Saad Z. Usmani, MD
Several key trials examining daratumumab (Darzalex) in multiple myeloma were presented late last year at the 2016 ASH Annual Meeting.
Researchers shared long-term data from the pivotal CASTOR1
trials, which supported the November 2016 FDA approval of 2 daratumumab-based triplet regimens. CASTOR randomized patients with relapsed/refractory multiple myeloma to bortezomib (Velcade) and dexamethasone alone or with daratumumab. POLLUX randomized patients with relapsed/refractory multiple myeloma to daratumumab combined with lenalidomide (Revlimid) and dexamethasone or lenalidomide plus dexamethasone alone.
The CASTOR update showed that at a median follow-up of 13 months, the overall response rate (ORR) was 84% in the daratumumab arm versus 63% in the bortezomib/dexamethasone arm. The 12-month progression-free survival (PFS) rate was 60% in the daratumumab arm versus 22% in the control arm.
In the POLLUX update, at a median follow-up of 17.3 months, the ORR was 93% in the daratumumab arm versus 76% in the lenalidomide/dexamethasone arm. The median PFS was still not reached in the daratumumab arm versus 17.5 months with lenalidomide/dexamethasone alone.
Data from another important daratumumab study presented at ASH, the phase Ib PAVO trial,3
showed that subcutaneous delivery of the drug was well tolerated with comparable efficacy to the FDA-approved intravenous (IV) dose in patients with relapsed/refractory multiple myeloma.
In an interview with OncLive
, Saad Z. Usmani, MD, department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute/Carolinas HealthCare System, who presented the POLLUX update and PAVO findings at ASH, discussed the latest developments with daratumumab.
OncLive: What is the significance of the CASTOR and POLLUX trial results for patients with multiple myeloma?
: The CASTOR and POLLUX trials are perhaps 2 of the most exciting trials that have been reported out this year. As we already know, as a result of those 2 studies, daratumumab is now approved for every line of therapy within the relapsed myeloma setting.
The POLLUX study was a large randomized phase III study. It was a global study comparing daratumumab, lenalidomide, and dexamethasone versus lenalidomide/dexamethasone in patients who have had 1 to 3 prior lines of therapy.
The CASTOR trial had a very similar inclusion criteria, but the combination was with daratumumab plus bortezomib/dexamethasone compared with bortezomib/dexamethasone.
Both of those trials showed that daratumumab can be partnered with either an immunomodulatory agent or proteasome inhibitor in that setting, and the 3-way combination seemed to be superior to the 2-way combination. There are some differences in the patient populations that accrued to both the studies and the way that the [trials] were designed.
The way that daratumumab partners with these mechanisms—either immunomodulatory agents or proteasome inhibitors—is probably a little different. That's why we do see a difference in the efficacy and depth of response. It would be unfair to compare both the studies head to head, but it does appear that lenalidomide/dexamethasone is a very strong partner for daratumumab in that line of therapy.
Looking at the efficacy data and trying to look at subgroup analyses, it appears that in patients who had earlier relapses and/or had higher cytogenetics, daratumumab plus lenalidomide/dexamethasone has a superior depth of response, as well as PFS compared with the control arm on either of the studies.
What role do you think these findings will play in the landscape going forward?
Now that daratumumab is approved for earlier lines of therapy, both of those studies will be impactful for practice in the United States. My feeling is that, depending on the kind of therapies the patients have received as their first-line treatment, you may be able to pair daratumumab either with lenalidomide or bortezomib. The concern here—in the grand scheme of things—is the long-term effects of daratumumab on the immune system. We haven't seen any clinically meaningful concerns there.
You presented findings at ASH of a phase I study looking at the subcutaneous infusion of daratumumab. Can you give some background?
One of the challenges of giving daratumumab, after it was FDA approved, was that the intravenous (IV) infusion takes a long time to administer—especially the first dose, which can take up to 7 or 8 hours. Once the patients get to their third or fourth weekly dose, the infusion time can be cut down to 3 or 4 hours. However, it becomes a convenience issue.