The primary objective of the study is :To assess MRD negativity rate by NGF after 9 cycles for all eligible ITT patients of KRd versus Rd in patients with high-risk SMMSecondary objectives:• To assess MRD (NGF) negativity rate after 4 cycles of…
ID
Source
Brief title
Condition
- Plasma cell neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• MRD negativity rate by NGF after cycle 9 for all eligible ITT patients;
eligible patients who achieve a MRD negativity after cycle 9 will be considered
as a success. All other eligible randomized ITT patients will be considered as
a failure, including patients going off-protocol before cycle 9, whatever the
cause.
Secondary outcome
• MRD negativity rate evaluated by means of next generation flow cytometry (cut
off 10-5) after cycle 4;
• MRD negativity rate evaluated by means of next generation flow cytometry (cut
off 10-5) after completion of maintenance
• Correlation of MRD (NGF) negativity rate with PFS
• Overall response rate (ORR; i.e. at least partial response (PR)) after 9
cycles induction treatment;
• Progression-free survival (PFS), defined as time from study entry to
progression or death, whichever comes first;
• 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 (NGF) negativity rate with PFS, PFS2, DOR and OS;
• Toxicity of combination therapy (carfilzomib, lenalidomide, and dexamethasone)
• Safety (type, frequency, and severity of adverse events (AE) and relationship
of AE to study drug, serious AE (SAEs))
• Disease heterogeneity in relation to clinical outcomes (molecular profiling
on bone marrow samples)
Background summary
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 high-risk SMM, to define new risk
stratifiers for outcome to treatment in SMM and to better understand the
biology of SMM.
Study objective
The primary objective of the study is :
To assess MRD negativity rate by NGF after 9 cycles for all eligible ITT
patients of KRd versus Rd in patients with high-risk SMM
Secondary objectives:
• To assess MRD (NGF) negativity rate after 4 cycles of induction treatment
• To assess MRD (NGF) negativity rate after completion of maintenance
treatment
• To assess correlation of MRD (NGF) negativity rate with PFS
• To assess overall response rate (ORR) after 4 and 9 cycles induction
treatment and after maintenance
• To determine progression-free survival (PFS)
• To determine progression-free survival-2 (PFS2)
• To determine duration of response (DOR)
• To determine overall survival (OS)
• To assess correlation of MRD (NGF) negativity rate with PFS, PFS2, DOR and OS
• To evaluate toxicity of combination therapy (carfilzomib, lenalidomide, and
dexamethasone)
• To evaluate safety (type, frequency, and severity of adverse events (AE) and
relationship of AE to study drug, serious AE (SAEs))
• 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.
Intervention
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).
Study burden and risks
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
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Dr. Molewaterplein 40
Rotterdam 3015 GD
NL
Listed location countries
Age
Inclusion criteria
• Patients must have histologically or cytologically confirmed Smoldering
Multiple Myeloma based on the 2014 International Myeloma Working Group Criteria:
o Serum M-protein >=3 g/dl
Or urinary monoclonal protein >500 mg per 24 hours
And/or monoclonal bone marrow plasma cells >=10-60 %
o Absence of CRAB symptoms and myeloma defining events.
• Patients must have high risk Smoldering Multiple Myeloma based on the Mayo
Clinic and/or the PETHEMA criteria
• Measurable disease
• Age >18 years
• WHO/ECOG performance status <=2
• Patients must have normal organ and marrow function
• Calculated Creatinine Clearance >= 50 ml/min
• Females of childbearing potential must have a negative serum or urine
pregnancy test within 10 - 14 days prior to entry and again within 24 hours of
starting lenalidomide treatment
• Patients must be willing and capable to use adequate contraception during and
after the therapy (all men, all pre-menopausal women) Patients must be able to
adhere to the requirements of the Lenalidomide Pregnancy Prevention Plan
• Written informed consent
• Patient is capable of giving informed consent
Exclusion criteria
• Patients with symptomatic multiple myeloma (i.e. having myeloma defining
events)
• Amyloid Light-chain (AL) amyloidosis
• Patients who are receiving any other investigational agents.
• Concurrent systemic treatment or prior therapy within 4 weeks for SMM
• Contraindication to any concomitant medication, including antivirals,
anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior
to therapy
• History of allergic reactions attributed to immunomodulatory agents and
proteasome inhibitors.
• Hypersensitive reaction to active substances or any excipients of the IMPs
• Uncontrolled hypertension or diabetes
• Pregnant or lactating females.
• Significant cardiovascular disease with NYHA grade III or IV symptoms, or
hypertrophic cardiomegaly, or restrictive cardiomegaly, or myocardial
infarction within 3 months prior to enrollment, or unstable angina, or unstable
arrhythmia
• Active hepatitis B or C infection
• Known or suspected HIV infection
• Incidence of gastrointestinal disease that would prevent absorption
• Patients with gastric or duodenal ulcers
• Significant neuropathy >=Grade 3 or grade 2 with pain within 14 days of
enrollment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or
active infection.
• History of other malignancy (apart from basal cell carcinoma of the skin, or
in situ cervix carcinoma) except if the patient has been free of symptoms and
without active therapy during at least 5 years
• Major surgery within 1 month prior to enrollment
• Pre-existing pulmonary, cardiac or renal impairement that prevents hydration
measures
• Any psychological, familial, sociological and geographical condition
potentially hampering compliance with the study protocol and follow-up schedule
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-000555-10-NL |
| CCMO | NL62302.078.17 |