Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized Phase 3b Study of Three Treatment Regimens in Subjects With Previously Untreated Multiple Myeloma Who Are Not Considered Candidates for High-Dose Chemotherapy and Autologous Stem Cell Transplantation: VELCADE, Thalidomide, and Dexamethasone Versus VELCADE and Dexamethasone Versus VELCADE, Melphalan, and Prednisone
Brief Summary: This is a randomized, open label, multicenter clinical trial to compare the efficacy and safety of Velcade (bortezomib) and dexamethasone versus Velcade, thalidomide, and dexamethasone versus Velcade, melphalan, and prednisone in patients with previously untreated multiple myeloma not considered candidates for high-dose chemotherapy and autologous stem cell transplantation.


Options:
A: Inclusion Criteria:

* Male or female 18 years of age or older
* Not a candidate for high-dose chemotherapy and stem cell transplantation (HDT/SCT) due to age, presence of important comorbid condition(s) likely to have a negative impact on tolerability of HDT-SCT, or subject preference.
* A Karnofsky Performance Status score of ≥50%
* 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 an asymptomatic lytic bone lesion or plasmacytoma, the presence of anemia (hemoglobin \<10 g/dL), renal function impairment (serum creatinine \> upper limit of normal \[ULN\]) or hypercalcemia (serum calcium \>ULN).
* Must have measurable disease requiring systemic therapy. Measurable disease is defined by at least 1 of the following criteria:

  * Quantifiable serum M-protein value (\>1 g/dL of immunoglobulin (Ig)G or IgM M-protein, \>0.5g/dL of IgA M-protein, \>0.5 g/dL of IgD M-protein)
  * Urine light-chain excretion ≥200 mg/24 hours
* Voluntary written informed consent must be given before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion Criteria:

* Diagnosis of smoldering multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS). Smoldering multiple myeloma is defined as asymptomatic multiple myeloma with absence of lytic bone lesions. MGUS is defined by presence of serum monoclonal protein \<3 g/dL; absence of lytic bone lesions, anemia, 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 immunoglobulin M (IgM) M-protein is present in the absence of a clonal plasma cell infiltration or lytic bone lesions.
* Previously or currently treated with any systemic therapy for multiple myeloma. Prior treatment of hypercalcemia or spinal cord compression with corticosteroids or radiation therapy, respectively, does not disqualify the subject (the dose of corticosteroids should not exceed the equivalent of 160 mg of dexamethasone in 2-week period).
* Radiation therapy within 2 weeks before randomization. Enrollment of patients who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 2 weeks have elapsed since the last date of therapy.
* Major surgery within 30 days before randomization (Kyphoplasty is not considered major surgery)
* History of allergy to any of the study medications, their analogues, or excipients in the various formulations
* ≥Grade 2 peripheral neuropathy on clinical examination within 21 days before enrollment.
* Any of the following clinical laboratory values within 21 days prior to enrollment:

  * Absolute neutrophil count (ANC) \<1000 cells/mm\^3
  * Platelets \<100,000 × 10\^9/L, or \<70 × 10\^9/L if thrombocytopenia is considered by the investigator to be due to myeloma infiltration of bone marrow
  * Aspartate aminotransferase \[serum glutamic oxaloacetic transaminase\] (AST \[SGOT\]) or alanine aminotransferase \[serum glutamic-pyruvic transaminase\] (ALT \[SGPT\]) \>2× the upper limit of normal (ULN)
  * Serum creatinine \>2 mg/dL (\>176.8 µmol/L); if the rise in creatinine is related to myeloma and there has been demonstrated a response to hydration, the subject may be enrolled.
* Myocardial infarction within 6 months prior to enrollment or New York Hospital Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities in the opinion of the investigator. Prior to study entry, any abnormality on electrocardiogram at screening must be determined and documented by the investigator as not medically relevant.
* Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the patient at unacceptable risk if he/she were to participate in the study. This includes but is not limited to serious medical conditions or psychiatric illness likely to interfere with participation in this clinical study.
* Prior malignancy except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ breast cancer, in situ prostate cancer, or other cancer for which the patient has been disease-free for at least 3 years.
* Female who is pregnant or breastfeeding. Female participants of childbearing potential must have a negative pregnancy test with a sensitivity of at least 50 mIU/mL during Screening.
* Use of any investigational drugs within 30 days before randomization.
B: Inclusion Criteria:

* Patients with multiple myeloma in need of treatment

Exclusion Criteria:

* Previous treatment against multiple myeloma
* Need of high dose chemotherapy with autologous stem cell support
* Women in fertile age
* Psychiatric disease or mental reduction leading to lack of cooperation
* Lack of consent
* Life expectancy below 3 months
* Active cancer of other etiology
C: Inclusion Criteria

1. Must understand and voluntarily sign an informed consent form
2. Age greater than or equal to 65 years at the time of signing the informed consent
3. Newly diagnosed with symptomatic multiple myeloma as defined by the 3 criteria below:

MM diagnostic criteria (all of next 3 required)

1. Monoclonal plasma cells in the bone marrow greater than or equal to 10% and/or presence of a biopsy-proven plasmacytoma
2. Monoclonal protein present in the serum and/or urine
3. Myeloma-related organ dysfunction (at least one of the following) \[C\] Calcium elevation in the blood (serum calcium \>10.5mg/dl or upper limit of normal) \[R\] Renal insufficiency (serum creatinine \>2mg/dl) \[A\] Anemia (hemoglobin \<10g/dl or 2g \< normal) \[B\] Lytic bone lesions or osteoporosis AND have measurable disease as defined by the following; IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level greater than or equal to 1.0 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgA multiple myeloma: Serum M-protein level greater than or equal to 0.5 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgD multiple myeloma: Serum M-protein level greater than or equal to 0.05 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours Light chain multiple myeloma: Serum M-protein level greater than or equal to 1.0 g/dL or urine M-protein level greater than or equal to 200 mg/24 hours IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by skeletal survey plain films): Serum M-protein level greater than or equal to 1.0g/dL or urine M-protein level greater than or equal to 200mg/24hours
4. Karnofsky performance status greater than or equal to 60%.
5. Able to adhere to the study visit schedule and other protocol requirements.
6. Women of Childbearing potential (WCBP) must:

   a. Have a negative medically supervised pregnancy test prior to the start of study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices and continues sexual abstinence.

   b Either commit to continued abstinence from heterosexual intercourse (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting study drug, during the study therapy (including dose interruptions), and for 28 days after discontinuation of study therapy.
7. Males Subjects must:

   1. Agree to use a condom during sexual contact with a WCBP, even if they have had a vasectomy, throughout study drug therapy, during any dose interruption and after the cessation of study therapy.
   2. Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.
8. All subjects must

   1. Have an understanding that the study drug could have potential teratogenic risk.
   2. Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy.
   3. Agree not to share study medication with another person.
   4. All patients must be counseled about pregnancy precautions and risks of fetal exposure.

Female Subjects:

Females of childbearing potential (FCBP) with regular cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 28 days while on study, at study discontinuation, and at day 28 following discontinuation from the study. If menstrual cycles are irregular, the pregnancy testing must occur weekly for the first 28 days and then every 14 days while on study, at study discontinuation, and at days 14 and 28 following discontinuation from the study.

In addition to the required pregnancy testing, the Investigator must confirm with FCBP that she is continuing to use two reliable methods of birth control at each visit. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood.

Pregnancy testing and counseling must be performed if a subject misses her period or if her pregnancy test or her menstrual bleeding is abnormal. Study drug treatment must be discontinued during this evaluation.

Females must agree to abstain from breastfeeding during study participation and for at least 28 days after the discontinuation from the study.

Male Subjects:

Counseling about the requirement for latex condom use during sexual contact with females of childbearing potential and the potential risks of fetal exposure must be conducted at a minimum of every 28 days. During counseling, subjects must be reminded to not share study drug and to not donate blood, sperm, or semen.

If pregnancy or a positive pregnancy test does occur in a study subject or the partner of a study subject during study participation, study drug must be immediately discontinued.

Exclusion Criteria

1. Previous treatment with antimyeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid \[i.e., less than or equal to the equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid treatment must not have been given within 28 days \[4 weeks\] of randomization\]).
2. Any serious medical condition, including the presence of laboratory abnormalities, which places the subject at an unacceptable risk if he or she participates in this study or confounds experimental the ability to interpret data from the study.
3. Pregnant or lactating females.
4. Radiotherapy within 14 days (2 weeks) of randomization.
5. Plasmapheresis within 28 days (4 weeks) of randomization.
6. Any of the following laboratory abnormalities:

   Absolute neutrophil count (ANC) \< 1,500 cells/mL (1.5\*10\^9/L) Platelet count \< 75,000 cells/uL (75\*10\^9/L) for subjects in whom \< 50% of bone marrow nucleated cells are plasma cells; but platelet count \<30,000/uL for subjects in whom \>= 50% of bone marrow nucleated cells are plasma cells Haemoglobin \< 8.0 g/dL (80 g/L) Serum creatinine \> 2.5 mg/dL (221 µmol/L) Serum aspartate aminotransferase (SGOT/AST) or alanine aminotransferase (SGPT/ALT) \> 3.0 times upper limit of normal (ULN)
7. Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for greater than or equal to 3 years.

   Exceptions include the following:

   Basal cell carcinoma of the skin Squamous cell carcinoma of the skin Carcinoma in situ of the cervix Carcinoma in situ of the breast Incidental histologic finding of prostate cancer (TNM Classification of Malignant Tumours (TNM) stage of T1a or T1b)
8. Neuropathy of \>= grade 2 severity.
9. Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis, type A, B or C.
D: Inclusion Criteria:

* Patient is, in the investigator(s) opinion, willing and able to comply with the protocol requirements.
* Patient has given voluntary written informed consent before performance of any study related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
* Patient is 65 years old or older at the time of signing the informed consent or younger patients not candidate to high dose therapy
* Female patient is either post-menopausal or surgically sterilized or, if at child-bearing potential†, must:

  * understand that the study medication could have an expected teratogenic risk
  * Agree to use, and be able to comply with, effective contraception without interruption, 4 weeks before starting study drug, throughout study drug therapy (including dose interruptions) and for 4 weeks after the end of study drug therapy, even if she has amenorrhea. This applies unless the subject commits to absolute and continued abstinence confirmed on a monthly basis. The following are effective methods of contraception\*
* Implant\*\*
* Levonorgestrel-releasing intrauterine system (IUS)\*\*
* Medroxyprogesterone acetate depot
* Tubal sterilisation
* Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses
* Ovulation inhibitory progesterone-only pills (i.e., desogestrel)

Combined oral contraceptive pills are not recommended. If a subject was using combined oral contraception, she must switch to one of the methods above. The increased risk of VTE continues for 4 to 6 weeks after stopping combined oral contraception.

* prophylactic antibiotics should be considered at the time of insertion particularly in patients with neutropenia due to risk of infection

  * Agree to have a medically supervised pregnancy test with a minimum sensitivity of 25 mIU/ml not more than 3 days before the start of study medication once the subject has been on effective contraception for at least 4 weeks. This requirement also applies to women of childbearing potential who practice complete and continued abstinence.
  * Agree to have a medically supervised pregnancy test every 4 weeks including 4 weeks after the end of study treatment, except in the case of confirmed tubal sterilization. These tests should be performed not more than 3 days before the start of next treatment. This requirement also applies to women of childbearing potential who practice complete and continued abstinence

    - Male subjects must
  * Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy if their partner is of childbearing potential and has no contraception.
  * Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.

    - All subjects must
  * Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
  * Agree not to share study medication with another person and to return all unused study drug to the investigator.

    - Patient was previously diagnosed with symptomatic MM based on standard criteria, and has measurable disease, defined as follows:
  * Secretory myeloma: any quantifiable serum monoclonal protein value (generally, but not necessarily, greater than 1 g/dL of IgG M-Protein and greater than 0.5 g/dL of IgA M-Protein) and, where applicable, urine light-chain excretion of \>200 mg/24 hours;
  * Non-secretory myeloma: \> 30% plasma cells in the bone marrow and at least one plasmacytoma \> 2 cm as determined by clinical examination or applicable radiographs (i.e., MRI or CT scan).

    * Patient has a baseline bone marrow sample available for cytogenetics, that will be processed and eventually centralized within each country.
    * Patient has a Karnofsky performance status _ 60%.
    * Patient has a life-expectancy \> 6 months
    * Patients must have a adequate cardiac function
    * Patients must have adequate pulmonary function
    * Patient has the following laboratory values within 14 days before Baseline (day 1 of the Cycle 1):
    * Platelet count ≥ 75 x 109/L without transfusion support within 7 days before the test.
    * Absolute neutrophil count (ANC) ≥1.0 x 109/L without the use of growth factors.
    * Corrected serum calcium ≤14 mg/dL (3.5 mmol/L).
    * Aspartate transaminase (AST): ≤2.5 x the upper limit of normal (ULN).
    * Alanine transaminase (ALT): ≤ 2.5 x the ULN.
    * Total bilirubin: ≤1.5 x the ULN.
    * Calculated or measured creatinine clearance: ≥30 mL/minute

Exclusion Criteria:

* Previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid; \< to the equivalent of dexamethasone 40 mg/day for 4 days).
* Any serious medical condition, including the presence of laboratory abnormalities, which places the subject at an unacceptable risk if he or she participates in this study or confounds the experimental ability to interpret data from the study.
* Pregnant or lactating females.
* Prior history of malignancies, other than multiple myeloma, unless the subject has been free of the disease for ≥3 years. Exceptions include the following: Basal cell carcinoma of the skin, Squamous cell carcinoma of the skin, Carcinoma in situ of the cervix, Carcinoma in situ of the breast, Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)

Answer: A