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Daratumumab regimen yields durable responses in relapsed, refractory multiple myeloma
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SAN DIEGO — Patients with relapsed or refractory multiple myeloma who received the addition of daratumumab to lenalidomide and dexamethasone continued to demonstrate encouraging PFS rates at 3 years, according to updated results of the multicenter, randomized, open-label, active-controlled, phase 3 POLLUX study presented at ASH Annual Meeting and Exposition.
Nizar Bahlis, M D, associate professor at University of Calgary in Alberta, Canada, presented updated findings from the study, which compared outcomes among 569 patients (median age, 65 years) with relapsed or refractor multiple myeloma treated with daratumumab (Darzalex, Janssen Oncology) plus lenalidomide (Revlimid, Celgene) and dexamethasone (n = 286) with those treated with lenalidomide and dexamethasone alone (n = 283).
Patients received16 mg/kg IV daratumumab — a human monoclonal antibody that targets CD38 — every week in cycles 1 to 2, every 2 weeks in cycles 3 to 6, and every 4 weeks until progressive disease. In both groups, patients received 25 mg oral lenalidomide on days 1 to 21 of each cycle with 40 mg oral dexamethasone every week until progressive disease.
Previous study results — after a median follow-up of 13.5 months — showed the addition of daratumumab to lenalidomide and dexamethasone reduced risk for progression by 63%, and increased the overall response rate (93% vs 76%; P < .001) complete response rate (43% vs 19%; P < .001) and very good partial response rate (76% vs 44%; P < .001).
Based on these data and others, FDA approved daratumumab for use as monotherapy or in combination with lenalidomide and dexamethasone, or with bortezomib and dexamethasone, for patients with released or refractor multiple myeloma.
The current analysis — conducted after a median 44.3 months of follow-up — includes updated 3-year data on sustained minimal residual disease (MRD) negativity and safety.
Results showed significantly longer median PFS in the daratumumab group than the lenalidomide/dexamethasone group (44.5 months vs. 17.5 months; HR = 0.44; 95% CI, 0.33-0.55).
Daratumumab also significantly prolonged PFS among patients with one previous line of treatment (HR = 0.42; 95% CI, 0.3-0.58), and across both high-risk (HR = 0.54; 95% CI, 0.32-0.91) and standard-risk (HR = 0.41; 95% CI, 0.31-0.55) cytogenetic status patients.
Using a sensitivity threshold of 10-5, researchers determined that 30% of patients in the daratumumab group and 5% of those in the non-daratumumab group reached MRD negativity (P < .000001).
Among the intent-to-treat population, sustained MRD negativity occurred among 16% of the daratumumab group and just 0.7% of the dexamethasone/lenalidomide group (P < .0001) at the 6-month or later cutoff point. By the 12-month or later cutoff, those rates were 13% with daratumumab and 0.4% without daratumumab (P < .0001).
Daratumumab was associated with an ORR of 93%, compared with 76% for the lenalidomide and dexamethasone alone (P < .0001). Similarly, the very good partial response (80% vs. 49%) and complete response rates (57% vs. 23%) significantly favored the daratumumab group (P < .0001 for both).
Safety data showed that grade 3/grade 4 neutropenia occurred among 56% of patients in the daratumumab group and 42% of those in the lenalidomide-dexamethasone group. Grade 3/grade 4 anemia and thrombocytopenia rates were comparable between the two groups, each ranging from 15% to 21%.
The discontinuation rate due to treatment-emergent adverse events was 15% in both groups. Second primary malignancies also occurred at the same rate (9%) in the groups, according to the findings.
The researchers concluded that after more than 3 years of follow-up, daratumumab with lenalidomide and dexamethasone continued to provide PFS improvements and deep responses in this patient population. Moreover, the regimen showed no negative impact on outcomes of subsequent treatment regimens, with no new safety signals.
“These updated data continue to support the use of [daratumumab plus lenalidomide and dexamethasone] in patients with relapsed or refractory multiple myeloma after first relapse,” the researchers wrote. – by Rob Volansky
Reference:
Bahlis NJ, et al. Abstract 1996. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosures : Bahlis reports honoraria and research funding from, or consultant roles with, Amgen, Celgene and Janssen. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Edward N. Libby, MD
Lenalidomide and dexamethasone previously were the gold standard, but the POLLUX trial changed the standard of practice in multiple myeloma with the addition of daratumumab. The original POLLUX study showed a 93% vs. a 76% ORR.
This 3-year follow-up gives us insight into how patients have done in the long-term. We see very impressive response rates. One of the things that stands out for me is the depth of response in the categories we care about, like very good partial response or better and complete response or better. In those categories, the depth of response essentially doubles compared with lenalidomide and dexamethasone. Those are dramatic and eye-catching numbers, with high statistical significance.
Another interesting addition to the study was a new category of sustained MRD negativity. This concept was applied in other myeloma trials at ASH this year. The question is whether a treatment can sustain MRD negativity for months or years.
Researchers reported a major improvement in 36-month PFS, with median PFS of 30 months vs. 20 months for the high-risk patients, an important part of this trial. In this study, MRD negative was defined as less than 10-5 presence of multiple myeloma. The patients who achieved a complete remission with MRD negativity had continued MRD testing at several time points afterward.
I think we are heading more and more in that direction in the multiple myeloma world. There was a small, but important, high-risk category within these 569 patients. Although these 65 high-risk patients were spread in both arms — which is not a huge group — they are still informative.
In terms of long-term side effects, there were no new safety signals among patients on the daratumumab regimen with 3 years of follow-up. This is a very comforting result. We know daratumumab is well tolerated in addition to being efficacious.
For me, the take-home is that at 3 years out, we continue to see a major benefit of the daratumumab/lenalidomide/dexamethasone triplet vs. lenalidomide and dexamethasone. Very significant differences were seen in the depth of response between the two regimens, and these responses were sustained.
The new benchmark of sustained MRD negativity could become a standard measurement in future trials.
Daratumumab is a game-changer and a difference-maker. In the search for the best outcomes for our patients, we can expect to see more trials of this agent in combination with all the standard backbone therapies for multiple myeloma.
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