Joseph Mikhael, MD, MEd


June 20, 2016

Editor's Note: Joseph Mikhael, MD, MEd, a myeloma specialist at Mayo Clinic in Arizona, covered a number of sessions on multiple myeloma at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting for Medscape's ASCO 2016 Live Blog, which are excerpted below.

For a review of the most important ASCO 2016 sessions across all topics and tumor types, visit Medscape's ASCO 2016 Live Blog.


The most anticipated study at ASCO in the myeloma world was presented as a late-breaking abstract during the plenary session. In fact, it has been years since myeloma was on the plenary docket. Antonio Palumbo, MD, director of the Myeloma Unit at the University of Torino in Italy, presented the results of a phase 3 trial of daratumumab-bortezomib-dexamethasone vs bortezomib-dexamethasone in patients with relapsed multiple myeloma, known as the CASTOR study.[1]

Daratumumab is a monoclonal antibody directed against the CD38 antigen which is present on nearly all myeloma cells. It is currently approved by the US Food and Drug Administration as monotherapy in patients with three or more prior lines of therapy or those who are double refractory to a proteasome inhibitor and an immunomodulatory drug.

In the trial, approximately 500 patients were randomly assigned to these two arms. Patients had relapsed disease with at least one prior line of therapy (and not refractory to bortezomib). Daratumumab is given weekly for three cycles, then every 3 weeks for three cycles, then monthly thereafter. The primary endpoint was progression-free survival (PFS). About one half of patients had had one prior line of therapy.

Median follow-up is only 7 months but the trial was discontinued due to the difference between the two arms. Discontinuations due to adverse events (AEs) were the same, indicating that the addition of daratumumab did not significantly add to serious AEs.

This was very different in regard to progression, favoring the daratumumab arm.

The hazard ratio in PFS was 0.39. The PFS for the combined daratumumab-bortezomib-dexamethasone arm has not been reached but was 7.2 months in the bortezomib-dexamethasone arm. This was highly statistically significant.

The 1-year PFS was 60.7% versus 26.9% in the two arms—dramatically favoring the three-drug combination.

The overall response rates were 83% versus 63%. Minimal residual disease negativity was 14% versus 3%.

The most common AEs were thrombocytopenia and peripheral neuropathy, as expected. These were slightly higher in the intervention arm, reflecting longer time on therapy. Other AEs were well balanced in the two groups.

Infusion reactions occurred in 45%; grade 3 reactions were seen in only 9%. Only two patients discontinued the drug due to reactions; 98% of reactions were with the first infusion.

It is too early to comment on overall survival (OS).

This study will have a very significant impact on the care of patients with myeloma because it will probably be one of the critical pieces of evidence moving the field toward combining novel agents with monoclonal antibodies. Although this has been done with elotuzumab, the potential to combine daratumumab with bortezomib (and soon lenalidomide, carfilzomib, and pomalidomide) is very attractive. It is a near ideal partner as it has significant single-agent activity and minimal overlapping toxicity. Indeed, despite the lengthy infusions—which may with time be mitigated by either subcutaneous administration or concentrated versions of the drug with shorter infusion times—this agent is very well tolerated.

The profound difference in outcomes that daratumumab has produced now places it earlier in the disease course (ie, one to three prior lines) where many options exist, such as carfilzomib-lenalidomide, ixazomib-lenalidomide, and elotuzumab-lenalidomide. The difference here is that partnering with bortezomib is helpful because many patients at first relapse are doing so while on maintenance lenalidomide (making the above combinations difficult).

This is another step in the inclusion of monoclonal antibodies both in combination with and earlier in the disease course of myeloma. Very soon we will be incorporating these agents into frontline therapy and in maintenance therapy. It may well indeed become "the rituximab of myeloma."


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