The Institute For Value-Based Medicine

Defining Value in Multiple Myeloma

Published Online: Thursday, June 16, 2016
A conference workshop sponsored by The Institute for Value-Based Medicine on value in the context of multiple myeloma.
Speaker:
Jatin J. Shah, MD
Associate Professor 
Department of Lymphoma/Myeloma 
Division of Cancer Medicine 
The University of Texas 
MD Anderson Cancer Center
Houston, TX

Moderator:
Andrew Pecora, MD
Chief Innovations Officer
Professor and Vice President of Cancer Services
John Theurer Cancer Center at Hackensack
University Medical Center
Regional Cancer Care Associates, LLC
Professor of Medicine and Oncology at Georgetown University
Hackensack, NJ
 

Multiple myeloma (MM) differs in several important respects from other malignancies, according to Dr Jatin J. Shah, associate professor at MD Anderson Cancer Center. First, the diagnosis itself is changing given the spectrum of disease from monoclonal gammopathy of undetermined significance to smoldering myeloma and symptomatic myeloma. With new recommendations of when to start therapy, what would have once been considered high-risk smoldering MM is being reclassified in order to start treatment sooner. Second, there is no true standard of care; rather, there are numerous variations of regimens with different drug combinations, different durations of treatment, and variable goals of therapy. This can make it particularly challenging to decide which combination is best for which patient. Third, the recycling of prior therapies is not uncommon, and is a concept unique to MM due to clonal evolution: a patient may become refractory to drug X at one point in the disease, but sensitive to it again later in the progression. Finally, advances have been coming remarkably rapidly, with 4 new drugs approved in 2015 and new indication and dosage of carfilzomib approved in 2016.
 

Advances in Review (2015)
Among the recent entries is panobinostat, which was approved based on a subgroup analysis of patients who had more than 2 lines of prior therapy, including bortezomib and an immunomodulatory drug (IMiD). In this subgroup, there was a clinically significant 8-month improvement in progression-free survival (PFS).
 
The ASPIRE trial evaluated the addition of carfilzomib to lenalidomide and dexamethasone in patients who had relapsed after 1 to 3 lines of therapy. The unique aspect of this trial was the fact that carfilzomib was stopped after 18 months instead of the usual practice of treating until progressive disease. Importantly, the response continued after discontinuation, with upwards of 26-month PFS, which is the longest PFS we have seen in the relapsed/refractory space. “There’s really a value added when you can stop therapy and have continued response and benefit to therapy,” remarked Dr Shah.
 
The third agent approved last year was daratumumab, a new drug class that targets CD38, which is ubiquitously expressed on myeloma cells. The monoclonal antibody was tested in patients with a significant unmet need: those who had progressed after more than 3 lines of previous therapy, including an IMiD and a proteasome inhibitor. The response rate was 30% in this difficult-to-treat group, with a PFS of 3.7 months.
 
The fourth drug approved in 2015 was ixazomib, an oral proteasome inhibitor. “We still have a lot to learn about how to use an oral proteasome inhibitor and how active ixazomib is in myeloma,” said Dr Shah. “In most myeloma trials, you’ll see an early separation in PFS within the first month or 2 with an active experimental arm, and here you don’t see separation in the PFS curves until at least 9 months; it will be necessary to understand why we see this late separation of the curve.”
 
“There’s some emerging data from the FDA’s statistical review, which is important. In their review, there was no benefit with ixazomib in the first relapse, whereas in the second- and third-line relapse, you do see PFS benefit. That is a little bit unusual because normally, the earlier you use these combinations, the greater the benefit. So, there is still a lot to be learned about this 3-drug combination.”
 
The ELOQUENT 2 study was a phase III trial evaluating the addition of elotuzumab—a monoclonal antibody with a novel immunotherapeutic mechanism of action—to a lenalidomide/dexamethasone backbone. The patients received elotuzumab infusions weekly for the first 3 cycles, dropping down to every other week indefinitely. A clinically significant 30% reduction in risk of progression or death, with minimal toxicity, was observed.1
 
The 2015 data set Dr Shah considered most practice-changing was the ENDEAVOR study, which was the first head-to-head comparison within the same class of MM drugs—namely proteasome inhibitors—in relapsed MM. Full dose carfilzomib 56 mg/m2 and /dexamethasone was compared with bortezomib/dexamethasone, showing a doubling in the complete response rate, PFS, and duration of response with carfilzomib. “This is a practice-informing and practice-changing study as opposed to the kind of standard 2- versus 3-drug comparison used for regulatory approval,” he remarked.
 

Long-Term Survival, Lifelong Treatment
Building on previous incremental advances, MM treatments introduced in the past decade have produced a cumulative effect, resulting in significant improvements in survival. “Survival has improved from 4 to 5 years to 6 and 7 years. That’s what we’re seeing now across multiple data sets,” said Dr Shah, presenting statistics from the Mayo Clinic and MD Anderson. “And so now, with all these new drugs over the last year, I anticipate significant improvements in overall survival, not just incremental benefits of 3 months.”
 
Curative treatment, however, remains elusive. “Myeloma is still non-curable in a classic definition and as patients define cure, which is where the myeloma is completely gone and never come back, and you don’t need to take life-long therapy. This is different than the functional cure we talk about, where we have to move the ‘goal posts’ and the patient will pass away from something other than myeloma. That, to me and patients, is not the definition of cure,” said Dr Shah.
 
“We do have a subset of patients (25%) that are living out to 10 and 15 years, and that’s what I define as long-term survivors. These are not cured patients because they’re still getting multiple relapses or getting systemic therapy or are on maintenance, but we are seeing more long-term survivors, and I think that’s how the paradigm has shifted over the last 10 years,” he continued.
 

Value From Various Perspectives
Of course, with long-term survival comes the cost of long-term treatment. In terms of value, Dr Shah thinks we need to get away from just measuring the cost of the drug divided by the response rate or PFS, as there is sustained and additional benefit beyond simple PFS. “Obviously, cost is an important part of it, but there is value beyond the response rate and PFS,” he remarked.
 
So, how do we define value in the treatment of MM? “For payers, it’s going to be a cost-driven issue,” noted Dr Shah. To them, he would point out the added value of prolonged duration of benefit seen beyond the defined period of therapy, as demonstrated with carfilzomib in the ASPIRE study. In that study carfilzomib was stopped at 18 months but the clinical benefit persisted beyond planned discontinuation with a PFS of 26+ months.
 
For patients and physicians, Dr Shah counts oral dosing and tolerability as value-adds. “There’s always some value in terms of oral therapy to both patients and physicians,” he said. “But I think we have to keep in mind that there appears to be a loss in terms of efficacy because we know that this is probably a less effective drug in terms of response rates. We need to be more vigilant to ensure compliance and that the oral therapies are taken as directed.”
 
“When you look at all these drugs, they’re very well tolerated,” he continued. “They are not associated with increased hospitalizations, use of healthcare resources, or discontinuations due to toxicities. In fact, the quality of life (QOL) is improved with the newer therapies, and there is less morbidity and less utilization of healthcare resources.”
 
“Ultimately, the value to the patient is not driven by only PFS and objective response rate, but by overall survival and improved QOL. We have clearly demonstrated improved overall survival and QOL benefit with new therapies, which is the ultimate goal of physicians and patients,” said Dr Shah. This has been demonstrated in all the recent studies when a third drug was added to regimen—the toxicity profile has been minimal and the QOL improved.
 
“The bottom line,” Dr Shah said in conclusion, “is that you see really significant value for patients. This is not limited to your rare responder. We’re talking about the vast majority of patients that are going to do well for a long, long time.”
 

Reference
1. Lonial S, Dimopoulos MA, Palumbo A, et al; ELOQUENT-2 Investigators. ELOQUENT-2: a phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;33(15, ASCO Annual Meeting suppl):8508. 
 
 

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