Currently in myeloma, there are at least five new agents that are either approved or in the late-stage of development with impending approval. Major questions in the field relate to how we, as clinicians, will use these new agents and where they will fit in the overall treatment schema.

The phase III ASPIRE trial—recently reported by Stewart and colleagues¹ and reviewed in this issue of The ASCO Post—evaluated the benefit of adding the second-generation proteasome inhibitor carfilzomib (Kyprolis) to a standard two-drug salvage regimen of lenalidomide (Revlimid) and dexamethasone. A number of lessons that may help us plan our way forward can be drawn from this very important clinical trial.

Impressive Outcomes

First, the trial showed that the addition of carfilzomib resulted in significant improvement in progression-free survival, overall response rate, and depth of response, as well as in patient-reported quality-of-life metrics. Strikingly, the improvement in progression-free survival was 9 months, and the aggregate progression-free survival of 27 months represents the longest progression-free survival reported to date in a phase III clinical trial in this setting—a major achievement. Although the patient population was predominately a relapsed and early-relapse population—both features that favor better outcomes—the duration of remission for the experimental arm is nevertheless unprecedented.

Tolerable Toxicity

Second, we learned that a carfilzomib-based combination could be safely used in the relapsed setting for a large number of patients. There were lingering questions following a phase II study of carfilzomib in the relapsed and refractory myeloma setting about potential cardiac issues associated with the agent. The adverse-event profile presented from ASPIRE indicated no significant difference in cardiac-related adverse events between the carfilzomib and control arms, providing reassurance in this regard. The carfilzomib group had an increased incidence of dyspnea, but in most cases, this did not result in dose modification or discontinuation.

Other adverse events were similar between the two treatment groups, further supporting the safety profile of the three-drug combination and countering one of the major arguments against combination therapy (i.e., toxicity of the therapy). It seems clear from both patient-reported outcomes and objective assessment of adverse events that toxicity associated with the addition of the third agent to the standard lenalidomide/dexamethasone salvage approach did not limit the potential benefit of the three-drug approach.

Time to Reevaluate the Benign Approach?

Third, the impressive results from this trial also begin to address a larger question currently being asked in the myeloma community. Should patients with early relapse be preferentially treated with a three-drug salvage regimen, or should we continue to use two drugs as we have traditionally done?

In the context of newly diagnosed myeloma, it is almost universally accepted now that a three-drug induction is preferable to a two-drug regimen in terms of overall response rate and depth of response and that better pretransplant response translates to improved post-transplant duration and depth of response. We are beginning to target not just conventional complete response, but minimal residual disease–negative complete response as a goal of therapy for newly diagnosed patients. Should we think about early relapse in the same fashion?

The arguments against this more-aggressive approach come from the “myeloma is an indolent disease” line of thought, in which it is typically proposed to “gently” treat patients, with the goal of pushing the ball forward one step at a time. Given the impressive results from the ASPIRE trial, is it time to reevaluate that ‘benign’ approach? There are patients who can clearly benefit from a more-intensive approach, as we see from the progression-free survival curve in ASPIRE, but is that benefit strictly in patients with early relapse?

In a subset analysis of the trial, it appears that one group that perhaps did not get the same magnitude of benefit from the three-drug regimen was the group older than age 65. These patients tend to be frailer than younger patients, so a better understanding of this group of patients is an important step as we begin to individualize treatment recommendations.  

Who Is Likely to Derive the Most Benefit?

However, with results of many more phase III trials evaluating three- vs two-drug combinations in the early relapse setting on the horizon, this question about who is likely to derive the most benefit will come up more and more. As we consider the intensity of therapy, the impact of combinations, and how to approach a relapsed patient, we should begin to think more about biology and less about “populations.” What happened at the time of relapse that allowed the clone to grow back, and is this an event that requires two or three drugs for control?

As we amass new phase III trial results, in the context of the ASPIRE trial, we must carefully consider the characteristics of the patients who were treated, the magnitude of benefits achieved, and the patient and disease characteristics associated with the differential benefit: Who are the patients who derive no or little benefit, and who are the patients who derive the greatest benefit, perhaps even “cure”?

The outstanding results reported by Stewart and colleagues represent a major step forward for our patients. But now, as clinicians and scientists, we must find a way to apply their data and forthcoming data in a way that results in meaningful long-term benefit for our patients as part of an overall long-term treatment strategy. ■

Disclosure: Dr. Lonial is on the scientific advisory boards of Millennium, Celgene, Novartis, Onyx, BMS, and Janssen.

Reference

1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al: Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 372:142-152, 2015.

Dr. Lonial is Professor and Vice Chair of Clinical Affairs in the Department of Hematology and Medical
Oncology at the Winship Cancer Institute, Emory University, Atlanta.