Evaluation of the Impact of the Update SMM Criteria on the Natural History of SMM to Establish New Recommendations.

Study Overview
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Brief Summary
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This study is a prospective open label interventional multicenter study evaluating the impact of the update multiple myeloma criteria on the natural history of smoldering myeloma in order to establish new recommendations about follow up and prognostic evaluation of smoldering myeloma.

Detailed Description
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In 2014, the International Myeloma Working Group (IMWG) proposed a revised classification of multiple myeloma (MM) and smoldering myeloma (SMM). Since the new definition of SMM proposed excludes ultra-high risk SMM, the evolution profile of SMM will change. Therefore, investigators need to update their knowledge of SMM to optimize the management of patients. This project is expected to describe more precisely the new landscape of SMM. The results will help to establish new recommendations for the standard care of SMM and especially for defining accurate follow-up and risk stratifying.

Official Title
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Evaluation of the Impact of the Update Multiple Myeloma Criteria on the Natural History of Smoldering Myeloma in Order to Establish New Recommendations About Follow-up and Prognostic Evaluation of Smoldering Myeloma (CARRISMM)

Conditions
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Smoldering Multiple Myeloma

Intervention / Treatment
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* Procedure: Myelogram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years. SMM defined by IMWG 2014 criteria Serum monoclonal protein (IgG or IgA) ≥30 g/L and/or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10-60% Absence of myeloma defining events or amyloidosis Diagnosed less than 1 year before the inclusion Able and willing to give valid written informed consent. Patients must give written informed consent (IC) in accordance with institutional and local guidelines. Exclusion Criteria: Previous antimyeloma treatment including bisphosphonates Second Primary Malignancy and/or auto-immune disease treated by immunosuppressive drugs. Evidence of end organ damage that can be attributed to the underlying SMM: Hypercalcaemia: serum calcium >0.25 mmol/L (>10 mg/L) higher than the upper limit of normal or >2.75 mmol/L (>110 mg/L) Renal insufficiency: creatinine clearance <40 mL/min or serum creatinine >177 μmol/L (>20 mg/L) Anaemia: haemoglobin value of >2 g/dL below the lower limit of normal, or a haemoglobin value <10 g/dL Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or Positron Emission Tomography-Computed Tomography (PET-CT) Presence of one of the following biomarkers of malignancy: Clonal bone marrow plasmocytosis ≥60% Involved/uninvolved serum Free Light Chain (FLC) ratio ≥ 100 (The involved free light chain must be ≥100 mg/L) Presence of one or more focal lesions on MRI studies (each focal lesion must be 5 mm or more in size) History of malignancy other than SMM within 3 years before inclusion Amyloidosis POEMS syndrome Contraindication to MRI Pregnancy Nursing mother Legally protected adults (under judicial protection, guardianship, or supervision)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Screening
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Test group<br>Each patient included in the study will be followed for 5 years | Procedure: Myelogram<br>* Two additional myelograms will be performed comparing to standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the annual risk estimated at 2 years of progression from SMM to MM | Progression to MM will be defined, according to IMWG 2014 revised classification, by the apparition of one or more myeloma defining events: Evidence of end organ damage that can be attributed to the underlying MM (CRAB criteria) Presence of one of the following biomarkers of malignancy (new criteria of MM introduced in 2014 IMWG recommendations) | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess the risk of progression to MM evaluating biological factors | Progression of monoclonal component level (serum M component, urine M component or FLC involved/uninvolved) defined by increase of ≥ 25% from inclusion value. Progression of percentage of phenotypically abnormal Bone Marrow Plasma Cells defined by increase of ≥ 10 % from inclusion value or an increase to over 95% | 5 years | 
| Assess the risk of progression to MM evaluating radiological markers | MRI progression : Progression of MRI abnormalities defined by any one or more of the following Appearance of new focal lesion or new diffuse infiltration of previously unaffected regions Growth of previously preexisting < 5mm focal(s) lesion(s) Progressive diffuse infiltration of already affected bones | 5 years | 
| Describe the clonal and sub-clonal evolution of SMM | Genetic analysis of bone marrow plasma cells at inclusion and during follow up to give data about the clonal and subclonal evolution of SMM (analysis of the mutations present in the tumor plasma cells, the allele frequency of each mutations, the determination of the clonal evolution mode for patients who will evolve to overt MM, the evaluation of copy number changes enabling to detect all the prognostic changes (1p32, 1q, 17p13), and (v) all the 14q32 translocations). | 5 years | 
| Describe annual risk of progression from SMM to MM at 5 years |  | 5 years |