Velcade

Dosage Form: injection, powder, lyophilized, for solution
FULL PRESCRIBING INFORMATION

Indications and Usage for Velcade

Multiple Myeloma

Velcade® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

Mantle Cell Lymphoma

Velcade (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Velcade Dosage and Administration

Dosage in Previously Untreated Multiple Myeloma

Velcade (bortezomib) is administered as a 3-5 second bolus intravenous (IV) injection in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, Velcade is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Velcade is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Velcade.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma

Twice Weekly Velcade (Cycles 1-4)
Week	1				2		3	4		5		6
Velcade (1.3 mg/m2)	Day 1	--	--	Day 4	Day 8	Day 11	rest period	Day 22	Day 25	Day 29	Day 32	rest period
Melphalan(9 mg/m2) Prednisone(60 mg/m2)	Day 1	Day 2	Day 3	Day 4	--	--	rest period	--	--	--	--	rest period
Once Weekly Velcade (Cycles 5-9 when used in combination with Melphalan and Prednisone)
Week	1				2		3	4		5		6
Velcade (1.3 mg/m2)	Day 1	--	--		Day 8		rest period	Day 22		Day 29		rest period
Melphalan(9 mg/m2) Prednisone(60 mg/m2)	Day 1	Day 2	Day 3	Day 4	--	--	rest period	--	--	--	--	rest period

Dose Modification Guidelines for Combination Therapy with Velcade, Melphalan and Prednisone

Prior to initiating any cycle of therapy with Velcade in combination with melphalan and prednisone:

• Platelet count should be at least 70 × 109/L and the absolute neutrophil count (ANC) should be at least 1.0 × 109/L


• Non-hematological toxicities should have resolved to Grade 1 or baseline

Table 2: Dose Modifications during Cycles of Combination Velcade, Melphalan and Prednisone Therapy

Toxicity	Dose modification or delay
For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Hematological toxicity during a cycle:
If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle	Consider reduction of the melphalan dose by 25% in the next cycle
If platelet count is not above 30 × 109/L or ANC is not above 0.75 × 109/L on a Velcade dosing day (other than day 1)	Velcade dose should be withheld
If several Velcade doses in consecutive cycles are withheld due to toxicity	Velcade dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)
Grade 3 or higher non-hematological toxicities	Velcade therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, Velcade may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For Velcade-related neuropathic pain and/or peripheral neuropathy, hold or modify Velcade as outlined in Table 3.

For dose modifications guidelines for peripheral neuropathy see Management of Peripheral Neuropathy section (2.5).

Dosage in Relapsed Multiple Myeloma and Mantle Cell Lymphoma

Velcade (1.3 mg/m2/dose) is administered as a 3 to 5 second bolus intravenous injection twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended therapy of more than 8 cycles, Velcade may be administered on the standard schedule or on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35) [see Clinical Studies section (14) for a description of dose administration during the trials]. At least 72 hours should elapse between consecutive doses of Velcade.

Dose Modification Guidelines for Relapsed Multiple Myeloma and Mantle Cell Lymphoma

Velcade therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see Warnings and Precautions (5)]. Once the symptoms of the toxicity have resolved, Velcade therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).

For dose modifications guidelines for peripheral neuropathy see Management of Peripheral Neuropathy section (2.5).

 2.5 Management of Peripheral Neuropathy

For the management of patients who experience Velcade-related neuropathic pain and/or peripheral neuropathy see Table 3. Patients with preexisting severe neuropathy should be treated with Velcade only after careful risk-benefit assessment.

Table 3: Recommended Dose Modification for Velcade related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy

Severity of Peripheral Neuropathy Signs and Symptoms*	Modification of Dose and Regimen
* Grading based on NCI Common Terminology Criteria CTCAE v4.0 † Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etc; ‡ Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden
Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function	No action
Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)†)	Reduce Velcade to 1 mg/m2
Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL ‡)	Withhold Velcade therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of Velcade at 0.7 mg/m2 once per week.
Grade 4 (life-threatening consequences; urgent intervention indicated)	Discontinue Velcade

Dosage in Patients with Hepatic Impairment

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Velcade dose. Patients with moderate or severe hepatic impairment should be started on Velcade at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance (see Table 4). [see Warnings and Precautions (5.10), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]

Table 4: Recommended Starting Dose Modification for Velcade in Patients with Hepatic Impairment

	Bilirubin Level	SGOT (AST) Levels	Modification of Starting Dose
Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range.
Mild	Less than or equal to 1.0x ULN	More than ULN	None
	More than 1.0x–1.5x ULN	Any	None
Moderate	More than 1.5x–3x ULN	Any	Reduce Velcade to 0.7 mg/m2 in the first cycle. Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.
Severe	More than 3x ULN	Any

Administration Precautions

The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose.

Velcade is an antineoplastic. Procedures for proper handling and disposal should be considered. [see How Supplied/Storage and Handling (16)]

In clinical trials, local skin irritation was reported in 5% of patients, but extravasation of Velcade was not associated with tissue damage.

Reconstitution/Preparation for Intravenous Administration

Proper aseptic technique should be used. Reconstitute with 3.5 mL of 0.9% Sodium Chloride resulting in a final concentration of 1 mg/mL of bortezomib. The reconstituted product should be a clear and colorless solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.

Stability: Unopened vials of Velcade are stable until the date indicated on the package when stored in the original package protected from light.

Velcade contains no antimicrobial preservative. Reconstituted Velcade should be administered within 8 hours of preparation. When reconstituted as directed, Velcade may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.

Dosage Forms and Strengths

Each single-use vial of Velcade contains 3.5 mg of bortezomib as a sterile lyophilized powder.

Contraindications

Velcade is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

Warnings and Precautions

Velcade should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with Velcade.

Peripheral Neuropathy

Velcade treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with Velcade. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of Velcade [see Dosage and Administration (2.5)]. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies [see Adverse Reactions (6)]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension

The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics [see Adverse Reactions(6)].

Cardiac Disorders

Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the Velcade and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the Velcade and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders

There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving Velcade. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and Velcade for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.

There have been reports of pulmonary hypertension associated with Velcade administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

There have been reports of RPLS in patients receiving Velcade. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue Velcade. The safety of reinitiating Velcade therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events

Velcade treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Reactions (6)] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia

Velcade is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 5. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥ Grade 3) was similar on both the Velcade (4%) and dexamethasone (5%) arms. Platelet count should be monitored prior to each dose of Velcade. Patients experiencing thrombocytopenia may require change in the dose and schedule of Velcade [see Table 2 and Dosage and Administration (2.4)]. There have been reports of gastrointestinal and intracerebral hemorrhage in association with Velcade. Transfusions may be considered. The incidence of febrile neutropenia was < 1%.

Table 5: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study

Pretreatment Platelet Count*	Number of Patients (N=331)†	Number (%) of Patients with Platelet Count < 10,000/µL	Number (%) of Patients with Platelet Count 10,000-25,000/µL
* A baseline platelet count of 50,000/µL was required for study eligibility † Data were missing at baseline for 1 patient
≥ 75,000/µL	309	8 (3%)	36 (12%)
≥ 50,000/µL-< 75,000/µL	14	2 (14%)	11 (79%)
≥ 10,000/µL-< 50,000/µL	7	1 (14%)	5 (71%)

Tumor Lysis Syndrome

Because Velcade is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events

Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of Velcade. There is limited re-challenge information in these patients.

Hepatic Impairment

Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with Velcade at reduced starting doses and closely monitored for toxicities. [see Dosage and Administration (2.6), Use In Specific Populations (8.7) and Clinical Pharmacology (12.3)]

Use in Pregnancy

Women of childbearing potential should avoid becoming pregnant while being treated with Velcade. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. [see Use in Specific Populations (8.1)]

Adverse Reactions

The following adverse reactions are also discussed in other sections of the labeling:

• Peripheral Neuropathy [see Warnings and Precautions (5.1); Dosage and Administration (2.5)(Table 3)]


• Hypotension [see Warnings and Precautions (5.2)]


• Cardiac Disorders [see Warnings and Precautions (5.3)]


• Pulmonary Disorders [see Warnings and Precautions (5.4)]


• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.5)]


• Gastrointestinal Adverse Events [see Warnings and Precautions (5.6)]


• Thrombocytopenia/Neutropenia [see Warnings and Precautions (5.7)]


• Tumor Lysis Syndrome [see Warnings and Precautions (5.8)]


• Hepatic Events [see Warnings and Precautions (5.9)]

Clinical Trials Safety Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma:

Table 6 describes safety data from 340 patients with previously untreated multiple myeloma who received Velcade (1.3 mg/m2) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) in a prospective randomized study.

The safety profile of Velcade in combination with melphalan/prednisone is consistent with the known safety profiles of both Velcade and melphalan/prednisone.

Table 6: Most Commonly Reported Adverse Events (≥ 10% in Velcade, Melphalan and Prednisone arm) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Multiple Myeloma Study

	Velcade, Melphalan and Prednisone			Melphalan and Prednisone
	(N=340)			(N=337)
MedDRA System Organ Class	Total	Toxicity Grade, n (%)		Total	Toxicity Grade, n (%)
Preferred Term	n (%)	3	≥ 4	n (%)	3	≥ 4
Blood and Lymphatic System Disorders
Thrombocytopenia	178 ( 52)	68 ( 20)	59 ( 17)	159 ( 47)	55 ( 16)	47 ( 14)
Neutropenia	165 ( 49)	102 ( 30)	35 ( 10)	155 ( 46)	79 ( 23)	49 ( 15)
Anemia	147 ( 43)	53 ( 16)	9 ( 3)	187 ( 55)	66 ( 20)	26 ( 8)
Leukopenia	113 ( 33)	67 ( 20)	10 ( 3)	100 ( 30)	55 ( 16)	13 ( 4)
Lymphopenia	83 ( 24)	49 ( 14)	18 ( 5)	58 ( 17)	30 ( 9)	7 ( 2)
Gastrointestinal Disorders
Nausea	164 ( 48)	14 ( 4)	0	94 ( 28)	1 ( <1)	0
Diarrhea	157 ( 46)	23 ( 7)	2 ( 1)	58 ( 17)	2 ( 1)	0
Constipation	125 ( 37)	2 ( 1)	0	54 ( 16)	0	0
Vomiting	112 ( 33)	14 ( 4)	0	55 ( 16)	2 ( 1)	0
Abdominal Pain	49 ( 14)	7 ( 2)	0	22 ( 7)	1 ( <1)	0
Abdominal Pain Upper	40 ( 12)	1 ( <1)	0	29 ( 9)	0	0
Dyspepsia	39 ( 11)	0	0	23 ( 7)	0	0
Nervous System Disorders
Peripheral Neuropathy	159 ( 47)	43 ( 13)	2 ( 1)	18 ( 5)	0	0
Neuralgia	121 ( 36)	28 ( 8)	2 ( 1)	5 ( 1)	1 ( <1)	0
Dizziness	56 ( 16)	7 ( 2)	0	37 ( 11)	1 ( <1)	0
Headache	49 ( 14)	2 ( 1)	0	35 ( 10)	4 ( 1)	0
Paresthesia	45 ( 13)	6 ( 2)	0	15 ( 4)	0	0
General Disorders and Administration Site Conditions
Pyrexia	99 ( 29)	8 ( 2)	2 ( 1)	64 ( 19)	6 ( 2)	2 ( 1)
Fatigue	98 ( 29)	23 ( 7)	2 ( 1)	86 ( 26)	7 ( 2)	0
Asthenia	73 ( 21)	20 ( 6)	1 ( <1)	60 ( 18)	9 ( 3)	0
Edema Peripheral	68 ( 20)	2 ( 1)	0	34 ( 10)	0	0
Infections and Infestations
Pneumonia	56 ( 16)	16 ( 5)	13 ( 4)	36 ( 11)	13 ( 4)	9 ( 3)
Herpes Zoster	45 ( 13)	11 ( 3)	0	14 ( 4)	6 ( 2)	0
Bronchitis	44 ( 13)	4 ( 1)	0	27 ( 8)	4 ( 1)	0
Nasopharyngitis	39 ( 11)	1 ( <1)	0	27 ( 8)	0	0
Musculoskeletal and Connective Tissue Disorders
Back Pain	58 ( 17)	9 ( 3)	1 ( <1)	62 ( 18)	11 ( 3)	1 ( <1)
Pain In Extremity	47 ( 14)	8 ( 2)	0	32 ( 9)	3 ( 1)	1 ( <1)
Bone Pain	37 ( 11)	7 ( 2)	1 ( <1)	35 ( 10)	7 ( 2)	0
Arthralgia	36 ( 11)	4 ( 1)	0	50 ( 15)	2 ( 1)	1 ( <1)
Metabolism and Nutrition Disorders
Anorexia	77 ( 23)	9 ( 3)	1 ( <1)	34 ( 10)	4 ( 1)	0
Hypokalemia	44 ( 13)	19 ( 6)	3 ( 1)	25 ( 7)	8 ( 2)	2 ( 1)
Skin and Subcutaneous Tissue Disorders
Rash	66 ( 19)	2 ( 1)	0	24 ( 7)	1 ( <1)	0
Pruritus	35 ( 10)	3 ( 1)	0	18 ( 5)	0	0
Respiratory, Thoracic and Mediastinal Disorders
Cough	71 ( 21)	0	0	45 ( 13)	2 ( 1)	0
Dyspnea	50 ( 15)	11 ( 3)	2 ( 1)	44 ( 13)	5 ( 1)	4 ( 1)
Psychiatric Disorders
Insomnia	69 ( 20)	1 ( <1)	0	43 ( 13)	0	0
Vascular Disorders
Hypertension	45 ( 13)	8 ( 2)	1 ( <1)	25 ( 7)	2 ( 1)	0
Hypotension	41 ( 12)	4 ( 1)	3 ( 1)	10 ( 3)	2 ( 1)	2 ( 1)

Relapsed Multiple Myeloma Randomized Study

The safety data described below and in Table 7 reflect exposure to either Velcade (n=331) or dexamethasone (n=332) in a study of patients with multiple myeloma. Velcade was administered intravenously at doses of 1.3 mg/m2 twice weekly for 2 out of 3 weeks (21 day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (9 months) with a median duration of 6 cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1 to 3 prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse events was similar in men and women, and in patients < 65 and ≥ 65 years of age. Most patients were Caucasian. [see Clinical Studies (14.1)]

Among the 331 Velcade-treated patients, the most commonly reported events overall were asthenic conditions (61%), diarrhea and nausea (each 57%), constipation (42%), peripheral neuropathy NEC (36%), vomiting, pyrexia, thrombocytopenia, and psychiatric disorders (each 35%), anorexia and appetite decreased (34%), paresthesia and dysesthesia (27%), anemia and headache (each 26%), and cough (21%). The most commonly reported adverse events reported among the 332 patients in the dexamethasone group were psychiatric disorders (49%), asthenic conditions (45%), insomnia (27%), anemia (22%), and diarrhea and lower respiratory/lung infections (each 21%). Fourteen percent (14%) of patients in the Velcade treated arm experienced a Grade 4 adverse event; the most common toxicities were thrombocytopenia (4%), neutropenia (2%) and hypercalcemia (2%). Sixteen percent (16%) of dexamethasone treated patients experienced a Grade 4 adverse event; the most common toxicity was hyperglycemia (2%).

Serious Adverse Events (SAEs) and Events Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study

Serious adverse events are defined as any event, regardless of causality, that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 144 (44%) patients from the Velcade treatment arm experienced an SAE during the study, as did 144 (43%) dexamethasone-treated patients. The most commonly reported SAEs in the Velcade treatment arm were pyrexia (6%), diarrhea (5%), dyspnea and pneumonia (4%), and vomiting (3%). In the dexamethasone treatment group, the most commonly reported SAEs were pneumonia (7%), pyrexia (4%), and hyperglycemia (3%).

A total of 145 patients, including 84 (25%) of 331 patients in the Velcade treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adve