Individualized Regimens Instrumental After Early Relapse in Myeloma

Michael Green, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Michael Green, MD

Multiple myeloma is a heterogeneous disease requiring diverse and individualized therapies for patients who experience early relapse, explained Michael Green, MD, adding that physicians fortunately have a number of regimens to choose from in this setting.

“There are a variety of treatment options for early relapse in multiple myeloma,” said Green. “We have to take into account patient preference, patient comorbidities, prior therapies, the pace of the relapse, and biological determinants of health. By doing that, we can construct a treatment strategy that improves people's lives.”

There is no standard first-line therapy for those who relapse early, but Green pointed to the triplet of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone as having impressive efficacy.

In June 2018, the FDA approved a supplemental new drug application, incorporating overall survival (OS) data from the phase III ASPIRE trial to the label for carfilzomib in the relapsed/refractory myeloma setting.

In the trial, the triplet of carfilzomib, lenalidomide, and dexamethasone demonstrated a 21% decrease in the risk of death versus lenalidomide and dexamethasone alone for patients who relapsed following 1 to 3 lines of therapy. The median OS was 48.3 months compared with 40.4 months with the triplet and doublet, respectively (HR, 0.79; 95% CI, 0.67-0.95; P = .0091).¹

Additionally, in August 2018, the FDA granted a priority review to a supplemental biologics license application for elotuzumab (Empliciti) for use in combination with pomalidomide (Pomalyst) and dexamethasone in the relapsed/refractory myeloma setting after 2 or more prior lines of therapy.

This decision follows data from the phase II ELOQUENT-3 trial, in which the triplet led to a 46% reduction in the risk of death or disease versus the combination of pomalidomide and dexamethasone alone.² OS data have yet to be reported.

Though the goal is to extend progression-free survival (PFS) and ultimately OS, Green noted that the length of remission gets shorter with each subsequent therapy, which makes sequencing another factor to consider.

OncLive: What is important to note when thinking about early relapse?

Can you elaborate on the factors that impact your choice of therapy?

What are some available regimens for patients who relapse?

Do you have a preferred regimen for these patient populations?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Green, of Northern California Oncologists, discussed treatment strategies following early relapse in multiple myeloma.Green: Multiple myeloma is an incurable blood cancer. Along that vein, the majority of people will have relapsed disease. It's a relapsing/remitting disease where the duration of remissions shortens with each successive therapy. Relapse is a common finding in patients with multiple myeloma. Our strategy for treatment needs to keep in mind not only prior therapies, but also future therapies and sequencing strategies that are mindful of the changing treatment landscape.Each patient is unique. Multiple myeloma is a heterogeneous disease, so we can't use a standard algorithmic “cookie-cutter” approach. You have to keep in mind that each patient is special as each disease is its own disease. When I talk about the pace of disease, [I’m referring to] a very quick and rapid clinical progression versus a low-velocity biochemical progression. When I talk about biological determinants, [I’m referring to] high-risk cytogenetics versus more standard-risk features. All of that needs to be kept in mind.There are so many combinations of therapies for multiple myeloma. The broad classes of therapies that are utilized are proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies. Those are the classes of treatments we have for early relapse. The combinations vary between all of the available agents. Some specific agents include carfilzomib, pomalidomide, and daratumumab (Darzalex).It's a very good question. I really individualize it for the patient. This kind of gets to whether there is a sequence that I prefer. I do have some regimens that I'm more comfortable with [giving], but I remember that can change depending on the person and their disease characteristics.

What are some studies that have informed the management of early relapse?

Do you want to give your most potent agents upfront or reserve them for later sequencing?

What area of research would you like to see addressed?

For example, [it matters whether] they have renal insufficiency or compromise to their kidneys. [It also depends] whether they have liver disease, whether they're experiencing neuropathy, and their functional abilities. You have to keep all of these in mind when devising a strategy for the person in front of you. I won't say I have a preferred regimen. I have tons of options, but I have to be mindful of what I use now, since it will impact what's available for the individual in the future.There are quite a few. The ASPIRE study looked at the combination of carfilzomib, lenalidomide, and dexamethasone and showed an improvement in PFS. There was a recent update that showed an improvement in OS. This is a large international study, so it has its own caveats that need to be kept in context in terms of access to drugs in different settings. Pomalidomide has activity in combination with dexamethasone in the relapsed setting. Daratumumab has shown improvements in PFS in early relapse in a variety of different combinations.It's unclear to me at this point. It is a very good question. I want to remember that this is a relapsing/remitting disease, so I want options that will benefit the patient in the future. If the data support using more potent therapies upfront as a benefit to the patient in terms of OS, then it's a reasonable option. Those data, to this point, have not been available. More studies need to be done in terms of sequencing and whether or not it makes an impact to use more potent therapies upfront versus later on.I would love to see our clinical trials use comparator arms that are contemporary in current practice. Comparing a triplet therapy to a doublet therapy has challenges for clinicians. How do [we] utilize that information? You wouldn't use a doublet in the relapsed setting, since the standard is a triplet regimen, so how do you use the data to support comparative efficacy between the triplets we often use? Moving forward, I would love to see studies that incorporate contemporary treatment practices for myeloma as comparator arms.

References

1. FDA approves addition of positive overall survival data from phase 3 ASPIRE trial to KYPROLIS® (carfilzomib) label. Amgen. Published June 11, 2018. https://bit.ly/2LFIJbA. Accessed June 12, 2018.
2. 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.