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Clinical picture: MM (Multiple Myeloom)

Trial: HOVON 147 SMM


News
1. Overview
Study details
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms


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1. Overview



Summary

Carfilzomib, Lenalidomide and Dexamethasone versus Lenalidomide and Dexamethasone in High- Risk Smoldering Multiple Myeloma: A Randomized Phase II Study.


Status

planned


Members

HOVON, USA, Italy (EMN), Czech Republic (CMG), Greece, Norway


Study details



Type of study

Prospective randomized Phase II study


Echelon level

Level C-HIC


Target number of patients

120


Date of first EC&CA submission

13-Jul-2017


Study objectives

Primary objectives
To assess the progression-free survival rate of KRd versus Rd in patients with high-risk SMM 4
To assess MRD status
To assess the correlation between PFS and MRD

Secondary objectives
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)


2. Patient eligibility criteria



Inclusion criteria

Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma based on the 2014 International Myeloma Working Group Criteria:

>> Serum M-protein ≥30 g/L, or urinary monoclonal protein >500 mg per 24 hours, and/or monoclonal bone marrow plasma cells ≥10-60 %
>>Absence of CRAB symptoms:
anemia: Hemoglobin <6.2 mmol/L (10 g/dl) or a hemoglobin value of >1.2 mmol/L (2 g/dL) below the lower limit of normal
renal failure: serum creatinine > 2.0 mg/dL or creatinine clearance < 40 ml/min
hypercalcemia: serum calcium >0·25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2·75 mmol/L (>11 mg/dL)
Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CT
>> Absence of myeloma defining events:
Involved/uninvolved serum free light chain ratio ≥100 with involved free light-chain concentration ≥10 mg/dl
Presence of 2 or more focal lesions by MRI (2 of which at least 5 mm)
Clonal bone marrow plasma cell percentage ≥60%

Patients must have high risk Smoldering Multiple Myeloma based on the Mayo Clinic or the PETHEMA criteria:
>> 3 factors of Mayo Clinic criteria:
Bone marrow plasma cells ≥10 %
Serum M-protein ≥ 3 g/dl
Serum free light-chain ratio <0.125 or >8
>> Or 2 factors of PETHEMA criteria:
≥95% abnormal plasma cells including decreased CD38 expression, expression of CD56, and absence of CD19 and/or CD45
Immunoparesis, a reduction (below the lower normal limit) in the levels of 1 or 2 of the uninvolved immunoglobulins (Ig)

Measurable disease defined by any one of the following:
>> Serum monoclonal protein ≥ 1.0 g/dl
>> Urine monoclonal protein >200 mg/24 hour
>> Serum immunoglobulin free light chain >10 mg/dL AND abnormal kappa/lambda ratio (reference 0.26-1.65)

Age >18 years
WHO/ECOG performance status <2 (see Appendix C).
Patients must have normal organ and marrow function as defined below:
Absolute neutrophil count >1.0 109 /L
Platelets ≥75 ×109 /L
Hemoglobin ≥10 g/dL (>6.2 mmol/l)
Total bilirubin <1.5 x institutional upper limit of normal
AST(SGOT)/ALT(SGPT) ≤3.0 × institutional upper limit of normal
Creatinine Clearance ≥ 50 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl = [(140 – Age) x Mass (kg)] / [72 x Serum Creatinine (mg/dL)(x [0.85 if Female). If calculated CrCl based on Cockcroft-Gault method is <50 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be ≥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; (see 9.1.4
Patients must be willing and capable to use adequate contraception during and after the therapy (all men, all pre-menopausal women) (see 9.1.4.); Patients must be able to adhere to the requirements of the Lenalidomide Clinical Trial 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 (if a patient has received any previous SMM therapy this must be discussed with the Principal Investigator before inclusion in the trial).
Treatment with corticosteroids for other indications is permitted
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
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.
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 as described at paragraph 9.1.4
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule


3. Registration (& randomization) of patients



Registration

Registration via Trial Online Process (TOP, https://www.hdc.hovon.nl/top).


4. Participating parties



5. Participating sites



6. Instruction videos



7. Download documentation / forms




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