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Generic Name: Bortezomib
Class: Antineoplastic Agents
VA Class: AN900
Chemical Name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propanoyl]amino]butyl]boronic acid
Molecular Formula: C19H25BN4O4
CAS Number: 179324-69-7

Introduction

Antineoplastic agent; inhibitor of 26S proteasome.1 5

Uses for Velcade

Previously Untreated Multiple Myeloma

Used in combination with melphalan and prednisone for previously untreated multiple myeloma.1 20

Relapsed Multiple Myeloma

Monotherapy for treatment of relapsed multiple myeloma.1 3 7

More effective than high-dose dexamethasone in achieving complete or partial response, prolonging time to disease progression, and improving survival in patients with progressive multiple myeloma who had received 1–3 prior chemotherapy regimens.1 8

Induction Therapy Prior to Stem-cell Transplantation in Newly Diagnosed Multiple Myeloma

Has been studied as a component of various induction regimens in patients newly diagnosed with multiple myeloma who were to undergo autologous stem-cell transplant.10002 10003 10004 10005 10006 10007 10008

Slideshow: Flashback: FDA Drug Approvals 2013

Use with dexamethasone may be considered a reasonable choice (accepted, with possible conditions) as an induction regimen in patients newly diagnosed with multiple myeloma who are to undergo an autologous stem-cell transplant.19 Additional data needed to correlate high posttransplant responses with impact on survival beyond 1 year and to fully establish survival benefit for bortezomib-dexamethasone compared with vincristine-doxorubicin-dexamethasone (VAD) regimen.19

Use in patients with newly diagnosed multiple myeloma who are to undergo an autologous stem-cell transplant as a component of other induction regimens (i.e., with thalidomide and dexamethasone [VTD]; with dexamethasone and either conventional doxorubicin [PAD] or pegylated liposomal doxorubicin [VDD]; with cyclophosphamide and dexamethasone [CyBorD and BCD regimens]; as BCD followed by bortezomib with thalidomide and dexamethasone [BTD]) is not established because of inadequate data, unclear risk/benefit, and/or inadequate experience.19 10003 10004 10005 10006 10007 10008

Mantle Cell Lymphoma

Treatment of mantle cell lymphoma in patients who have received at least 1 prior chemotherapy regimen.1 13 14 21

Velcade Dosage and Administration

General

  • Consult specialized references for procedures for proper handling and disposal of antineoplastics including use of gloves and protective clothing.1

Antiviral Prophylaxis

  • Consider initiating antiviral prophylaxis.1 (See Herpes Virus Infection under Cautions.)

Administration

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Administer by IV injection over 3–5 seconds.

Reconstitution

To reconstitute, add 3.5 mL of 0.9% sodium chloride injection to vial containing 3.5 mg of bortezomib.

Administer within 8 hours after reconstitution.

Dosage

Consult specialized references and published protocols for dosage (including dosage adjustments in special populations), method of administration, and administration sequence of drugs in combination regimens.1

Calculate dose carefully to prevent overdosage; drug quantity contained in one 3.5-mg vial may exceed usual single dose required.1

Adults

Previously Untreated Multiple Myeloma
Bortezomib, Melphalan, and Prednisone (VMP regimen)
IV

Cycles 1–4 (of the recommended nine 6-week cycles): Bortezomib 1.3 mg/m2 IV twice weekly during weeks 1, 2, 4, and 5 (days 1, 4, 8, 11, 22, 25, 29, and 32 of the 6-week cycle) followed by a 10-day rest period (days 33–42).1 20

Cycles 5–9: Bortezomib 1.3 mg/m2 IV once weekly during weeks 1, 2, 4, and 5 (days 1, 8, 22, and 29) followed by a 13-day rest period.1 20

In all 9 cycles: Administer oral melphalan 9 mg/m2 and oral prednisone 60 mg/m2 once daily on days 1–4.1

At least 72 hours should elapse between consecutive doses of bortezomib.1

Dosage Modification for Toxicity for VMP Regimen
IV

Before administering any VMP cycle, platelet counts should be ≥70,000/mm3, ANC should be ≥1000/mm3, and any nonhematologic toxicities should have resolved to grade 1 or baseline.1

Table 1. Dosage Modification for VMP Regimen in Previously Untreated Multiple Myeloma1

Toxicity

Dose Modification or Delay

If prolonged grade 4 neutropenia or thrombocytopenia or thrombocytopenia with bleeding observed in previous VMP cycle

Consider reduction of melphalan dose by 25% in next cycle

Platelet count ≤30,000/mm3 or ANC ≤750/mm3 on a day when bortezomib is to be administered (other than on day 1)

Withhold bortezomib dose

If several doses of bortezomib were withheld in consecutive cycles because of toxicity

Reduce bortezomib dose by one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2 or a dose of 1 mg/m2 reduced to 0.7 mg/m2)

Grade ≥3 nonhematologic toxicity

Withhold bortezomib until toxicity resolves to grade 1 or baseline; may then reinitiate bortezomib with a reduction of one dose level (i.e., 1.3 mg/m2 per dose reduced to 1 mg/m2 per dose; 1 mg/m2 per dose reduced to 0.7 mg/m2 per dose)

Bortezomib-related neuropathic pain and/or peripheral neuropathy

See Table 2 under Dosage Modification for Peripheral Neuropathy in Relapsed Multiple Myeloma

Relapsed Multiple Myeloma
IV

Standard regimen: 1.3 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21).1 4 5

For extended therapy of >8 treatment cycles, continue standard 21-day regimen or initiate 35-day maintenance regimen of 1.3 mg/m2 once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period (days 23–35).1

At least 72 hours should elapse between consecutive doses.1

In clinical studies, patients expected to benefit from extended therapy received a median of 7 additional treatment cycles, for a total median of 14 treatment cycles.1

Dosage Modification for Peripheral Neuropathy in Relapsed Multiple Myeloma
IV

Adjust dosage and/or frequency of administration if severe peripheral neuropathy occurs.1 6

Table 2. Dosage Modification for Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy1

Severity of Neuropathy and Manifestations

Comments

Grade 1 (paresthesias, weakness, and/or loss of reflexes) without pain or loss of function

No dosage modification necessary

Grade 1 with pain

Reduce dose to 1 mg/m2

Grade 2 (interfering with function but not with activities of daily living)

Reduce dose to 1 mg/m2

Grade 2 with pain

Temporarily discontinue; after manifestations of toxicity resolve, reinitiate at dosage of 0.7 mg/m2 once weekly

Grade 3 (interfering with activities of daily living)

Temporarily discontinue; after manifestations of toxicity resolve, reinitiate at dosage of 0.7 mg/m2 once weekly

Grade 4 (disabling sensory neuropathy or motor neuropathy that is life-threatening or leads to paralysis)

Discontinue bortezomib

Dosage Modification for Other Severe Adverse Nonhematologic or Hematologic Effects in Relapsed Multiple Myeloma
IV

Temporarily discontinue therapy if grade 3 nonhematologic (other than peripheral neuropathy) or grade 4 hematologic toxicities (e.g., grade 4 thrombocytopenia [platelet count <25,000/mm3]) occur.1 6

Once manifestations of toxicity resolve, reinitiate but reduce bortezomib dosage by 25% (i.e., reduce from 1.3 mg/m2 per dose to 1 mg/m2 per dose; reduce from 1 mg/m2 per dose to 0.7 mg/m2 per dose).1

Administer the adjusted regimen for 2 weeks, followed by a 10-day rest period.6

Induction Therapy Prior to Stem-cell Transplantation in Newly Diagnosed Multiple Myeloma
Bortezomib and Dexamethasone (VD regimen)
IV

Bortezomib 1.3 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12–21) has been used.10002

In cycles 1 and 2, regimen included dexamethasone 40 mg orally on days 1–4 and 9–12; in cycles 3 and 4, dexamethasone 40 mg was administered orally on days 1–4.10002

Patients in the clinical trial received four 21-day cycles of VD.10002

Mantle Cell Lymphoma
IV

Standard regimen: 1.3 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21).1

For extended therapy of >8 treatment cycles, continue standard 21-day regimen or initiate 35-day maintenance regimen of 1.3 mg/m2 once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period (days 23–35).1

At least 72 hours should elapse between consecutive doses.1

In clinical studies, patients who responded to therapy received a median of 8 treatment cycles.1

Dosage Modification for Peripheral Neuropathy in Mantle Cell Lymphoma
IV

Adjust dosage and/or frequency of administration if severe peripheral neuropathy occurs.1 6

Table 3. Dosage Modification for Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy1

Severity of Neuropathy and Manifestations

Comments

Grade 1 (paresthesias, weakness, and/or loss of reflexes) without pain or loss of function

No dosage modification necessary

Grade 1 with pain

Reduce dose to 1 mg/m2

Grade 2 (interfering with function but not with activities of daily living)

Reduce dose to 1 mg/m2

Grade 2 with pain

Temporarily discontinue; after manifestations of toxicity resolve, reinitiate at dosage of 0.7 mg/m2 once weekly

Grade 3 (interfering with activities of daily living)

Temporarily discontinue; after manifestations of toxicity resolve, reinitiate at dosage of 0.7 mg/m2 once weekly

Grade 4 (disabling sensory neuropathy or motor neuropathy that is life-threatening or leads to paralysis)

Discontinue bortezomib

Dosage Modification for Other Severe Adverse Nonhematologic or Hematologic Effects in Mantle Cell Lymphoma
IV

Temporarily discontinue therapy if grade 3 nonhematologic (other than peripheral neuropathy) or grade 4 hematologic toxicities (e.g., grade 4 thrombocytopenia [platelet count <25,000/mm3]) occur.1 6

Once manifestations of toxicity resolve, reinitiate but reduce bortezomib dosage by 25% (i.e., reduce from 1.3 mg/m2 per dose to 1 mg/m2 per dose; reduce from 1 mg/m2 per dose to 0.7 mg/m2 per dose).1

Administer the adjusted regimen for 2 weeks, followed by a 10-day rest period.6

Special Populations

Hepatic Impairment

Moderate (i.e., bilirubin concentrations >1.5–3 times ULN with any AST concentrations) or severe (i.e., bilirubin concentrations >3 times ULN with any AST concentrations) hepatic impairment: Reduce bortezomib dose during first cycle to 0.7 mg/m2.1 Based on patient tolerance, either increase dosage in subsequent cycles to 1 mg/m2 or further reduce to 0.5 mg/m2.1

Mild hepatic impairment (i.e., bilirubin concentrations at or below ULN with AST concentrations exceeding ULN or bilirubin concentrations >1 to 1.5 times ULN with any AST concentrations): Administer usual recommended initial dose.1

Renal Impairment

Dosage adjustment not required.1

Dialysis may decrease bortezomib concentrations; administer after a dialysis procedure.1 (See Special Populations under Pharmacokinetics.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Velcade

Contraindications

  • Known hypersensitivity to bortezomib, boron, or mannitol.1

Warnings/Precautions

Experience of Supervising Clinician

Use under supervision of a qualified clinician experienced in therapy with antineoplastic agents.1

Fetal/Neonatal Morbidity and Mortality

Possible fetal harm; embryolethality and decreased fetal weight demonstrated in animals.1 Avoid pregnancy during therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Nervous System Effects

Risk of severe (≥grade 3) new-onset peripheral neuropathy or exacerbation of preexisting peripheral neuropathy.1 Occurs predominantly as peripheral sensory neuropathy, but severe peripheral motor neuropathy also reported.1 Incidence of peripheral neuropathy reportedly higher in patients with mantle cell lymphoma than in patients with relapsed multiple myeloma.1 Manifestations improved or returned to baseline in some patients with relapsed multiple myeloma following dosage reduction or discontinuance of bortezomib; long-term outcome of peripheral neuropathy not evaluated in patients with mantle cell lymphoma.1

Monitor patients for manifestations of neuropathy (e.g., burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, weakness).1 Adjust dosage and/or frequency of administration if new-onset or exacerbation of peripheral neuropathy occurs.1 (See Dosage under Dosage and Administration.)

Use in patients with preexisting severe neuropathy only after careful assessment of the risks and benefits for the individual patient.1

Severe (≥grade 3) asthenic conditions (including fatigue, malaise, and weakness) reported.1

Hypotension

Risk of severe (grade 3) hypotension, orthostatic hypotension, and syncope.1

Use with caution in patients with history of syncope or who are dehydrated or receiving drugs associated with hypotension.1

Orthostatic hypotension may be managed with adjustment of antihypertensive therapy, hydration, or administration of mineralocorticoids and/or sympathomimetics.1

Cardiovascular Effects

Acute development or exacerbation of CHF and/or new onset of decreased left ventricular ejection fraction reported, including in patients with no risk factors for decreased left ventricular ejection fraction.1 Other heart failure events (e.g., acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) also reported.1 Risk of death from cardiogenic shock, CHF, or cardiac arrest.1 Closely monitor patients with existing heart disease or patients with increased risk for heart disease.1

Prolongation of QTc interval reported; however, causal relationship with bortezomib not established.1

Pulmonary Disorders

Fatal respiratory insufficiency/failure reported.1 Pneumonitis, interstitial pneumonia, lung infiltration, and ARDS reported; sometimes fatal.1 Pulmonary hypertension (in absence of left heart failure or significant pulmonary disease) also reported.1

If new or worsening cardiopulmonary symptoms occur, promptly conduct comprehensive diagnostic evaluation.1

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

RPLS reported.1 May manifest as seizures, hypertension, headache, lethargy, confusion, blindness, and other visual and neurologic disturbances.1 Brain imaging, preferably MRI, necessary to confirm diagnosis.1

If RPLS develops, discontinue bortezomib.1 Safety of reinitiating bortezomib in patients previously experiencing RPLS not known.1

GI Effects

Risk of nausea, diarrhea, constipation, and vomiting; ileus also may occur.1

Adverse GI effects may be severe and require use of antiemetics and antidiarrheals.1 Fluid and electrolyte replacement recommended to prevent dehydration.1

Hematologic Effects

Risk of severe (grade 3 or 4) thrombocytopenia.1 Platelet count nadir typically occurs following last dose of each treatment cycle and recovers before initiation of next cycle.1 Pattern of platelet count decrease and recovery remains consistent over 8 treatment cycles of twice-weekly dosing; no evidence of cumulative thrombocytopenia.1 Platelet count nadir averages approximately 40% of baseline.1 Risk of GI and intracerebral hemorrhage associated with thrombocytopenia.1

Risk of severe (grade 3 or 4) neutropenia.1 Neutrophil count nadir typically occurs following last dose of each treatment cycle and recovers before initiation of next cycle.1 Pattern of neutrophil count decrease and recovery remains consistent over 8 treatment cycles of twice-weekly dosing; no evidence of cumulative neutropenia.1

Risk of febrile neutropenia and severe (grade 3) anemia.1

Monitor platelet count prior to each dose.1 In addition, regularly monitor CBC during treatment and adjust dosage as appropriate.1 (See Dosage under Dosage and Administration.) Consider transfusions when deemed necessary.1

Tumor Lysis Syndrome

Possible tumor lysis syndrome following rapid lysis of malignant cells.1 Increased risk in patients with large tumor burden; closely monitor such patients and take appropriate precautions.1

Hepatic Effects

Acute liver failure reported in patients with serious underlying medical conditions who were receiving bortezomib with multiple concomitant drugs.1 Increases in hepatic enzyme concentrations, hyperbilirubinemia, and hepatitis also reported; may be reversible upon discontinuance of bortezomib.1 16 Information on results of rechallenge in these patients is limited.1 (See Hepatic Impairment under Dosage and Administration.)

Pyrexia

Risk of severe (≥ grade 3) pyrexia.1

Herpes Virus Infection

Risk of herpes zoster reactivation and herpes simplex infection.1 In phase 3 study, risk of herpes zoster reactivation appeared to be reduced when VMP was administered with antiviral prophylaxis.1 (See Antiviral Prophylaxis under Dosage and Administration.)

Herpes meningoencephalitis and ophthalmic herpes virus infection reported rarely.1

Specific Populations

Pregnancy

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether bortezomib is distributed into milk.1 Discontinue nursing or the drug because of potential risk to nursing infants; consider importance of drug to the woman.1

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 6

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1 In clinical studies, patients ≥65 years of age with relapsed multiple myeloma had longer median time to progression, longer median duration of response, higher overall response rates, and higher incidence of grade 3 or 4 adverse effects compared with younger adults.1

Hepatic Impairment

Increased exposure to bortezomib in patients with moderate or severe hepatic impairment; reduce dosage and monitor closely for adverse effects.1 23 (See Hepatic Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Renal Impairment

Pharmacokinetics not affected by renal impairment.1 (See Renal Impairment under Dosage and Administration and Special Populations under Pharmacokinetics.)

Common Adverse Effects

Asthenic conditions (including fatigue, malaise, and weakness), diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, decreased appetite and anorexia, neutropenia, neuralgia, leukopenia, anemia.1

Interactions for Velcade

Appears to be metabolized principally by CYP isoenzymes 3A4, 2C19, and 1A2; metabolism by CYP2D6 and CYP2C9 is minor.1 5 May inhibit CYP2C19; poor inhibitor of CYP isoenzymes 1A2, 3A4, 2C9, and 2D6.1 Does not induce CYP1A2 or CYP3A4 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of CYP3A4: Potential pharmacokinetic interaction.1 Closely monitor patients for potential toxicities or reduced efficacy.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (increased exposure to drugs metabolized by CYP2C19).1

Specific Drugs

Drug

Interaction

Comment

Antidiabetic agents, oral

Possible hypoglycemia or hyperglycemia1 5

Monitor blood glucose concentrations carefully and adjust dosage of antidiabetic agent1

Hypotensive agents

Increased risk of hypotension1

Dosage adjustment of hypotensive agents may be necessary1

Ketoconazole

Increased bortezomib AUC1

Closely monitor for potential toxicities if used concomitantly1

Melphalan

Concomitant administration with melphalan and prednisone caused a 17% increase in mean bortezomib AUC1

Unlikely to be clinically relevant1

Omeprazole

Concomitant administration did not affect bortezomib exposure1

Prednisone

Concomitant administration with melphalan and prednisone caused a 17% increase in mean bortezomib AUC1

Unlikely to be clinically relevant1

Ritonavir

Possible increased bortezomib exposure1

Closely monitor for potential toxicities if used concomitantly1

Velcade Pharmacokinetics

Absorption

Bioavailability

Mean dose-normalized peak plasma concentration and AUC of bortezomib are comparable between male and female patients.1

Onset

Maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood observed 5 minutes following administration.1 Maximum inhibition of 20S proteasome activity is comparable following administration of bortezomib doses of 1 mg/m2 (70–84%) and 1.3 mg/m2 (73–83%).1

Special Populations

Exposure increased about 60% in patients with moderate (i.e., bilirubin concentrations >1.5–3 times ULN with any AST concentrations) or severe (i.e., bilirubin concentrations >3 times ULN with any AST concentrations) hepatic impairment.1 23

In patients with varying degrees of renal impairment or normal renal function, exposure (based on dose-normalized AUC and maximum plasma concentrations) was comparable among all the groups.1 Dialysis may decrease concentrations; administer after a dialysis procedure.1 (See Renal Impairment under Dosage and Administration.)

Mean dose-normalized peak plasma concentration and AUC of bortezomib are 25% lower in patients <65 years of age than in those ≥65 years of age.1

Distribution

Extent

Distributed extensively to peripheral tissues.1

Not known whether bortezomib is distributed into milk.1

Plasma Protein Binding

83%.1

Elimination

Metabolism

Metabolized principally by CYP3A4, 2C19, and 1A2 to inactive metabolites; metabolism by CYP2D6 and 2C9 is minor.1 5

Elimination Route

Elimination pathways have not been characterized in humans.1

Half-life

40–193 or 76–108 hours following multiple dosing with 1- or 1.3-mg/m2 regimen, respectively.1

Stability

Storage

Parenteral

Powder for Injection

25°C (may be exposed to 15–30°C) in original package.1 Protect from light.1

Store reconstituted solution at 25°C in the original vial6 or in the syringe for up to 8 hours.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible1

Sodium chloride 0.9%

Actions

  • A modified dipeptidyl boronic acid.1 4 5

  • Reversibly inhibits the 26S proteasome, a large protein complex that degrades ubiquitinated proteins, preventing targeted proteolysis and causing disruption of normal homeostatic mechanisms, which can lead to cell death.1 5

  • Cytotoxic to a variety of cancer cell types in vitro.1 5

  • Has been shown to delay tumor growth in tumor models, including multiple myeloma.1

Advice to Patients

  • Risk of fatigue, dizziness, syncope, or orthostatic hypotension; avoid driving or operating machinery if these symptoms occur.1

  • Importance of taking appropriate measures to avoid dehydration caused by vomiting and/or diarrhea.1 Importance of informing clinician if dizziness or light-headedness develops and immediately seeking medical attention if fainting occurs.1

  • Advise women to use an effective method of contraception and to avoid breast-feeding while receiving bortezomib therapy.1 Importance of women informing a clinician immediately if they are or plan to become pregnant or plan to breast-feed.1 Advise pregnant women of risk to the fetus.1

  • For patients with diabetes receiving oral antidiabetic agents, importance of monitoring blood glucose concentrations frequently and informing clinician of any unusual change.1

  • Importance of informing clinician of new-onset or worsening symptoms of peripheral neuropathy (e.g., tingling, numbness, pain, burning sensation in hands or feet, weakness in arms or legs).1

  • Importance of informing clinician if rash, shortness of breath, cough, swelling (of the feet, ankles, or legs), seizures, persistent headache, reduced eyesight, increase in BP, or blurred vision occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Bortezomib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

3.5 mg

Velcade (preservative-free)

Millennium

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 9, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Millennium Pharmaceuticals. Velcade(bortezomib) for injection prescribing information. Cambridge, MA; 2010 Dec.

2. Food and Drug Administration, Center for Drug Evaluation and Research. Drug information: questions and answers on Velcade. From FDA website.

3. Anon. Press release: FDA approves VELCADE (bortezomib) for injection for the treatment of relapsed and refractory multiple myeloma. May 13, 2003. From Millennium website.

4. Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003; 348:2609-17. [IDIS 500112] [PubMed 12826635]

5. Anon. Bortezomomib (Velcade) for multiple myeloma. Med Lett Drugs Ther. 2003; 45:57-58. [PubMed 12865865]

6. Millennium, Cambridge, MA: Personal communication.

7. Multiple myeloma and other plasma cell neoplasms. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 Apr 12.

8. Richardson PG, Sonneveld P, Schuster MW et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005; 352:2487-98. [IDIS 535206] [PubMed 15958804]

9. Dispenzieri A. Bortezomib for myeloma—much ado about something. N Engl J Med. 2005; 352:2546-8. [IDIS 535212] [PubMed 15958811]

10. Jagannath S, Barlogie B, Berenson J et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 2004; 127:165-72. [PubMed 15461622]

11. Jagannath S, Barlogie B, Berenson JR et al. Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function. Cancer. 2005; 103:1195-200. [IDIS 530731] [PubMed 15690325]

12. Adult non-Hodgkin’s lymphoma. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2005 Jun 23.

13. Goy A, Younes A, McLaughlin P et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2005; 23:667-75. [IDIS 532649] [PubMed 15613697]

14. O’Connor OA, Wright J, Moskowitz C et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol. 2005; 23:676-84. [PubMed 15613699]

15. Engelhardt M, Muller AM, Maier W et al. Severe irreversible bilateral hearing loss after bortezomib (VELCADE) therapy in a multiple myeloma (MM) patient. Leukemia. 2005; 19:869-70. [PubMed 15772697]

16. Rosinol L, Montoto S, Cibeira MT et al. Bortezomib-induced severe hepatitis in multiple myeloma: a case report. Arch Intern Med. 2005; 165:464-5. [PubMed 15738379]

17. Jagannath S, Durie BG, Wolf J et al. Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma. Br J Haematol. 2005; 129:776-83. [PubMed 15953004]

18. Millennium Pharmaceuticals. Velcade (bortezomib) for injection prescribing information. Cambridge, MA; 2006 Mar.

19. Bortezomib Final Determination. Published June 2008.

20. San Miguel JF, Schlag R, Khuageva N et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359:906-17. [PubMed 18753647]

21. Fisher RI, Bernstein SH, Kahl BS et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006; 24:4867-74. [PubMed 17001068]

23. Food and Drug Administration, Center for Drug Evaluation and Research. FDA alert: Velcade (bortezomib) Starting dose adjustment for patients with hepatic impairment. Rockville MD: Food and Drug Administration; 2010 Jan 26. Available from FDA website. Accessed 2010 Sep 24. From FDA website.

10001. San Miguel JF, Schlag R, Khuageva N, et al. MMY-3002: A phase 3 study comparing bortezomib-melphalan-prednisone (VMP) with melphalan-prednisone (MP) in newly diagnosed multiple myeloma. Blood. 2007; 110: Abstract 76 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 9).

10002. Harousseau JL, Mathiot C, Attal M, et al. Velcade/Dexamethasone (Vel/D) versus VAD as induction treatment prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM): updated results of the IFM 2005/01 trial. Blood. 2007; 110: Abstract 450 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).

10003. Cavo M, Patriarca F, Tacchetti P, et al. Bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) in preparation for autologous stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple myeloma (MM). Blood. 2007. 110; Abstract 73 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 9).

10004. Palumbo A, Avonto I, Patriarca F et al. Bortezomib, pegylated-lyposomal-doxorubicin and dexamethasone followed by melphalan 100 mg/m2 in elderly new diagnosed patients: an interim analysis. Blood. 2007; 110: Abstract 448 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).

10005. Popat R, Oakervee H, Hallam S, et al. Bortezomib, doxorubicin, and dexamethasone (PAD) front line treatment of multiple myeloma: updated results after long term follow up. Br J Haematol. 2008; 141: 512-516.

10006. Reeder CB, Stewart AK, Hentz JG et al. Efficacy of induction with CyBorD in newly diagnosed multiple myeloma. J Clin Oncol. 2008; 26: Abstract 8517 (presented at the 44th Annual ASCO meeting. Chicago, IL: 2008 May 31).

10007. Reeder C, Reece D, Fonseca R, et al. A phase II trial of myeloma induction therapy with cyclophosphamide, bortezomib and dexamethasone (Cybor-D): improved response over historical lenalidomide-dexamethasone controls. Blood. 2007; 110: Abstract 3601.

10008. Jagannath S, Bensinger B, Vescio R, et al. A phase II study of bortezomib, cyclophosphamide, thalidomide and dexamethasone as first-line therapy for multiple myeloma. Blood. 2007; 110: Abstract 188 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 10).

10009. Facon T, Mary JY, Hulin C et al. Melphalan and prednisone plus thalidomide versus melphalan and prednisone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomized trial. Lancet. 2007; 370: 1209-18.

10010. Palumbo A, Bringhen S, Caravita T et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: a randomized trial. Lancet. 2006: 367; 825-831.

10011. Hulin C, Facon T, Rodon P, et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates a significant survival advantage in elderly patients ≥ 75 years with multiple myeloma compared with melphalan-prednisone (MP) in a randomized, double-blind, placebo-controlled trial, IFM-01/01. Blood. 2007; 110; Abstract 75 (presented at the 49th annual ASH meeting. Atlanta, GA: 2007 Dec 9).

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