Carfilzomib Combination Fails To Improve Newly Diagnosed Multiple Myeloma Outcomes

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Initial therapy with carfilzomib, lenalidomide and dexamethasone (KRd) does not improve progression-free survival (PFS) for newly diagnosed multiple myeloma (MM) compared with the conventional bortezomib-based regimen, research shows. 

Speaking at the virtual 2020 ASCO Annual Meeting, Shaji Kumar, from the Mayo Clinic in Rochester, Minnesota, USA, reported the phase III ENDURANCE trial findings for patients without high-risk features who were not candidates for upfront haemopoietic stem cell transplantation (HSCT). 

He explained that the next-generation proteasome inhibitor carfilzomib has been shown to be more effective than bortezomib in the relapse setting and the current study was designed to test whether nine cycles of the KRd regimen would improve PFS compared with 12 cycles of bortezomib, lenalidomide and dexamethasone (VRd). 

The second co-primary endpoint of overall survival (OS) assessing for a benefit with lenalidomide maintenance until disease progression versus a fixed 2-year regimen is ongoing, the presenter said. 

Shaji Kumar described the trial arms as being “well balanced”, noting that approximately a third of patients were aged at least 70 years and 12.2% of the patients were African Americans, with a quarter of participants having stage III disease and 9.4% positive for translocation 4;14. 

Overall, 61.6% of the 526 patients randomly assigned to receive KRd completed induction therapy versus 43.3% of the 527 patients given VRd. Patients in the KRd arm were less likely than their VRd counterparts to discontinue treatment because of adverse events (9.9 vs 17.3%), patient withdrawal or refusal (4.2 vs 7.4%) or use of an alternative therapy (13.7 vs 17.7%). 

In all, 26.8% of the KRd group underwent HSCT after a median 8.9 months, as did 28.0% of the VRd arm after a median 6.5 months. 

Presenting PFS findings from the receipt of the induction regimen, Shaji Kumar described the Kaplan–Meier curves for the KRd and VRd arms as “identical”, with median PFS values of 34.6 and 34.4 months, respectively. 

When assessing only patients aged 70 years and older, median PFS was 28 and 37 months, respectively, while the corresponding values were 32.8 and 31.7 months after censoring for HSCT or alternative therapy, with trends towards better PFS with VRd in male patients and those aged over 70 years. 

The majority of patients in both the KRd and VRd arms achieved at least a partial response (86.7 vs 84.3) and a similar proportion achieved a complete response (18.3 vs 14.8%), but KRd-treated patients were significantly more likely to achieve a very good partial response or better (73.8 vs 64.7%). 

After a median 29 months, OS also “appears to be identical between VRd and KRd”, the investigator said, with deaths occurring in 13.8% of the KRd and 13.5% of the VRd arms. Median OS has not been reached in either arm but the 3-year OS probability is around 85% for both groups, he remarked. 

Reporting the safety analysis, Shaji Kumar said that overall haematological and nonhaematological toxicity was comparable between the KRd and VRd arms at grade 3–5 (65.6 vs 59.4%) and grade 4–5 (13.3 vs 11.6%). 

When nonhaematological events were assessed separately, however, the KRd regimen was associated with significantly higher rates than VRd at grade 3–5 (48.3 vs 41.4%) and grade 4–5 (8.2 vs 4.0%).  

Moreover, analysis of treatment-related adverse events of special interest revealed that KRd was associated with a significantly lower rate of any-grade peripheral neuropathy than VRd (24.4 vs 53.4%) but significantly more  cardiac, pulmonary and renal toxicity at any grade (16.1 vs 4.8%). 

Finally, the presenter noted that quality of life measures reflected the increased peripheral neuropathy with the VRd regimen but functional scores were comparable between the two groups.  

Shaji Kumar concluded: “Based on this data, the combination of bortezomib, lenalidomide, and dexamethasone should remain the standard of care for initial therapy of newly-diagnosed symptomatic multiple myeloma, and should be considered to be the backbone for adding new drugs such as monoclonal antibodies in the development of normal regimes for initial therapy of myeloma.” 

Reference 

Kumar S, Jacobus SJ, Cohen AD, et al. Carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM): Results of ENDURANCE (E1A11) phase III trial. J Clin Oncol 38: (suppl; abstr LBA3). DOI: 10.1200/JCO.2020.38.18_suppl.LBA3