Adding Velcade (bortezomib) to standard chemotherapy is well-tolerated but does not improve the survival outcomes of patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL), even after stratifying patients according to their cell of origin, a Phase 3 trial shows.
The study, “Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial,” was published in The Lancet Oncology.
For the past 15 years, R-CHOP chemotherapy — containing Rituxan (rituximab), cyclophosphamide, doxorubicin, vincristine, and prednisolone — has been the standard of care for DLBCL patients.
Since then, researchers have been trying to improve its efficacy, adding new therapies to the combination, but these approaches have mostly fallen short.
The reason for this, researchers believe, is that DLBCL is very heterogeneous, with treatments that improve outcomes in some DLBCL subtypes not being effective in other disease subtypes.
With the development of new sequencing techniques, researchers have been able to group DLBCL into two subtypes, depending on the cell of origin — germinal center B-cell-like (GCB) and activated B-cell (ABC) DLBCL.
The ABC subtype has an overactive NF-κB signaling pathway, which seems to help cancer cells proliferate and thrive. But Takeda Oncology‘s Velcade — a treatment approved for multiple myeloma and mantle cell lymphoma — appears to suppress this signaling pathway, suggesting it could improve the outcomes of some DLBCL patients.
Thus, investigators at Cancer Research UK aimed to determine whether adding Velcade to R-CHOP chemotherapy could extend the time DLBCL patients lived without disease worsening, and whether different cell of origin subtypes responded differently to the combination.
The REMoDL-B Phase 3 trial (NCT01324596) recruited 918 adult participants from 107 cancer centers in the U.K. and Switzerland, who had been newly diagnosed with DLBCL and were indicated to undergo full-course chemotherapy treatment.
All patients initially received one 21-day cycle of R-CHOP chemotherapy. During this period, tissue samples were analyzed to determine the disease subtype and patients in each subgroup were randomized to continue R-CHOP alone or in combination with Velcade.
The trial’s primary goal was to determine the number of patients alive and whose disease had not worsened at 30 months for the ABC and GCB subtypes. Secondary measures included overall survival, time to disease progression, duration of responses, complete and overall response rates, safety, and quality of life.
“This is the first large-scale study in diffuse large B-cell lymphoma to use real-time molecular characterization for prospective stratification, randomization, and subsequent analysis of biologically distinct subgroups of patients,” researchers said.
Overall, 244 (26.6%) patients had activated B-cell disease, 475 (51.7%) had germinal center B-cell disease, and 199 (21.7%) had unclassified disease.
After a median follow-up of 29.7 months, there was no significant difference the number of patients alive and progression-free at 30 months in the combined ABC and GCB populations — 70.1% for the R-CHOP group versus 74.3% for the Velcade group.
Overall survival at 30 months was also similar in the combined population — 82.7% in the R-CHOP group and 83.6% in the R-CHOP plus Velcade-treated group.
An analysis by disease subtype also showed that Velcade did not improve progression-free survival or overall survival in either the ABC or GCB subtypes, or those with unclassifiable disease. Patients with mutations known to be associated with NF-κB activation also did not benefit from Velcade.
Researchers found, however, that among those receiving R-CHOP chemotherapy only, patients with genetic rearrangements in the MYC and BCL2/BCL6 genes lived significantly shorter times without disease progression.
In general, Velcade did not affect the treatment’s safety profile. Blood toxicity was the most common adverse event reported during the trial, occurring in 178 patients receiving R-CHOP and 187 patients receiving R-CHOP plus Velcade.
More patients in the Velcade group had neuronal damage, but the difference was not significant. Serious adverse events and the number of deaths related to treatment were similar between the two groups.
While REMoDL-B failed its primary goal, the trial “shows that real-time characterization of diffuse large B-cell lymphoma is feasible by use of molecular biology with RNA extracted” from tissue samples, Fabrice Jardin, MD, PhD, of Rouen University in France, said in an editorial piece.
“The selection of DLBCL patients on the basis of biological markers before the first treatment, therefore, remains a crucial challenge,” he said.