Daratumumab Triplet Hailed as New Standard for Advanced Myeloma

Antonio Palumbo, MD

Following the promising addition of a monoclonal antibody, the 3-drug regimen of daratumumab (Darzalex), bortezomib (Velcade), and dexamethasone should seamlessly become the new standard of care for relapsed/refractory patients with multiple myeloma, according to Antonio Palumbo, MD.

Encouraging findings from the phase III CASTOR trial, which were presented at the 2016 ASCO Annual Meeting, demonstrated that when daratumumab was added to bortezomib and dexamethasone, it led to a 61% reduction in the risk of progression or death.

The median progression-free survival (PFS) was 7.2 months in the 2-drug arm and was not yet reached in the daratumumab arm (HR, 0.39; 95% CI, 0.28-0.53; P <.0001). The overall response rates were 83% and 63% (P <.0001) in the experimental and control arms, respectively.

“The conclusion of this study could be that we observed a major advantage in terms of outcome—we saw a 61% reduction in the risk of disease progression, a doubling of the remission duration for patients receiving this combination of therapy, and a very good safety profile without any cumulative toxicity over the control arm,” says Palumbo, the lead CASTOR investigator.

OncLive: Can you share the design and exciting findings of the CASTOR trial?

In an interview with OncLive, Palumbo, chief of the Myeloma Unit, Department of Oncology, University of Torino, discusses the practice-changing findings for relapsed/refractory patients and what questions remain with the 3-drug regimen.Palumbo: These are major findings coming from a randomized study comparing the 3-drug combination of daratumumab plus bortezomib and dexamethasone versus the 2-drug combination of bortezomib and dexamethasone, which is the current standard of care for the treatment of relapsed/refractory patients with multiple myeloma.

In this study, almost 500 patients were randomized to receive daratumumab, bortezomib, and dexamethasone or bortezomib and dexamethasone alone. The primary endpoint of the study was PFS.

The major finding from this study was the reduction in the risk of disease progression of 61%; this is unprecedented in comparison to other studies in relapsed/refractory multiple myeloma. This translated into a doubled remission time for patients who received this 3-drug combination.

What was the safety profile of the triplet regimen?

We also observed a major increase in response rate, leading to a most profound cytoreduction. The rate of complete response was doubled from 10% to 20%, and the rate of very good partial response was almost doubled from nearly 30% to 60%. This has relevant consequences because, in patients who have achieved profound cytoreduction, it did not only double the remission duration—it almost tripled the remission duration.From a safety point of view, the combination was very well tolerated. The major message is that they were no cumulative toxicities with the addition of the monoclonal antibody. The toxicities that were observed in the control arm were mainly the same in the experimental arm. Monoclonal antibodies do not usually have toxicities that are observed with chemotherapy combinations.

What are the next steps following this study?

Are there any patients who are unfit to receive the triplet?

How will these findings impact the treatment landscape of myeloma?

What other remaining questions with this regimen should be answered?

Looking ahead, what does the future hold for this field?

The only increased toxicity was the infusion reaction from the infusion of the antibody. This was present in 45% of patients, was mainly grade 1/2, and, in 98% of those cases, that adverse event was confined to the first infusion.Certainly, we need a longer follow-up. We still need to see if overall survival (OS) will give a major signal. At present, the follow-up is very short—only 7 months&mdash;so we do not have any data on OS. Although the hazard ratio is already 0.7, it is, of course, not significant.It is very well tolerated in all subgroups, including patients who are younger and older, have good or bad prognosis, and are in early-stage or late phases of disease. We do not have a specific exclusion for a subset of patients right now. The message here is to use it as early as possible because in early phases of disease, the efficacy is much higher.We have a new treatment paradigm. We will certainly include monoclonal antibodies in every single combination. R-CHOP has been the major standard of lymphoma, and, probably now, we are starting to see that daratumumab is the equivalent standard in including monoclonal antibodies for multiple myeloma.The next question is to move to early phases of diseases because, now, the study has been performed in relapsed/refractory patients. We need to move quickly in the newly diagnosed patient, because, if we can copy what has been done here, the median remission of 1 to 2 years can be doubled to 2 to 4 years at diagnosis. A remission of 4 to 5 years could be doubled to 8 to 10 years, and that is the major expectation for the future.In the last 10 years, myeloma has had major improvements in survival. In the next couple of years, I do expect a further improvement in OS and probably will include the use of those agents in newly diagnosed patients—providing the opportunity to achieve a cure in a significant proportion of patients.

Palumbo A, Chanan-Khan A, Weisel K et. al. Phase 3 randomized controlled study of daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM): CASTOR. J Clin Oncol 34, 2016 (suppl; abstr LBA4).