On Location
16th International Myeloma Workshop
UPDATES IN MYELOMA TREATMENT
CLINICAL NEWS t the 16th International Myeloma Workshop , held March
1-4 , 2017 , myeloma specialists from around the world gathered in New Delhi , India , to discuss advances in the biology and treatment of multiple myeloma . Here , we share some of the research highlights from the meeting , including a comparison of the proteasome inhibitors bortezomib and carfilzomib , a look at genomics-based risk prediction , and a new agent for managing skeletal-related events in myeloma patients .
The Multiple Myeloma Genome Project : Developing a Risk Stratification System for Multiple Myeloma
An update from the Multiple Myeloma Genome Project ( MMGP ), presented at the 16th International Myeloma Workshop ( IMW ), revealed several associations between the development of multiple myeloma ( MM ) and specific molecular abnormalities , that could be therapeutic targets . These results could aid in the development of improved , genomic-based risk stratification systems for the disease , according to MMGP researchers .
“ MM is a heterogenous disease with many genomic alterations , and segmenting it into subgroups with distinct pathogenesis and clinical behavior is important to understand the molecular subtypes and advance therapy ,” presenter Mehmet Samur , PhD , of the Dana-Farber Cancer Institute , told ASH Clinical News . “ However , previous studies have evaluated different aspects of the MM genome with a limited number of samples . The [ MMGP ] has created one of the largest genomics and clinical data sets in MM to redefine molecular groups to advance our understanding of the disease .”
MMGP is a global initiative to create a repository of molecular profiling data and associated clinical outcome data from multiple sources , including the Myeloma XI trial , Intergroupe Francophone du Myeloma / Dana-Farber Cancer Institute , the UAMS Myeloma Institute , and the Multiple Myeloma Research Foundation .
In the analysis presented at this year ’ s IMW , Dr . Samur and colleagues collected genomic data from more than 2,000 patients , then categorized genetic abnormalities into five major translocation groups ( t [ 4 ; 14 ], t [ 6 ; 14 ], t [ 11 ; 14 ], t [ 14 ; 16 ] and t [ 14 ; 20 ]) and recurrent copy number changes ( deletion of CDKN2C and TP53 ). They then evaluated clinical data for outcomes associated with “ mutational , chromosomal , and gene-expression alterations to develop a classification system to segment MM into therapeutically meaningful subgroups .”
Genomic data were collected from 2,161 patients via :
• whole-exome sequencing ( n = 1,436 )
• whole-genome sequencing ( n = 708 )
• targeted panel sequencing ( n = 993 )
• expression data from RNA-seq and expression arrays ( n = 1,497 )
Integrated analyses revealed 28 significantly mutated genes that were present in samples from newly diagnosed patients ( 17 genes in > 2 % of samples ). The main recurrent mutations included KRAS , NRAS , and negative regulators of the NF-κB pathway . The researchers also identified novel genes and recurrent copy number abnormalities , which could be potential therapeutic targets , and a subset of high-risk patients with specific copy number abnormalities and single nucleotide variants , including inactivation of CDKN2C , RB1 , and TP53 .
Though this is one of the largest genomic data sets in MM , Dr . Samur commented that the study ’ s findings were limited by the variation among the data sources and missing information from included clinical trials .
REFERENCE
Samur M , Ashby C , Wardell C , et al . The Multiple Myeloma Genome Project : development of a molecular segmentation strategy for risk stratification of multiple myeloma . Abstract # 521 . Presented at the 16th International Myeloma Workshop , March 4 , 2017 ; New Delhi , India .
Denosumab Delays Skeletal- Related Events in Newly Diagnosed Multiple Myeloma
Denosumab ( a monoclonal antibody that targets the RANK ligand ) was noninferior to zoledronic acid ( ZA ) in delaying the time to a first skeletal-related event ( SRE ) in patients with newly diagnosed multiple myeloma ( NDMM ), according to results from a phase III study presented at the 16th International Myeloma Workshop .
“ Bone disease is a common complication of multiple myeloma , with approximately 80 percent of patients presenting with detectable lesions ,” Noopur Raje , MD , from Massachusetts General Hospital in Boston , said during her presentation of the results . “ The results of this study showed that denosumab may be an effective , novel option that is not cleared through the kidneys that may help prevent bone complications .”
In this international , randomized , double-blind trial , Dr . Raje and colleagues evaluated the efficacy and safety of denosumab compared with ZA in 1,718 patients with NDMM . Patients were excluded if they had renal insufficiency ( baseline creatinine clearance < 30 mL / min ).
Patients were randomized 1:1 to receive either denosumab 120 mg administered subcutaneously every four weeks ( n = 859 ) or ZA 4 mg administered intravenously every four weeks ( n = 859 ) along with antimyeloma therapy . Baseline demographics and disease characteristics were balanced between both groups , and about one-quarter of patients had poor renal function ( ≤60 mL / min ), Dr . Raje and researchers noted . During the primary blinded treatment period ( median follow-up = 17.4 months ), the time to first on-study SRE ( primary endpoint ) was similar between denosumab- and ZA-treated patients : 43.8 percent and 44.6 percent , respectively . Throughout the study , the median time to first onstudy SRE remained similar between both treatment arms : 22.83 months in the denosumab group and 23.98 months in the ZA group .
Treatment with denosumab was noninferior to ZA in delaying time to first on-study SRE ( hazard ratio [ HR ] = 0.98 ; 95 % CI 0.85-1.14 ; p = 0.01 ). Superiority was not demonstrated for time to first on-study SRE or time to first-and-subsequent on-study SRE ( secondary endpoints ; p = 0.82 and 0.84 for each comparison ).
Rates of overall survival ( OS ) also were similar between the denosumab and ZA groups ( HR = 0.90 ; 95 % CI 0.70-1.16 ; p = 0.41 ). There was an improvement in progression-free survival ( PFS ) among denosumabtreated patients ( HR = 0.82 ; 95 % CI 0.68-0.99 ; p = 0.036 )
“ The lack of OS difference is reassuring … and the PFS data is provocative ,” Dr . Raje said , but these findings will need further follow-up and investigation .
The rates of treatment-emergent adverse events ( AEs ) were similar between groups and comparable to known safety profiles , Dr . Raje reported , and led to study protocol discontinuation in 12.2 percent of all patients ( 12.9 % in denosumab-treated patients and 11.5 % in ZA-treated patients ).
The most common all-grade AEs ( occurring in > 25 % of patients ) included diarrhea ( 33.5 % and 32.4 %) and nausea ( 31.5 % and 30.4 %). Rates of serious AEs were 46 percent in denosumab-treated patients and 47.3 percent in ZA-treated patients ; these included hypocalcemia ( 0.9 % and 0.2 %) and osteonecrosis of the jaw ( 4.1 % and 2.8 %). Notably , fewer AEs potentially related to renal toxicity occurred with denosumab treatment ( 10.0 % and 17.1 %).
The study was limited by the lack of information about the patients ’ myeloma therapies ; the types of therapies could have affected the risk of developing bone lesions , the researchers noted .
REFERENCE
Raje N , Terpos E , Willenbacher W , et al . An international , randomized , double blind trial comparing denosumab with zoledronic acid ( ZA ) for the treatment of bone disease in patients ( pts ) with newly diagnosed multiple myeloma . Abstract # 546 . Presented at the 16th International Myeloma Workshop , March 4 , 2017 ; New Delhi , India .
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