Main info

Identificatie:

HO147 SMM

Sponsor:

HOVON

Working group party:

Myeloma

Age:

>= 18

Stadium:

1st lijn

Echelon:

Level C-HIC

Included patients:

58

(of 81)

Active sites:

15

(of 19)

1 sites are pending

Title:

Carfilzomib, Lenalidomide and Dexamethasone versus Lenalidomide and Dexamethasone in High- Risk Smoldering Multiple Myeloma: A Randomized Phase 2 Study.

Timeline

Details

Phase:

Prospective randomized Phase II study

Monitoring Type:

Study Specific

Objectives:

Primary 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 induction treatment
• To assess MRD (NGF) negativity rate after completion of maintenance treatment
• To assess the correlation between 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)

Eligibility

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed Smoldering Multiple Myeloma based on the 2014 International Myeloma Working Group Criteria:
  • Serum M-protein ≥3.0 g/dl, 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 Clinic2 and/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
  • And/Or 2 factors of PETHEMA criteria:
    • Of the plasma cell population ≥95% abnormal plasma cells (presence or absence of CD38, CD56, CD19 and/or CD45)
    • Immunoparesis, a reduction (below the lower normal limit) in the levels of 1 or 2 of the uninvolved immunoglobulins (Ig) (an exception can be made in FLC disease in which all three uninvolved immunoglobulins can be below the lower limit of normal)
• 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 x109 /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. Creatinine clearance may be calculated using Cockcroft-Gault or eGFR (Modified Diet in Renal Disease [MDRD]). Detailed information regarding the different calculations are shown in protocol Appendix G.
• 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 of protocol)
• 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. of protocol); 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 not 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
• 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 impairment that prevents hydration measures as described at paragraph 9.1.4 of the protocol
• Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Registration Details

Participating Sites

= Active hospitals

= Inactive hospitals