Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Prospective, Randomized Clinical Study of VELCADE-Thalidomide-Dexamethasone (VTD) Versus Thalidomide-Dexamethasone (TD) for Previously Untreated Multiple Myeloma (MM) Patients Who Are Candidates to Receive Double Autologous Transplantation
Brief Summary: Thalidomide-Dexamethasone (TD) is a standard induction therapy for Multiple Myeloma (MM). The present study is designed to compare TD with VELCADE-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan-based double autologous stem cell transplantation for previously untreated patients aged ≤65 years with symptomatic MM. Primary study endpoint is the rate of complete response (CR) plus near-complete response (nCR) to induction treatment. Secondary endpoints include the rate of CR plus nCR to double transplantation and subsequent consolidation therapy, time to progression (TTP), progression-free survival (PFS),overall survival (OS) and toxicity profile of both VTD and TD.


Options:
A: 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.
B: Inclusion criteria:

* Confirmed diagnosis of symptomatic MM based on standard criteria.
* No prior or current systemic therapy for MM, including steroids.
* At least 18 years and less than 65 years of age.
* Presence of quantifiable M protein in serum (e.g. greater than 1 g/dL for IgG MM, greater than 0.5 g/dL of IgA or IgD MM) or urine (e.g. greater than 200 mg/day for BJ MM).
* Karnofsky performance status (PS) at least 60%.
* Willing and able to comply with the protocol requirements.
* Agreement from both male and female patients to follow the risk management program established for the prevention of pregnancy, including double methods for contraception and beta-HCG tests for women of childbearing potential and contraception for males.
* Adequate organ function, including heart, liver, kidney (serum creatinine less than 2 mg/dL)
* Platelet count at least 70 x 10/mcL and absolute neutrophil count at least 1 x 10/mcl

Exclusion criteria:

* Diagnosis of asymptomatic MM or of MGUS based on standard criteria.
* Diagnosis of non-secretory MM.
* Diagnosis of AL Amyloidosis.
* Prior or current systemic therapy for MM, including steroids (with exception of bisphosphonates).
* Patient has received other investigational drugs within 30 days before enrollment.
* Female subjects pregnant or breastfeeding
* Patient has Grade 2 or higher peripheral neuropathy (NCI criteria).
* Patient has a prior history of thrombosis or venous thromboembolism or pulmonary embolism.
* Patient has a previous diagnosis of antiphospholipid antibodies or lupus anticoagulant, factor V Leiden mutation, prothrombin G21210A mutation, antithrombin, protein C or S deficiency.
* Patient has a clear indication to receive a specific other anti-platelet therapy (e.g. clopidogrel, ticlopidine).
* Patient has a clear indication to receive long-term anticoagulant therapy (e.g. prosthetic heart valve, atrial fibrillation).
* Active bleeding or high risk of bleeding (gastrointestinal bleeding within the past 12 months; endoscopic diagnosis of peptic ulcer disease or ulcerative esophagitis within the past 6 months unless there is documented endoscopic evidence of healing; intracranial bleeding within the past year; amyloidosis; known bleeding diathesis).
* Seropositive for HIV, or active hepatitis A, B or C infection.
* Poorly controlled hypertension or diabetes mellitus (if receiving antidiabetic agents, subjects must be on a stable dose for at least 3 months before the start of therapy) or other serious medical or psychiatric conditions that could interfere with adherence to or completion of this study.
* Patient has hypersensitivity to bortezomib, boron or mannitol.
* Serious medical or psychiatric illness likely to interfere with participation in this clinical study
* Previous or concurrent malignancies at other sites, with the exception of appropriately treated localized epithelial skin or cervical cancer. Patients with remote histories (\>5 years) of other cured tumors may be entered.
* Receipt of extensive radiation therapy, systemic chemotherapy, or other antineoplastic therapy within 4 weeks before enrolment.
C: Inclusion Criteria:

1. Must be able to comply with the protocol requirements
2. Must voluntary sign the informed consent before performance of any study-related procedure not part of normal medical care,
3. Age \<65 years and possibly to do an autologous transplant.
4. Patient recently diagnosed with symptomatic Multiple Myeloma who has not received any previous chemotherapy treatment for Multiple Myeloma.
5. Patient has a measurable disease defined as quantifiable serum monoclonal protein value and, where applicable, urine Light-chain excretion of ≥ 200 mg/24 hours.
6. ECOG \< 2.
7. El patient has a life-expectancy \> 3 months.
8. Patient has the following laboratory values before beginning induction treatment:

   1. Platelet count ≥ 50000/mm3, hemoglobin ≥ 8 g/dl and absolute neutrophil count ≥ 1000/mm3. Lower values are allowed if they are due to marrow infiltration.
   2. Corrected serum calcium \<14mg/dl.
   3. Aspartate transaminase (AST): ≤ 2.5 x the upper limit of normal.
   4. Alanine transaminase (ALT): ): ≤ 2.5 x the upper limit of normal.
   5. Total bilirubin: ≤1.5 x the upper limit of normal.
   6. Serum creatinine ≤ 2 mg/dl.
9. For Patients included in Thalidomide branches: women of childbearing age must not have sex unless they use two anticonceptive methods beginning 4 weeks before the first dose, during all the study until 4 weeks after the last one.

Exclusion Criteria:

1. Non-secretor Myeloma.
2. Patients previously received treatment to Multiple Myeloma, except steroids doses for urgency or bisphosphonates or radiotherapy before beginning treatment.
3. Patients with \< Grade 2 peripheral neuropathy within 14 days before enrolment.
4. Patient had major surgery within 4 weeks before enrolment.
5. Patient has hypersensitivity to bortezomib, boron or mannitol or Thalidomide.
6. Patient has received other investigational drugs within 30 days before enrolment.
7. Patient is known to be seropositive for the human immunodeficiency virus (HIV), Hepatitis B surface antigen-positive or active hepatitis C infection.
8. Patient had a myocardial infarction within 6 months of enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
9. Patient is enrolled in another clinical research study and/or is receiving an investigational agent for any reason.
10. Pregnancy or breast-feed women.
D: Inclusion Criteria:

* Symptomatic myeloma diagnosis according to criteria in attachment 3
* ASCT is performed or has been performed in the last five weeks (time limit two weeks for patients randomised at 2nd transplantation) as a part of primary therapy
* Signed informed consent given prior to any study related activities have been performed

Exclusion Criteria:

* Prior exposure to bortezomib
* Allogeneic transplantation scheduled as a part of the primary treatment
* Neuropathy \> Grade 2 (neurological symptoms interfering with ADL)
* Non-secreting myeloma
* Other concurrent disease making bortezomib treatment unsuitable
* Positive pregnancy test (only applicable for women with childbearing potential)
* Has known or suspected hypersensitivity or intolerance to boron, mannitol, or heparin, if an indwelling catheter is used
* Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrolment, New York Heart Association (NYHA) Class III or IV heart failure (Attachment 6, NYHA Classification of Cardiac Disease), uncontrolled angina, clinically significant pericardial disease, or cardiac amyloidosis
* History of hypotension or has decreased blood pressure (sitting systolic blood pressure \[SBP\] £100 mmHg and/or sitting diastolic blood pressure \[DBP\] £60 mmHg)
* Serious medical or psychiatric illness likely to interfere with participation in this clinical study
* Have received an experimental drug or used an experimental medical device within 4 weeks prior to inclusion into the study

Answer: B