© Todd Buchanan 2016
SAN DIEGO—Daratumumab added to standard of care regimens drives deep clinical responses beyond complete response (CR), a magnitude that is “unprecedented” in the relapsed/refractory multiple myeloma (MM) setting, according to a speaker at the 2016 ASH Annual Meeting.
Investigators added daratumumab to lenalidomide/dexamethasone in the POLLUX trial and to bortezomib/dexamethasone in the CASTOR trial.
In both phase 3 trials, the addition of daratumumab resulted in significant improvements in progression-free survival (PFS), overall response rate, and minimal residual disease (MRD) negativity when compared to control groups.
“The magnitude of daratumumab-induced MRD negativity in the relapsed setting is unprecedented and, for me, was not expected,” said Hervé Avet-Loiseau, MD, of Centre Hospitalier Universitaire Rangueil, Unité de Genomique du Myelome in Toulouse, France.
Dr Avet-Loiseau presented the MRD findings from CASTOR and POLLUX at the ASH Annual Meeting as abstract 246.*
He noted that, based on these studies, daratumumab received US Food and Drug Administration approvals for use in combination with standard of care regimens for MM patients who had received 1 or more prior lines of treatment.
Daratumumab had been previously approved as monotherapy for relapsed or refractory MM.
Study designs and findings from the POLLUX and CASTOR trials have been described earlier in Hematology Times.
Dr Avet-Loiseau provided updated PFS figures for the 2 studies.
At 18 months’ follow-up in the POLLUX study, the PFS rate for patients treated with daratumumab/lenalidomide/dexamethasone was 76%, compared to 49% in the lenalidomide/dexamethasone arm (P<0.0001).
At 12 months’ follow-up in the CASTOR study, the PFS with daratumumab was 60%, compared to 22% for bortezomib/dexamethasone (P<0.0001).
MRD criteria
In both studies, MRD assessments were conducted at suspected complete response (CR). Assessments were also conducted at 3 months and 6 months after CR in the POLLUX study and at 6 months and 12 months after the first study dose in the CASTOR study.
For the assessment of MRD, investigators used bone marrow aspirate samples and the ClonoSEQTM NGS-based assay.
Investigators evaluated MRD at 3 sensitivity thresholds: 10-4, 10-5, and 10-6.
And they used a stringent, unbiased evaluation, Dr Avet-Loiseau said. Any patient in the intent-to-treat population who was not assessed to be MRD negative was scored as MRD positive.
And the minimum cell input equivalent to the sensitivity threshold was required to determine MRD negativity.
MRD results
In the POLLUX study, 24.8% of patients achieved MRD negativity at the 10-5 cutoff, and 11.9% achieved MRD negativity at the 10-6 cutoff with the daratumumab combination.
This compared to 5.7% and 2.5% MRD negativity at the 10-5 and 10-6 cutoffs, respectively, without daratumumab (P<0.0001).
In the CASTOR study, the daratumumab-treated patients achieved 10.4% and 4.4% MRD negativity at the 10-5 and 10-6 cutoffs, respectively.
This compared to 2.4% and 0.8% MRD negativity in the control arm at the 10-5 and 10-6 cutoffs (P<0.005 and P<0.05), respectively.
“So, definitely, the addition of daratumumab improved the MRD negativity rate in both studies,” Dr Avet-Loiseau said.
“If you just look at the patients who did achieve CR in the POLLUX study, almost 50% of the patients [treated with daratumumab] achieved CR, and half of them were MRD negative at the cutoff of 10-5.”
In the CASTOR study, 25% of the patients treated with daratumumab achieved a CR. The MRD negativity rate was one-third in these patients.
“So again, we have consistently higher MRD negative rates in patients who achieve CR when they were treated in the daratumumab arms,” Dr Avet-Loiseau said.
“What is interesting, I think, is that the achievement of molecular CR was very rapid. [A]t 3 months, some patients did already achieve MRD negativity, and so we continued to see an improvement. [W]e still continue to see some achievement of MRD negativity.”
Investigators continue to follow the patients annually.
The investigators also analyzed MRD at 10-5 by cytogenetic risk and did not observe any MRD negativity in the control arm in either the POLLUX or CASTOR study.
“In contrast, we did observe some significant MRD negativity in the experimental arm with daratumumab—18% (POLLUX) and 14% (CASTOR) in high-risk patients,” Dr Avet-Loiseau said. “The most important prognostic factor is to achieve MRD negativity.”
However, even for patients who did not achieve MRD negativity, the PFS was much better in the experimental arms than in the control arms, he added.
This study, presented as a “Best of ASH” abstract, was funded by Janssen Research & Development, LLC.
*Information in the abstract differs from that presented at the meeting.