Isatuximab and Iberdomide as immunotherapy for high risk smouldering myeloma

Research summary

The overall aims of the study are: •To determine if the combination of iberdomide and isatuximab with dexamethasone is safe and well tolerated •To determine if the treatment is efficacious in inducing disease response in high-risk smouldering myeloma,thus preventing the development of active multiple myeloma The primary endpoints are: •Treatment deliverability,measured by treatment discontinuation before completion of 26 cycles •Efficacy measured by best overall response rate =by the end of treatment The secondary endpoints are: •Progression Free Survival •Time to biochemical progression •Progression Free Survival 2 •Best overall response to subsequent line of therapy •Overall Survival •Minimal Residual Disease negativity rates •Very Good Partial Response and Complete Response + Minimal Residual Disease negative rates •Adverse Event and Adverse Device Effect rates •Median and cumulative doses of Iberdomide and Isatuximab •Treatment compliance (including study drugs and device deficiencies) •Patient Reported Outcome Measures The translational biological and exploratory studies include: •Immune phenotype and function,including T-cells,natural killer cells and myeloid cells,T cell receptor sequence and clonality,cytokines in serum. •Tumour genomics. Genomic structural variants,short nucleotide variants,epigenetic modifications and expression changes at baseline and on therapy. Subclonal architecture,neo-antigen burden,transcriptional profile pre and post-therapy. •Examination of stromal elements including bone forming and resorbing cells. •Spatial analysis of tumour and non-tumour cells in bone marrow and effect of therapy. •Establish organoids from bone marrow cells to study effect of treatment. •Proteomic,cell-free DNA and circulating tumour cells analysis in blood samples. •Genomic,cytogenetic and immune features correlation with response to treatment and risk of progression (defined as biochemical progression). •Comparisons will be made with the matched untreated patients in the observational cohort study COSMOS. •Compare clinical outcomes and translational data with results obtained in the phase 2 study comparing iberdomide vs iberdomide/dexamethasone to treat high risk smouldering myeloma (NCT04776395). •Describe reasons why eligible patients choose not to take part in the study. Methodology: Primary Objectives: Treatment delivery: The number and proportion of patients who complete all 26 cycles of trial treatment per protocol (allowing for delays/reductions/omissions deemed acceptable by the protocol) will be presented with two-sided 90% confidence interval. While the sample size is based off of 57 patients being assessable for this endpoint,all eligible patients will be included in the analysis and conclusions will be based on the lower bound of the 90% confidence interval. Patients who do not complete treatment for reasons unrelated to disease or toxicity will be excluded from this analysis (e.g. patient moving away or becoming pregnant),however sensitivity analyses will be performed where these patients are assumed to complete/not complete treatment. Efficacy: The number and proportion of patients who achieve disease response (PR,VGPR,CR or sCR) at any point over the duration of treatment or at the 1 month FU response assessment will be presented with two-sided 90% confidence interval. While the sample size is based off of 53 patients being assessable for this endpoint,all eligible patients will be included in the analysis and conclusions will be based on the lower bound of the 90% confidence interval. All patients who have completed at least one response assessment or stopped protocol treatment early due to toxicity,insufficient response,progression or death will be included in this analysis.

Principal Investigator

Dr Joe Browning

Contact us

Email: Latephasehaematology@ouh.nhs.uk

IRAS number

1007214