Frontline use of triple therapy with bortezomib (Velcade, Millennium), lenalidomide (
So say researchers reporting results from a phase 3 trial of the combination, published online December 23 in The Lancet.
"Our results are clear," commented the study's principal investigator, Brian G.M. Durie, MD, chairman of the International Myeloma Foundation. "Using bortezomib in combination with lenalidomide and dexamethasone in front-line treatment — hitting the disease early and hard — makes a meaningful difference for myeloma patients," he said in a statement.
"This is a landmark study that lends clarity to frontline therapy of myeloma," added study coauthor Vincent Rajkumar, MD, from Mayo Clinic, Rochester, Minnesota.
Myeloma experts not involved in the study agreed. When the study was presented last year at the American Society of Hematology annual meeting, they said that there is now enough data to convince even skeptics of the benefits of using a triplet instead of a doublet upfront, as reported at the time by Medscape Medical News.
On the basis of the findings from this study, the VRd triplet "can be established as an effective regimen for first-line treatment in transplant and non-transplant eligible patients," write Heinz Ludwig, MD, from the Wilhelminen Cancer Research Institute, Vienna, Austria, and Michel Delforge, MD, from the University Hospital Leuven, Belgium, in an accompanying editorial.
However, that position is already being challenged by an ongoing phase 3 trial that compares VRd with another triplet, which includes carfilzomib (Kyprolis, Amgen) in addition to lenalidomide-dexamethasone (KRd), they note.
Data showing high response rates so far suggest that such carfilzomib/immunomodulatory drug–based protocols will improve survival when given as frontline therapies, especially if boosted by adding drugs such as daratumumab (Darzalex, Janssen Biotech) to the mix, they suggest.
The drawback will be the cost. "This path of success will be substantially affected by the very high costs for these novel anti-myeloma combination protocols," the editorialists write.
Dr Rajkumar commented that "newer alternatives to VRd may be more expensive, cumbersome, or toxic. These regimens will therefore need to show superiority over VRd in randomized trials."
Also worth noting, Dr Rajkumar said, is that the VRd regimen will become even more cost-effective as the drugs in this combination become generic over time.
Improvement in All Endpoints
The phase 3 study (known as SWOG S0777) reported by Dr Durie and colleagues was conducted in 525 patients with newly diagnosed multiple myeloma without intent for immediate autologous stem-cell transplant.
These patients were treated at 139 participating institutions and were randomly assigned to receive front-line treatment with the VRd triplet or to receive the doublet combination of lenalidomide with dexamethasone (Rd).
VRd was given as eight 21-day cycles: bortezomib given at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 and combined with oral lenalidomide, 25 mg daily, on days 1 to 14 plus oral dexamethasone, 20 mg daily, on days 1, 2, 4, 5, 8, 9, 11, and 12.
Rd was given as six 28-day cycles: 25 mg oral lenalidomide once a day for days 1 to 21 plus 40 mg oral dexamethasone once a day on days 1, 8, 15, and 22.
Median progression-free survival (the study's main endpoint) was significantly improved in the VRd group compared with the Rd group; 43 months vs 30 months (stratified hazard ratio [HR], 0.712; one-sided P = .0018).
The median overall survival was also significantly improved for patients receiving VRd (75 months vs 64 months in the Rd group; HR, 0.709; two-sided P = .025).
Overall response rates were 82% (176/216) for the VRd group and 72% (153/214) for the Rd group; 16% (34/216) and 8% (18/214) of patients who were evaluable achieved a complete response or better.
Adverse events were fairly well balanced between both groups. The most common hematologic adverse events (grade 3 or greater) were anemia, lymphopenia, neutropenia, and thrombocytopenia, and most common nonhematologic adverse events (grade 3 or greater) were fatigue, sensory neuropathy, hyperglycaemia, thrombosis or embolism, hypokalaemia, muscle weakness, diarrhea, and dehydration.
As expected, note the authors, grade 3 or worse neurologic toxicities were experienced more frequently among patients receiving VRd (33% vs 11%; P < .0001).
In addition, 20 patients (10 in each group) developed a second primary cancer.
The editorialists comment that the addition of bortezomib to the doublet was associated with few additional toxic effects — mainly a higher rate and grade of polyneuropathy aggravated by intravenous administration of bortezomib. If the study were repeated, toxic effects would be substantially reduced because of subcutaneous bortezomib administration (which is used now), they add.