Please select the eligibility criteria that correspond to the clinical trial below.
Title: An Open-Label, Randomized Study of VELCADE/Melphalan/Prednisone Versus Melphalan/Prednisone in Subjects With Previously Untreated Multiple Myeloma
Brief Summary: The primary reason for this study is to determine whether the addition of VELCADE (bortezomib) for injection to standard melphalan/prednisone (MP) therapy improves the time to disease progression (TTP) in subjects with previously untreated multiple myeloma.


Options:
A: Inclusion Criteria:

* Age \> 65 year old and not a candidate for stem cell transplant, or younger who refuses or is not eligible for high-dose therapy
* Symptomatic multiple myeloma or asymptomatic multiple myeloma with related organ or tissue damage
* Presence of measurable disease
* Karnofsky performance status (PS) \> 60%
* Able to read and complete the HRQOL instruments
* Agrees to use an acceptable barrier method for contraception for the duration of the study
* Pretreatment clinical laboratory values within 14 days of randomization:

platelet count ≥ 100x109/L

* hemoglobin ≥ 8 g/dL
* absolute neutrophil count (ANC) ≥ 1.0x109/L
* AST ≤ 2.5 times the upper limit of normal
* ALT ≤ 2.5 times the upper limit of normal
* total bilirubin ≤ 1.5 times the upper limit of normal
* serum creatinine ≤ 2.5mg/dL
* corrected serum calcium \<14 mg/dL (\<3.5 mmol/L)
* Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.
* Women of child-bearing potential must agree to use 2 methods of contraception: 1 effective (for example hormonal or tubal ligation) and 1 barrier (for example latex condom, diaphragm) for at least 4 weeks before starting the therapy, during the Treatment Period, and for 4 weeks after the last dose;
* Males must agree to use barrier contraception (latex condoms) when engaging in reproductive activity during the Treatment Period and for 4 weeks after the last dose.

Exclusion Criteria:

* Diagnosis of smoldering multiple myeloma or MGUS.
* Diagnosis of Waldenstrom's disease
* Prior or current systemic therapy for multiple myeloma including steroids (with exception of emergency use of a short course \[maximum 4 days\] of steroids before randomization or prior or current use of biphosphonates)
* Radiation therapy within 30 days before randomization
* Plasmapheresis within 30 days before randomization
* Major surgery within 30 days before randomization (Kyphoplasty is not considered major surgery)
* History of allergic reaction attributable to compounds containing boron or mannitol, or to Thalidomide
* Peripheral neuropathy Grade 2 or higher, as defined by National Cancer Institute Common Toxicity Criteria (NCI CTC) 3.0
* Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
* Other malignancy within the past 5 years. Exceptions: basal cell or non metastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or FIGO Stage 1 carcinoma of the cervix
* Concurrent medical condition or disease (e.g., active systemic infection, uncontrolled diabetes, pulmonary disease) that is likely to interfere with study procedures or results, or that in the opinion of the investigator would constitute a hazard for participating in this study
* Use of any investigational drugs within 30 days before randomization.
* Pregnant or lactating women. A serum β-hCG pregnancy test must be performed at the Screening visit, for female patients of child-bearing potential. If the test is positive, the patient must be excluded from the study. Confirmation that the patient is not pregnant must be established by a negative serum or urinary pregnancy test with the result obtained 1 day prior to the Baseline visit (or the day of the visit if results are available before drug delivery).
B: Inclusion Criteria:

* Recently diagnosed MM according to the criteria of the South West Oncology Group (SWOG)
* Not previously treated, apart from local radiotherapy, in the case of a threatening or incapacitating lesion, and/or a 4-day block of dexamethasone (40 mg/mL) in an emergency
* Stage II or III disease according to the Durie and Salmon classification or Stage I disease with symptomatic bone lesion
* \< 65 years of age
* Ability to give signed informed consent
* Secretion of a measurable monoclonal spike (\> 10 g/l in the serum or 0.2 g/24h in the urine)
* Negative pregnancy test at inclusion (if necessary)
* Absence of active infection. In the case of infection, appropriate antibiotic therapy must be administered and patients must have been apyretic for 48 hours before the start of treatment with VAD or Velcade®/dexamethasone

Exclusion Criteria:

* ECOG performance status \> 2
* History of cancer (other than basal cell carcinoma or carcinoma of the cervix in situ)
* Life expectancy \< 2 months
* Confirmed amyloidosis
* Positive HIV serology
* Serious psychiatric item in the history
* Renal failure requiring dialysis
* Uncontrolled diabetes, contra-indicating the use of corticosteroids
* Peripheral neuropathy National Cancer Institute (NCI) grade \> 2 (Annex 5)
* Clinical signs of heart failure or coronary heart disease
* Bilirubin \> 3 x normal
* Transaminases or gamma-glutamyl transpeptidase (GT) \> 4 x normal
* Platelets \< 50 x 10\^9/l during the 15 days prior to inclusion
* Neutrophils \< 0.75 x 10\^9/l during the 15 days prior to inclusion
* Use of an investigational medicinal product during the 30 days prior to inclusion
* Known hypersensitivity to bortezomib, boron or mannitol
C: Inclusion Criteria:

Subjects must satisfy the following criteria to be enrolled in the study:

* Male or female
* Not a candidate for HDT/SCT due to: age - subject is 65 years or older or in subjects less than 65 years of age - presence of important comorbid condition(s) likely to have a negative impact on tolerability of HDT/SCT.
* Symptomatic multiple myeloma or asymptomatic multiple myeloma with related organ or tissue damage. Asymptomatic multiple myeloma-related organ or tissue damage can include presence of asymptomatic lytic bone lesion or plasmacytoma, or presence of anemia, renal function impairment, or hypercalcemia, as long as the criteria for pre-treatment clinical laboratory values indicated below are met.
* Presence of measurable disease, defined as:

  * For secretory multiple myeloma, measurable disease is defined as any quantifiable serum monoclonal protein value.
  * For oligosecretory or nonsecretory multiple myeloma, measurable disease is defined by the presence of measurable soft tissue or organ (not bone) plasmacytomas as determined by clinical examination or applicable radiographs.
* Karnofsky performance status score of equal or greater then 60%.
* Willing and able to complete the PRO instruments
* Agrees to use an acceptable barrier method for contraception for the duration of the study (for male subjects); If female subjects are still having menstrual periods and are not surgically sterile, they must be practicing an effective method of birth control before entry, and throughout the study, and have a negative serum B-HCG pregnancy test at screening.
* Have pretreatment clinical laboratory values meeting the criteria as described in the protocol within 14 days before randomization.
* Subjects (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

Potential subjects who meet any of the following criteria will be excluded from participating in the study:

* Diagnosis of smoldering multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS, hypercalcemia, and renal insufficiency related to the monoclonal protein; and (if determined) proportion of plasma cells in the bone marrow of 10% or less.
* Diagnosis of Waldenström's disease or other conditions in which IgM M protein is present in the absence of a clonal plasma cell infiltration with lytic bone lesions
* Prior or current systemic therapy for multiple myeloma including steroids (with the exception of emergency use of a short course \[maximum of 4 days\] of steroids before randomization or of prior or current use of bisphosphonates)
* Radiation therapy within 30 days before randomization
* Plasmapheresis within 30 days before randomization
* Major surgery within 30 days before randomization (kyphoplasty is not considered major surgery)
* History of allergic reaction attributable to compounds containing boron or mannitol
* Peripheral neuropathy or neuropathic pain Grade 2 or higher.
* Uncontrolled or severe cardiovascular disease, including myocardial infarction, within 6 months of enrollment, uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
* Other malignancy within the past 5 years. Exceptions if treated and not active include the following: basal cell or nonmetastatic squamous cell carcinoma of the skin, cervical carcinoma in situ or International Federation of Gynecology and Obstetrics (FIGO) Stage 1 carcinoma of the cervix
* Concurrent medical condition or disease (e.g., active systemic infection, uncontrolled diabetes) that is likely to interfere with study procedures or results, or that, in the opinion of the investigator would constitute a hazard for participating in this study
* Use of any investigational drugs within 30 days before randomization
* Employees of the investigator or study center, with direct involvement in the proposed study or other studies under the direction of that investigator or study center, or family members of the employees or the investigator.
D: Inclusion Criteria:

* Disease Related

  * Multiple myeloma
  * Subjects must have measurable disease defined as one of the following:

    * Serum M-protein ≥ 1 g/dL
    * Urine M-protein ≥ 200 mg/24 hours
    * Serum FLC ≥ 10 mg/dL with abnormal ratio (A0 Only)
    * Quantitative immunoglobulin levels using nephelometry or turbidometry (only if protein electrophoresis was felt to be unreliable for M-protein measurement) (A0 Only)
  * Subjects must have been responsive (i.e., achieved an MR or better) to first-line, standard of care therapy
  * Refractory to the most recently received therapy. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy.
  * Subjects must have received ≥ 2 prior regimens for relapsed disease. Induction therapy and stem cell transplant will be considered as one regimen (A1 Only)
  * Subjects must have received prior treatment with bortezomib, and either thalidomide or lenalidomide
  * Subjects must have received an alkylating agent either alone or in combination with other myeloma treatments (history of stem cell transplant is acceptable) (A1 Only)
  * Subjects must have received an anthracycline either alone or in combination with other myeloma treatments, unless not clinically indicated (A1 Only)
* Demographic

  * Males and females \> 18 years of age
  * Life expectancy of more than three months
  * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
* Laboratory

  * Adequate hepatic function, with bilirubin less than 2.0 times the upper limit of normal, and AST and ALT of less than 3.0 times the upper limit of normal
  * Uric acid within normal range (A0 Only)
  * Total white blood cell (WBC) count ≥ 2.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.0 × 109/L, hemoglobin ≥ 8.0 g/dL, and platelet count ≥ 50.0 × 109/L (A0 Only)
  * Absolute neutrophil count \> 1,000/mm3, hemoglobin \> 8.0 g/dL, and platelet count \> 50,000/mm3 (A1 Only)

    * Subjects should be platelet transfusion independent
    * Screening ANC should be independent of G-CSF or GM-CSF support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks
    * Subjects may receive red blood cell (RBC) or platelet transfusions or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines
  * Calculated and measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault \[(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)\]. Multiply result by 0.85 if female.
* Ethical / Other

  * Written informed consent in accordance with federal, local, and institutional guidelines
  * Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (\> 45 years old and without menses for \> 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.

Exclusion Criteria:

* Disease Related

  * Multiple Myeloma IgM (A1 Only)
  * Subjects who failed to achieve at least a confirmed MR(≥ 25% reduction in M-protein for ≥ 6 weeks) (A1 Only)
  * Subjects with non-secretory multiple myeloma, defined as \< 1 g/dL M-protein in serum and \< 200 mg/24 hr M-protein in urine
  * Subjects with disease measurable only by serum free light chain (SFLC) analysis (A1 Only)
  * Glucocorticoid therapy (prednisone \> 10 mg/day orally or equivalent) within the last three weeks
  * POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
  * Plasma cell leukemia
  * Chemotherapy with approved or investigative anticancer therapeutics including steroid therapy within the three weeks prior to first dose
  * Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose
  * Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to Day 1, whichever time is greater
  * Prior treatment with carfilzomib
* Concurrent Conditions

  * Major surgery within three weeks before Day 1
  * Congestive heart failure (New York Heart Association class III to IV), symptomatic cardiac ischemia, cardiomyopathy, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months, LVEF \< 40
  * Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose
  * Known or suspected HIV infection or subjects who are HIV seropositive
  * Active hepatitis A,B,or C infection
  * Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer \<Gleason Grade 6 with stable PSA
  * Subjects with treatment related myelodysplastic syndrome
  * Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation
  * Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac or renal impairment (A1 Only)
  * Subjects with known or suspected amyloidosis (A1 Only)
  * Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis (A1 Only)
  * Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent (A1 Only)
* Ethical / Other

  * Female subjects who are pregnant or lactating
  * Serious psychiatric or medical conditions that could interfere with treatment

Answer: C