Carfilzomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in High- Risk SMM
- Conditions
- Smouldering Myeloma
- Interventions
- Registration Number
- NCT03673826
- Lead Sponsor
- Stichting Hemato-Oncologie voor Volwassenen Nederland
- Brief Summary
Randomized (2:1) multi-center open-label phase II trial. Patients with high-risk SMM will be enrolled on the study and treated with KRd combination (Cycles 1-9 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9) or Rd combination (Cycles 1-9 lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles).
- Detailed Description
Background of the study:
A recent study has shown that intervention with the use of novel agents in smoldering myeloma (SMM) resulted in prolonged PFS and OS without significant toxicity. A more recent pilot study in high-risk smoldering myeloma using carfilzomib, lenalidomide in combination with dexamethasone resulted in 100% CR rate and 10 out of 12 patients reached MRD negativity. These studies formed the rationale to compare the efficacy and safety of carfilzomib, lenalidomide and dexamethasone vs. lenalidomide, dexamethasone, both followed by 24 months of lenalidomide maintenance in high-risk SMM.
This study is designed to compare 2 treatment modalities to find the optimal treatment in efficacy and safety for highrisk SMM, to define new risk stratifiers for outcome to treatment in SMM and to better understand the biology of SMM.
Objective of the study:
The primary objective of the study is :
To assess the progression-free survival rate of KRd versus Rd in patients with high-risk SMM
Secondary objectives:
* To assess MRD status after 4 and 9 cycles induction treatment
* To assess the correlation between PFS and MRD
* To determine progression-free survival-2 (PFS2 )
* To determine duration of response (DOR)
* To determine overall survival (OS)
* To assess correlation of MRD status with PFS2, DOR and OS To evaluate toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone).
* To evaluate disease heterogeneity in relation to clinical outcomes (molecular profiling on bone marrow samples)
Study design:
Randomized multi-center open-label phase 2 trial.
Study population:
Patients with high-risk SMM, age 18 years or older
Intervention (if applicable):
Patients will be treated with KRd combination 9 cycles a 28 days (carfilzomib , lenalidomide , dexamethasone) or Rd combination (lenalidomide , dexamethasone ); followed by extended lenalidomide dosing (for 24 cycles a 28 days).
Primary study parameters/outcome of the study:
- Progression-free survival rate, defined as time from study entry to progression or death, whichever comes first;
Secundary study parameters/outcome of the study (if applicable):
* MRD status after induction cycle 4 and 9,
* Progression-free survival-2 (PFS2), defined at time from randomization to progression after second-line treatment or death, whichever comes first;
* Duration of response (DOR), defined as time from response to progression or death, whichever comes first;
* Overall survival (OS), defined as time from study entry to death from any cause. Patients still alive at the date last contact will be censored;
* Correlation of MRD status with PFS, PFS2, DOR and OS;
* Toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone). Nature and extent of the burden and risks associated with participation, benefit and group relatedness (if applicable): Given the high rates of progression specific to the high risk SMM populations and low toxicity profile of combination therapy, risk of exposure does not seem to outweigh the clinical benefit that patients may derive from therapy. More importantly, much of patient morbidity in MM is associated with pain from irreversible skeletal related events. This study aims to treat or cure the disease before irreversible bone damage occurs or before aggressive clinical MM occurs.
Discomfort from venipuncture, bone marrow biopsy, and CT scan is minimal and of limited risk
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 58
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm B Dexamethasone KRd combination (Cycles 1-9 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles). Arm B Lenalidomide KRd combination (Cycles 1-9 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles). Arm A Dexamethasone Rd combination (Cycles 1-9 lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles). Arm A Lenalidomide Rd combination (Cycles 1-9 lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles). Arm B Carfilzomib KRd combination (Cycles 1-9 carfilzomib 20/36 mg/m2, lenalidomide 25 mg, dexamethasone 20 mg cycles 1-4 and 10 mg cycles 5-9); followed by extended lenalidomide dosing (10 mg days 1-21 of a 28 day cycle for 24 cycles).
- Primary Outcome Measures
Name Time Method Progression-free survival rate Until 5 years after randomization or death, whatever comes first Time from study entry to progression or death, whichever comes first
- Secondary Outcome Measures
Name Time Method MRD status 9 months MRD assessment by immunophenotyping in bone marrow after induction cycles 4 and 9
Overall survival (OS) Until 5 years after randomization or death, whatever comes first Time from study entry to death from any cause. Patients still alive at the date last contact will be censored.
Toxicity of combination therapy with Carfilzomib. Lenalidomide and Dexamethasone Through induction treatment and extrended treatment, up to 3 years after randomization Measured by tabulation of the incidence of adverse events with CTCAE grade 1 or more, separately for induction treatment and for extended treatment, by randomization arm.
Progression-free survival-2 (PFS2), Until 5 years after randomization or death, whatever comes first Time from randomization to progression after second-line treatment or death, whichever comes first
Duration of response (DOR), Until 5 years after randomization or death, whatever comes first Time from response to progression or death, whichever comes first
MRD status correlation Until 5 years after randomization or death, whatever comes first Correlation of MRD status with PFS, PFS2, DOR and OS
Trial Locations
- Locations (16)
IT-Roma-SAPIENZA
🇮🇹Roma, Italy
NL-Hoofddorp-SPAARNEGASTHUIS
🇳🇱Hoofddorp, Netherlands
CZ-Brno-UHBRNO
🇨🇿Brno, Czechia
CZ-Ostrava-Poruba-FNO
🇨🇿Ostrava, Czechia
IT-Ancona-UMBERTOA
🇮🇹Ancona, Italy
IT-Bologna-MALPHIGI
🇮🇹Bologna, Italy
IT-Brescia-SPEDALICIVILI
🇮🇹Brescia, Italy
NL-Amsterdam-VUMC
🇳🇱Amsterdam, Netherlands
IT-Torino-MOLINETTE
🇮🇹Torino, Italy
NL-Leeuwarden-MCL
🇳🇱Leeuwarden, Netherlands
NL-Den Bosch-JBZ
🇳🇱Den Bosch, Netherlands
NL-Nijmegen-RADBOUDUMC
🇳🇱Nijmegen, Netherlands
NL-Rotterdam-ERASMUSMC
🇳🇱Rotterdam, Netherlands
NO-Oslo-OSLOUH
🇳🇴Oslo, Norway
NL-Sittard-Geleen-ZUYDERLAND
🇳🇱Sittard, Netherlands
NL-Utrecht-UMCUTRECHT
🇳🇱Utrecht, Netherlands