Combination Therapy Benefits High-Risk Patients With MM, Study Says

A new analysis found patients with high-cytogenetic-risk multiple myeloma benefitted from adding daratumumab to their therapy.

Daratumumab with bortezomib/dexamethasone (D-Vd) led to better progression-free survival (PFS) than bortezomib/dexamethasone (Vd) alone in patients with relapsed or refractory multiple myeloma (RRMS), even if the patients had high cytogenetic risk.

Those findings are based on a new subgroup analysis of the CASTOR study,1 which was originally published in 2016. That study showed patients had higher rates of minimal residual disease (MRD) negativity when treated with D-Vd, and a 69% reduction in risk of progression or death after 3 years.

In the new analysis, corresponding author Katja Weisel, MD, of University Medical Center Hamburg-Eppendorf, in Germany, and colleagues sought to see whether those overall findings held true in a specific subgroup: patients with high cytogenetic risk. Their report was published in the Journal of Hematology & Oncology.2

Weisel and colleagues used the International Myeloma Working Group’s definition of high cytogenetic risk, which includes any patient testing positive for at least 1 of the following abnormalities: t(4;14), t(14;16), or del17p, as identified by fluorescence in situ hybridization. These patients are more likely to have poor outcomes compared to patients without the abnormalities.

The initial CASTOR study had 498 patients. Of those 40 in the D-Vd group and 35 in the Vd group were identified as high-risk in Weisel’s new analysis.

After isolating those patients’ data, the authors looked at the results in standard-risk versus high-risk patients after a median follow-up of 40 months.

In standard-risk patients, D-Vd led to PFS of 16.6 months, versus 6.6 months in the Vd group. Likewise, the authors found D-Vd achieved PFS of 12.6 months in high-cytogenetic-risk patients, versus 6.2 months for the patients treated with Vd.

D-Vd also had higher rates of MRD negativity, and patients in that cohort also had better rates of sustained MRD negativity (using a threshold of 10-5). The authors found this held true regardless of whether a patient had high cytogenetic risk or not.

“These updated data reinforce the effectiveness and tolerability of daratumumab-based regimens for RRMM, regardless of cytogenetic risk status,” they wrote.

Weisel and colleagues found that the benefit of D-Vd was particularly notable in patients who had already undergone 1 prior line of therapy. In those patients, the risk of disease progression or death fell by 75% for standard-risk patients and 80% for high-risk patients.

As for the safety profile, the authors said they found no significant differences among standard-risk and high-risk patients.

The authors said the results of this analysis line up with other studies into similar questions. However, they said there are some key limitations. For one, 29% of patients in the CASTOR study did not undergo cytogenetic testing. Also, since testing was done locally and no per-protocol cut-off values were set, the cut-off values used by individual testing sites to identify abnormalities are not known. Finally, the authors noted that MRD testing was not done universally; patients who achieved very good partial responses (VGPR) and some patients who achieved complete responses did not undergo the testing.

“Of patients with available cytogenetic abnormality data, patients without MRD assessment were considered MRD positive, potentially underestimating the rate of MRD negativity,” Weisel and colleagues wrote.

Even with those limitations, the authors said the data support daratumumab’s inclusion in the treatment plans of patients with high cytogenetic risk MM.


  1. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med. 2016;375(8):754-766. doi:10.1056/NEJMoa1606038
  2. Weisel, K., Spencer, A., Lentzsch, S. et al. Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hematol Oncol 13, 115 (2020).
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