progressing on lenalidomide maintenance, I tend not to use lenalidomide as part of my salvage therapy, and think about a proteasome inhibitor or pomalidomide as a partner,” Lonial concluded.

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 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract LB2606.
2. Richardson PG, Rocafiguera AO, Beksac M, et al. Pomalidomide (POM), bortezomib, and low&#8208;dose dexamethasone (PVd) vs bortezomib and low-dose dexamethasone (Vd) in lenalidomide (LEN)-exposed patients (pts) with relapsed or refractory multiple myeloma (RRMM): phase 3 OPTIMISMM trial. J Clin Oncol. 2018;36 (suppl; abstr 8001).