ORLANDO, Florida — A new triplet therapy, comprising carfilzomib (Kyprolis, Amgen), dexamethasone, and daratumumab (Darzalex, Amgen), known as KdD, should become a new standard of care in the treatment of patients with relapsed or refractory multiple myeloma (RRMM), say researchers reporting the phase 3 CANDOR trial.
The trial was sponsored by Amgen, which says it is preparing regulatory submission on the basis of these study results. At present, daratumumab is approved for use in relapsed/refractory multiple myeloma as monotherapy, in combination with dexamethasone, or with dexamethasone and lenalidomide.
Results from the trial were reported here at the American Society of Hematology (ASH) 2019 in a late-breaking abstract.
They show that triplet therapy with daratumumab, carfilzomib, and dexamethasone yielded "markedly improved" progression-free survival compared with the doublet of carfilzomib and dexamethasone (median not reached vs 15.4 months).
"Treatment with KdD resulted in a significant progression-free survival benefit compared with Kd, with a 37% reduction in the risk of progression or death," said lead author Saad Z. Usmani, MD, MBBS, from Atrium Health, Charlotte, North Carolina. "Patients treated with KdD also achieved deeper responses than patients treated with Kd, with a nearly 10 times higher MRD-negative complete response rate at 12 months vs Kd-treated patients."
On the basis of these results, triplet therapy with these agents should be considered as a novel, efficacious, and tolerable immunomodulator-free treatment option for relapsed or refractory multiple myeloma, Usmani emphasized.
Best of All Worlds
Approached by Medscape Medical News for an independent comment, Joshua Richter, MD, an assistant professor of medicine in the Tisch Cancer Institute at Mt. Sinai, New York City, said that the triplet therapy in this trial is the "best of all worlds wrapped up into one regimen.
"One of the things that stands out about this is that regardless of whether patients are transplant eligible, most patients are on lenalidomide in the up-front setting and remain on it until progression," he said. "In the last few years, we've seen trials of triplet therapy that really didn't allow patients to be lenalidomide refractory, so it's difficult to extrapolate from those studies because it's not really following the way we practice."
These findings show that for patients who present with an aggressive relapse, "we have an all-parenteral regimen that we can give at a moment's notice. It's applicable to people who are lenalidomide refractory, and it's very effective and well tolerated," Richter explained. "So in some ways it is practice changing ― it is another option, but this disease is so heterogeneous that another option is an amazing feat."
Overall survival was not reached in either group, so for now, it is unknown whether the triplet therapy will confer a survival advantage. But this is the "benefit of modern day myeloma treatment," he said. "The control arms in studies are very effective, so we will need a much longer follow-up to see if overall survival is improved."
Superior to Double Therapy
The CANDOR study randomly assigned 466 patients with RRMM to either KdD (n = 312) or the doublet of carfilzomib with dexamethasone (Kd, n = 154) in 102 global sites. All patients had measurable disease and had previously received one to three lines of therapy, for which they demonstrated a partial response or better. One third of patients were lenalidomide refractory, and 42.3% and 90.3% previously received lenalidomide- and bortezomib-containing regimens, respectively.
Both cohorts received carfilzomib (K) as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle (20 mg/m2 on days 1 and 2 during cycle 1 and 56 mg/m2 thereafter). Daratumumab (8 mg/kg) was given on days 1 and 2 of cycle 1 and at 16 mg/kg once weekly as the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3 to 6), and every 4 weeks after that. All patients received dexamethasone 40 mg weekly, either orally or intravenously (20 mg for patients older than 75 years).
At a median follow-up of 16.9 months for the KdD arm and 16.3 months for the Kd arm, the primary endpoint was met. Median progression-free survival was not reached for the KdD arm; for the Kd arm, median progression-free survival was 15.8 months (hazard ratio [HR], 0.63; P = .0014). The benefit in the KdD arm was observed across prespecified subgroups.
Of note, median progression-free survival was not reached among lenalidomide-exposed patients in the KdD group; in the Kd group, it was 12.1 months (HR, 0.52). It was also not reached (vs 11.1 months for Kd) among patients who were refractory to lenalidomide (HR, 0.45).
The median time to first response was 1 month in both arms. The overall response rate favored KdD (84.3% vs 74.7%; P = .0040). The rate of complete response or better was 28.5% vs 10.4%. In addition, the MRD-negative complete response rate at 12 months was 12.5% for KdD vs 1.3% for Kd (P < .0001).
At a median follow-up of 17 months, overall survival was not reached in either arm (HR, 0.75; P = .08). The median duration of treatment was longer in the KdD arm compared with the Kd arm (70.1 vs 40.3 weeks).
The incidence of adverse events of grade 3 or higher was greater in the triplet group (82.1% vs 73.9%), as were serious events (56.2% vs 45.8%). Rates of treatment discontinuation because of toxicity were similar in both arms (KdD, 22.4%; Kd, 24.8%). Five treatment-related deaths were reported; all occurred in the KdD arm (pneumonia, sepsis, septic shock, acinetobacter infection, and cardiorespiratory arrest [n = 1 each]).
Usmani noted that the rate of cardiac failure of grade 3 or higher was 3.9% vs 8.5%. The rate of cardiac failure leading to carfilzomib discontinuation was 3.9% vs 4.6%. "It was surprising, and we're not sure how that happened, but we are looking into the comorbidity profiles," he said.
Commenting on this higher toxicity with the triplet, Richter said that if treatment is managed appropriately, "it is extremely manageable, and this kind of therapy can be given to almost anyone."
Another expert agreed that in the refractory setting, triplet therapy is better, and in this regimen, toxicity was manageable.
"It's too early to show a benefit for overall survival, but this triplet therapy is easy to give and well tolerated," commented Robert Rifkin, MD, FACP, medical director of biosimilars for McKesson, associate chair of hematology research and myeloma disease lead for the US Oncology Network, and hematologist with Rocky Mountain Cancer Centers, Denver, Colorado.
Rifkin doesn't think that these new data are necessarily practice changing, but this triplet does offer another option for patients. "This is an important option for patients who have failed on lenalidomide," he said. "This will also be an easier option for patients once subcutaneous daratumumab is available, and the dosing schedule for carfilzomib has also been improved."
Usmani and coauthors have disclosed numerous financial relationships with industry, as noted in the abstract. Richter has participated in the speakers bureaus of Celgene and Janssen and on the advisory boards or has consulted with Celgene, Janssen, Karyopharm, Oncopeptides, Adaptive Biotechnologies, and Antengene. Rifkin has disclosed no relevant financial relationships.
American Society of Hematology (ASH) 2019: Abstract LBA 6. Presented December 10, 2019.
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Cite this: New Triplet, New Standard of Care in Relapsed Myeloma? - Medscape - Dec 10, 2019.