Conference Coverage
Elotuzumab plus len-dex extends remissions of multiple myeloma
Key clinical point: The novel antibody elotuzumab extended multiple myeloma remissions when added to standard therapy. Major finding: Mean...
What may be more important going forward is how these three drugs will be used in clinical trials, Dr. Rajkumar observed.
“We’d rather put all patients on clinical trials than any of the recommendations I made,” he said. “The problem is that clinical trials have to be appropriately designed.”
Several phase III trials are already ongoing comparing a doublet versus a triplet (IRd vs. Rd, elotuzumab-Rd vs. Rd, and daratumumab-Rd vs. Rd) in the frontline setting, so the key question for future trials is which triplet: VRd, KRd, elotuzumab-Rd, or daratumumab-Rd, and to what endpoint.
Progression-free survival can remain a primary endpoint for comparing two triplets in the frontline, but PFS alone is not enough in the maintenance setting and investigators should look to other primary endpoints such as PFS2, PFS1 vs. PFS2, overall survival with a higher type 1 error than currently used, or PFS plus validated patient-reported or quality of life outcomes, Dr. Rajkumar said.
Relapsed/refractory disease
Speaking on how the three new agents fit into the relapsed or refractory space,Dr. Paul Richardson, of Dana-Farber Cancer Institute, Boston, said three-drug platforms are emerging as a standard of care for relapsed or refractory disease after studies have shown time and time again they are better than doublets.
Patrice Wendling/Frontline Medical News
Dr. Paul Richardson
He highlighted phase III data reported at ASH by Dr. Philippe Moreau from TOURMALINE-MM1 (Abstract 727) showing a 35% improvement in PFS with weekly oral ixazomib plus lenalidomide-dexamethasone vs. Rd alone in relapsed and/or refractory multiple myeloma.
This translated into a median 6-month gain in PFS compared with an almost 9-month PFS benefit seen in ASPIRE with carfilzomib plus Rd, but cross-trial comparisons should be approached with some caution and both hazard ratios were very robust, he said. In addition, as previously observed, ixazomib is remarkably well tolerated.
“I think ixazomib, particularly in older patients and particularly in patients with high-risk disease, will be very useful in the context of the three-drug or even greater combinations. So there’s a strong rationale for its use,” Dr. Richardson said.
He went on to say that elotuzumab has shown remarkable anti-myeloma activity in the relapsed and refractory setting, improving both the overall response rate and PFS when used in combination with Ld vs. Ld alone in the ELOQUENT-2 trial. Updated results from ELOQUENT-2 were presented at the ASH meeting (Abstract 28).
A PFS benefit was also seen when elotuzumab was added to bortezomib and dexamethasone, with a 24% reduction in the risk of disease progression or death reported in a study presented at ASH by myeloma expert Dr. Antonio Palumbo (Abstract 510).
“My point in showing this is that when you think of elotuzumab being used with lenalidomide and dexamethasone in relapse, many of our patients are actually on them as maintenance when it occurs, therefore elotuzumab may have a role in combination, for example, with proteasome inhibitors in this same setting,” Dr. Richardson said.
Several pomalidomide-based triple therapy combinations have been evaluated in advanced relapsed or refractory myeloma, with a phase II study (Abstract 506) reported that morning at ASH showing the third-generation immunomodulatory drug (IMiD) pomalidomide induced responses in 60% of heavily pretreated patients when partnered with pembrolizumab and dexamethasone.
Combination strategies with daratumumab are also very provocative, particularly in the context of IMiDs, he noted. A phase Ib study reported in the same early morning session by Dr. Ajai Chari (Abstract 508) had a “very encouraging” overall response rate of 71% with daratumumab plus pomalidomide and dexamethasone in heavily pretreated patients, including 43% very good partial responses or better, and an overall response rate of 67% among double-refractory patients.
“Daratumumab and elotuzumab, in my view, as first-in-class monoclonal antibodies, are paradigm-changing agents,” Dr. Richardson concluded. “They provide us with this mutation-driven ability to overdrive the impact of those mutations and the important point is that they prescribe an entirely non-crossresistant strategy that can be easily added to existing platforms of drugs.”
Dr. Rajkumar reported discussion of off-label drug use for elotuzumab, daratumumab, ixazomib, and carfilzomib in untreated myeloma, maintenance, and early relapse. Dr. Richardson reported membership on a board of directors or advisory committee for Millennium Takeda, Celgene, Janssen, Bristol-Myers Squibb, and Novartis, and research funding from Millennium Takeda and Celgene.
