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Velcade

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

Medically reviewed on Aug 6, 2018

Introduction

See also: Pomalyst

Antineoplastic agent; inhibitor of 26S proteasome.1 5

Uses for Velcade

Previously Untreated Multiple Myeloma

In combination with melphalan and prednisone for previously untreated multiple myeloma.1 20 24

Relapsed Multiple Myeloma

Treatment of multiple myeloma in patients who have received at least 1 prior therapy.1 3 7

Retreatment of multiple myeloma in patients who previously responded to bortezomib-based therapy and relapsed ≥6 months following therapy.1 29

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 for newly diagnosed multiple myeloma in transplant-eligible patients.10002 10003 10004 10005 10006 10007 10008 10012 10013 10014 10015 10016 10019 10020 10021 10022 10023 10024 10025 10026 10027 10028 10029

Use with dexamethasone10012 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients.10032 Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.10032

Use with thalidomide and dexamethasone10013 10014 10016 10027 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients;10033 however, use of a modified bortezomib-thalidomide-dexamethasone regimen using reduced bortezomib and thalidomide dosages10015 is not fully established because of unclear risk/benefit and/or inadequate experience.10033 Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.10033

Use with doxorubicin (or pegylated liposomal doxorubicin) and dexamethasone10023 10024 10025 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients;10034 however, in the absence of longer follow-up data, use of a modified bortezomib-pegylated liposomal doxorubicin-dexamethasone regimen using reduced bortezomib and pegylated liposomal doxorubicin dosages10026 is not fully established because of unclear risk/benefit and/or inadequate experience.10034 Consider performance status and preexisting conditions (e.g., peripheral neuropathy) when selecting a combination chemotherapy regimen.10034

Use with cyclophosphamide and dexamethasone10019 10021 10022 10028 10029 may be considered a reasonable choice (accepted, with possible conditions) as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients.10035 Consider cytogenetic features, performance status, preexisting conditions (e.g., peripheral neuropathy), and tolerability when selecting a combination chemotherapy regimen.10035

Mantle Cell Lymphoma

In combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for previously untreated mantle cell lymphoma.1 26

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

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

Dispensing and Administration Precautions

Administer only by IV or sub-Q injection (see Contraindications under Cautions); sub-Q injection may be considered in patients with preexisting peripheral neuropathy and those at high risk for developing peripheral neuropathy.1

When dispensing, label syringe holding the individual dose with sticker provided by the manufacturer indicating route of administration.1

IV Administration

Reconstitution

To reconstitute, add 3.5 mL of 0.9% sodium chloride injection to vial containing 3.5 mg of bortezomib to yield final concentration of 1 mg/mL.1

Administer within 8 hours after reconstitution.1 (See Storage under Stability.)

Rate of Administration

Administer by IV injection over 3–5 seconds.1

Sub-Q Administration

Administer by sub-Q injection in thigh or abdominal region; rotate injection sites.1

Give new injections ≥1 inch from previous injection site; do not give injections into areas where skin is tender, erythematous, bruised, or indurated.1

Reconstitution

To reconstitute, add 1.4 mL of 0.9% sodium chloride injection to vial containing 3.5 mg of bortezomib to yield final concentration of 2.5 mg/mL.1 If local injection site reactions occur, the manufacturer recommends reconstituting the drug to a final concentration of 1 mg/mL or considering IV administration.1

Administer within 8 hours after reconstitution.1 (See Storage under Stability.)

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

Use caution when calculating dose and respective volume of bortezomib 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 or Sub-Q

Cycles 1–4 (of the recommended nine 6-week cycles): Bortezomib 1.3 mg/m2 IV or sub-Q 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 or sub-Q 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 or Sub-Q

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 (excluding neuropathy)

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

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 or Sub-Q

Standard regimen: 1.3 mg/m2 IV or sub-Q 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 IV or sub-Q once weekly for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period (days 23–35).1

Retreatment following prior response to bortezomib therapy and disease progression ≥6 months following last therapy: Administer last tolerated dose of bortezomib IV or sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21) for up to 8 cycles.1 May be administered with or without dexamethasone.1

At least 72 hours should elapse between consecutive doses.1

Dosage Modification for Peripheral Neuropathy in Relapsed Multiple Myeloma
IV or Sub-Q

Adjust dose and/or frequency of administration if new or worsening peripheral neuropathy occurs.1 6 (See Table 2.)

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

Severity of Neuropathy and Manifestations

Comments

Grade 1 (asymptomatic, loss of deep tendon reflexes, paresthesia) without pain or loss of function

No dosage modification necessary

Grade 1 with pain

Reduce dose to 1 mg/m2

Grade 2 (moderate symptoms resulting in interference with instrumental activities of daily living [ADL])

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 (severe symptoms resulting in interference with self-care ADL)

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 Nonhematologic or Hematologic Effects in Relapsed Multiple Myeloma
IV or Sub-Q

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
IV

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 during cycles 1 and 2 and then on days 1–4 during cycles 3 and 4.10002 10012 Treatment cycles repeated every 21 days for 4 cycles.10002 10012

Bortezomib, Dexamethasone, and Thalidomide
IV

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 and thalidomide 200 mg orally daily (after initial dosage escalation during cycle 1 with 100 mg on days 1–14 followed by 200 mg orally daily thereafter).10013 Treatment cycles repeated every 21 days for 3 cycles.10013

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 and thalidomide 200 mg orally daily (after initial dosage escalation during cycle 1 with 50 mg orally on days 1–14 followed by 100 mg orally on days 15–28).10014 Treatment cycles repeated every 4 weeks for 6 cycles.10014

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 and thalidomide 100 mg orally daily.10016 10027 Treatment cycles repeated every 3 weeks for 4 cycles.10016 10027

Sub-Q

Bortezomib 1.3 mg/m2 sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11) along with dexamethasone 40 mg orally on days 1–4 and 9–12 and thalidomide 100 mg orally daily.10016 10027 Treatment cycles repeated every 3 weeks for 4 cycles.10016 10027

Bortezomib, Dexamethasone, and Doxorubicin (or Pegylated Liposomal Doxorubicin)
IV

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with doxorubicin hydrochloride 9 mg/m2 IV per day on days 1–4 and dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 of each 28-day cycle for 3 cycles.10023

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with pegylated liposomal doxorubicin hydrochloride 30 mg/m2 IV on day 4 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during cycle 1.10024 During cycles 2–6, same dosages of bortezomib and pegylated liposomal doxorubicin administered along with dexamethasone 20 mg orally daily.10024 Treatment cycles repeated every 3 weeks for a total of 6 cycles.10024

Bortezomib, Dexamethasone, and Cyclophosphamide
IV

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 and dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 of each 28-day cycle for 4 cycles.10019

Bortezomib 1.5 mg/m2 IV once weekly (days 1, 8, 15, and 22) along with cyclophosphamide 300 mg/m2 orally on days 1, 8, 15, and 22 of each 28-day cycle for 4 cycles, with dexamethasone 40 mg orally on days 1–4, 9–12, and 17–20 during cycles 1 and 2 and then once weekly during cycles 3 and 4.10021

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 300 mg/m2 IV on days 1 and 8 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 1–3) followed by bortezomib 1 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with thalidomide 100 mg orally daily and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles (cycles 4–6).10029

Bortezomib 1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 900 mg/m2 IV on day 1 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles.10028

Sub-Q

Bortezomib 1.3 mg/m2 sub-Q twice weekly for 2 weeks (days 1, 4, 8, and 11) along with cyclophosphamide 900 mg/m2 IV on day 1 and dexamethasone 40 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for 3 cycles.10028

Previously Untreated Mantle Cell Lymphoma
Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (VR-CAP regimen)
IV

1.3 mg/m2 IV twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12–21); rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin hydrochloride 50 mg/m2 IV on day 1; and prednisone 100 mg/m2 orally on days 1–5 of each 3-week cycle.1 26

If response is first observed at cycle 6, manufacturer recommends 2 additional cycles.1

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

Dosage Modification for Toxicity for VR-CAP Regimen
IV

Before administering cycles 2–6 of VR-CAP, platelet counts should be ≥100,000/mm3, ANC should be ≥1500/mm3, hemoglobin concentration should be ≥8 g/dL, and nonhematologic toxicities should have resolved to grade 1 or baseline.1

Table 3. Dosage Modification for VR-CAP Regimen in Previously Untreated Mantle Cell Lymphoma1

Toxicity

Dose Modification or Delay

If grade ≥3 neutropenia or platelet count ≤25,000/mm3 on a day when bortezomib is to be administered (other than on day 1)

Withhold bortezomib dose for up to 2 weeks until ANC ≥750/mm3 and platelet counts ≥25,000/mm3; may then reinitiate bortezomib with a reduction of one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2); if toxicity has not resolved, discontinue bortezomib therapy

Grade ≥3 nonhematologic toxicity (excluding neuropathy) on a day when bortezomib is to be administered (other than on day 1)

Withhold bortezomib until toxicity resolves to grade ≤2; may then reinitiate bortezomib with a reduction of one dose level (i.e., a dose of 1.3 mg/m2 reduced to 1 mg/m2; a dose of 1 mg/m2 reduced to 0.7 mg/m2)

Bortezomib-related neuropathic pain and/or peripheral neuropathy

See Table 4 under Dosage Modification for Peripheral Neuropathy in Relapsed Mantle Cell Lymphoma

Relapsed Mantle Cell Lymphoma
IV or Sub-Q

Standard regimen: 1.3 mg/m2 IV or sub-Q 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.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 Relapsed Mantle Cell Lymphoma
IV or Sub-Q

Adjust dose and/or frequency of administration if new or worsening peripheral neuropathy occurs.1 (See Table 4.)6

Table 4. Dosage Modification for Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy1

Severity of Neuropathy and Manifestations

Comments

Grade 1 (asymptomatic, loss of deep tendon reflexes, paresthesia) without pain or loss of function

No dosage modification necessary

Grade 1 with pain

Reduce dose to 1 mg/m2

Grade 2 (moderate symptoms resulting in interference with instrumental ADL)

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 (severe symptoms resulting in interference with self-care ADL)

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 Nonhematologic or Hematologic Effects in Relapsed Mantle Cell Lymphoma
IV or Sub-Q

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 1.3-mg/m2 dose to 1-mg/m2 dose; reduce 1-mg/m2 dose to 0.7-mg/m2 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 (except for local reactions) to bortezomib, boron, or mannitol.1 Anaphylactic reactions reported.1

  • Intrathecal administration.1 Fatal if administered intrathecally.1

Warnings/Precautions

Peripheral Neuropathy

Risk of severe (grade 3 or greater) 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 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

Incidence of peripheral neuropathy reportedly higher in patients with relapsed multiple myeloma receiving bortezomib by IV injection compared with those receiving the drug by sub-Q injection.1 Consider sub-Q administration in patients with preexisting peripheral neuropathy and those at high risk for developing peripheral neuropathy.1

Monitor patients for manifestations of neuropathy (e.g., burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, weakness).1 Adjust dose 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

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 Events including acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, and cardiogenic shock reported.1 Risk of death from cardiogenic shock, CHF, or cardiac arrest.1 Closely monitor patients with existing heart disease and patients with increased risk for heart disease.1

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

Pulmonary Effects

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; consider temporarily withholding bortezomib therapy pending 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, vomiting, loss of appetite, dyspepsia, and dysgeusia; 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 If severe adverse GI effects occur, temporarily interrupt bortezomib therapy.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 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

No evidence of cumulative thrombocytopenia or neutropenia with the treatment regimens evaluated for multiple myeloma or mantle cell lymphoma.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.) Administer supportive care (e.g., transfusions) according to published guidelines.1

Tumor Lysis Syndrome

Tumor lysis syndrome reported.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.1 16

The manufacturer recommends temporary interruption of bortezomib therapy for assessment of reversibility of adverse hepatic effects.1 Information on results of rechallenge in these patients is limited.1 (See Hepatic Impairment under Dosage and Administration.)

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

Herpes Virus Infection

Risk of reactivation of varicella zoster virus infection.1 In phase 3 study, antiviral prophylaxis appeared to reduce risk of reactivation in patients receiving VMP regimen.1 Consider antiviral prophylaxis in patients receiving bortezomib.1

Similar frequencies of herpes simplex virus infection reported with bortezomib and comparator therapies in clinical studies in multiple myeloma patients.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

Efficacy not established in pediatric patients with relapsed pre-B acute lymphoblastic leukemia (ALL).1 In pediatric and young adult patients, the addition of bortezomib to intensive reinduction chemotherapy did not alter complete remission rates at day 36 compared with a historical control.1 No new safety concerns identified.1

Clearance (normalized to body surface area [BSA]) similar to clearance in adults.1

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

Exposure may be increased in geriatric patients compared with younger adults.1 (See Geriatric Patients under Dosage and Administration and see Absorption: Special Populations, under Pharmacokinetics.)

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 see Absorption: Special Populations, under Pharmacokinetics.)

Renal Impairment

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

Common Adverse Effects

IV bortezomib in combination with melphalan and prednisone (VMP) in patients with previously untreated multiple myeloma: Thrombocytopenia,1 24 neutropenia,1 24 peripheral neuropathy,1 24 nausea,1 diarrhea,1 neuralgia,1 anemia,1 24 leukopenia,1 24 vomiting,1 fatigue,1 constipation,1 lymphopenia,1 24 anorexia,1 asthenia,1 pyrexia,1 paresthesia,1 herpes zoster,1 rash,1 abdominal pain (upper quadrant),1 insomnia.1

IV bortezomib monotherapy in patients with relapsed multiple myeloma: Nausea,1 diarrhea,1 fatigue,1 peripheral neuropathy,1 thrombocytopenia,1 constipation,1 vomiting,1 anorexia,1 pyrexia,1 paresthesia,1 anemia,1 headache,1 neutropenia,1 rash,1 decreased appetite,1 dyspnea,1 abdominal pain,1 dizziness (excluding vertigo),1 weakness.1

IV bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) in patients with previously untreated mantle cell lymphoma: Neutropenia,1 26 thrombocytopenia,1 26 leukopenia,1 26 anemia,1 26 peripheral neuropathy,1 26 lymphopenia,1 26 diarrhea,1 26 nausea,1 26 pyrexia,1 26 cough,26 constipation,1 26 fatigue,1 26 febrile neutropenia,1 26 loss of appetite,1 26 peripheral edema,26 alopecia,1 asthenia,1 26 pneumonia,26 neuralgia,1 vomiting.1

IV bortezomib monotherapy in patients with relapsed mantle cell lymphoma: Peripheral neuropathy,1 fatigue,1 diarrhea,1 nausea,1 constipation,1 rash,1 vomiting,1 dizziness (excluding vertigo),1 thrombocytopenia,1 anorexia,1 anemia,1 weakness,1 headache,1 pyrexia.1

Sub-Q bortezomib monotherapy in patients with relapsed multiple myeloma: Peripheral neuropathy,1 27 thrombocytopenia,1 27 neuralgia,1 27 neutropenia,1 27 anemia,1 27 diarrhea,1 27 leukopenia,1 27 nausea,1 27 pyrexia,1 27 vomiting,27 asthenia,27 weight loss,27 constipation,27 fatigue.27

Interactions for Velcade

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

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased systemic exposure of bortezomib.1 Closely monitor patients for potential toxicities and consider reducing bortezomib dosage.1

Potent CYP3A4 inducers: Possible decreased systemic exposure and reduced efficacy of bortezomib.1 Avoid concomitant use.1

Weak CYP3A4 inducers: Pharmacokinetic interaction not observed to date.1

Potent CYP2C19 inhibitors: Pharmacokinetic interaction not observed to date.1

Specific Drugs

Drug

Interaction

Comment

Antidiabetic agents, oral

Possible hypoglycemia or hyperglycemia1 5

Monitor blood glucose concentrations carefully and adjust dosage of antidiabetic agent as necessary1

Dexamethasone

Concomitant administration did not affect bortezomib exposure1

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 concomitantly and consider reducing bortezomib dosage1

Melphalan

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

Unlikely to be clinically relevant1

Rifampin

Expected to decrease bortezomib AUC by at least 45%1

Avoid concomitant use1

St. John’s wort (Hypericum perforatum)

Possible decreased bortezomib AUC1

Avoid concomitant use1

Velcade Pharmacokinetics

Absorption

Bioavailability

Systemic exposure of bortezomib was comparable following repeated IV or sub-Q administration.1 27 31

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 peak 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 CYP1A2, 2C19, and 3A4 to inactive metabolites; metabolism by CYP2C9 and 2D6 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

Special Populations

Clearance (normalized to BSA) in pediatric patients similar to clearance in adults.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, light-headedness, fainting spells, or muscle cramps develop.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

  • Risk of RPLS.1 Importance of reporting any possible manifestations of RPLS (e.g., seizure, persistent headache, reduced eyesight, blurred vision, confusion, lethargy, inability to think, difficulty walking).1

  • Risk of cardiac effects.1 Importance of informing clinician if swelling (of the feet, ankles, or legs) or other cardiac-related problems occur.1

  • Risk of pulmonary effects.1 Importance of informing clinician if shortness of breath, cough, or other pulmonary problems occur.1

  • Risk of hepatotoxicity.1 Importance of reporting any possible manifestations of hepatotoxicity (e.g., jaundice, abdominal pain [particularly in the right upper quadrant]).1

  • Importance of informing clinician if rash, severe injection site reactions, or dermatologic pain occurs.1

  • Risk of reactivation of latent varicella zoster virus infection.1 Importance of discussing with clinician whether to initiate antiviral prophylaxis.1

  • Importance of informing clinician if increase in BP, bleeding, fever, constipation, or loss of appetite occurs.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., St. John’s wort), 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Bortezomib

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV or subcutaneous use

3.5 mg

Velcade

Millennium

AHFS DI Essentials™. © Copyright 2018, Selected Revisions August 6, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, 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; 2015 Sept.

2. Food and Drug Administration, Center for Drug Evaluation and Research. Drug information: questions and answers on Velcade. From FDA website. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm106502.htm

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. http://www.mlnm.com/media/index.asp

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. http://www.ncbi.nlm.nih.gov/pubmed/12826635?dopt=AbstractPlus

5. Anon. Bortezomomib (Velcade) for multiple myeloma. Med Lett Drugs Ther. 2003; 45:57-58. http://www.ncbi.nlm.nih.gov/pubmed/12865865?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15958804?dopt=AbstractPlus

9. Dispenzieri A. Bortezomib for myeloma—much ado about something. N Engl J Med. 2005; 352:2546-8. http://www.ncbi.nlm.nih.gov/pubmed/15958811?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15461622?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15690325?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15613697?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15613699?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15772697?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15738379?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/15953004?dopt=AbstractPlus

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

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. http://www.ncbi.nlm.nih.gov/pubmed/18753647?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/17001068?dopt=AbstractPlus

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. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm198424.htm

24. Mateos MV, Richardson PG, Schlag R et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010; 28:2259-66. http://www.ncbi.nlm.nih.gov/pubmed/20368561?dopt=AbstractPlus

25. Dimopoulos MA, Richardson PG, Schlag R et al. VMP (Bortezomib, Melphalan, and Prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol. 2009; 27:6086-93. http://www.ncbi.nlm.nih.gov/pubmed/19858394?dopt=AbstractPlus

26. Robak T, Huang H, Jin J et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015; 372:944-53. http://www.ncbi.nlm.nih.gov/pubmed/25738670?dopt=AbstractPlus

27. Moreau P, Pylypenko H, Grosicki S et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011; 12:431-40. http://www.ncbi.nlm.nih.gov/pubmed/21507715?dopt=AbstractPlus

28. Arnulf B, Pylypenko H, Grosicki S et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica. 2012; 97:1925-8. http://www.ncbi.nlm.nih.gov/pubmed/22689676?dopt=AbstractPlus

29. Petrucci MT, Giraldo P, Corradini P et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013; 160:649-59. http://www.ncbi.nlm.nih.gov/pubmed/23293914?dopt=AbstractPlus

30. San Miguel JF, Schlag R, Khuageva NK et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol. 2013; 31:448-55. http://www.ncbi.nlm.nih.gov/pubmed/23233713?dopt=AbstractPlus

31. Moreau P, Karamanesht II, Domnikova N et al. Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma. Clin Pharmacokinet. 2012; 51:823-9. http://www.ncbi.nlm.nih.gov/pubmed/23018466?dopt=AbstractPlus

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).

10012. Harousseau JL, Attal M, Avet-Loiseau H et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010; 28:4621-9. http://www.ncbi.nlm.nih.gov/pubmed/20823406?dopt=AbstractPlus

10013. Cavo M, Tacchetti P, Patriarca F et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010; 376:2075-85. http://www.ncbi.nlm.nih.gov/pubmed/21146205?dopt=AbstractPlus

10014. Rosiñol L, Oriol A, Teruel AI et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012; 120:1589-96. http://www.ncbi.nlm.nih.gov/pubmed/22791289?dopt=AbstractPlus

10015. Moreau P, Avet-Loiseau H, Facon T et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011; 118:5752-8; quiz 5982. http://www.ncbi.nlm.nih.gov/pubmed/21849487?dopt=AbstractPlus

10016. Ludwig H, Viterbo L, Greil R et al. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol. 2013; 31:247-55. http://www.ncbi.nlm.nih.gov/pubmed/23091109?dopt=AbstractPlus

10017. GEM05 for patients with multiple myeloma under 65 years (GEM05MENOS65). From ClinicalTrials.gov registry. Accessed 2016 Nov 18.

10019. Reeder CB, Reece DE, Kukreti V et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009; 23:1337-41. http://www.ncbi.nlm.nih.gov/pubmed/19225538?dopt=AbstractPlus

10020. Ludwig H, Greil R, Masszi T et al. Bortezomib, thalidomide and dexamethasone, with or without cyclophosphamide, for patients with previously untreated multiple myeloma: 5-year follow-up. Br J Haematol. 2015; 171:344-54. http://www.ncbi.nlm.nih.gov/pubmed/26153365?dopt=AbstractPlus

10021. Reeder CB, Reece DE, Kukreti V et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010; 115:3416-7. http://www.ncbi.nlm.nih.gov/pubmed/20413666?dopt=AbstractPlus

10022. Reeder CB, Reece DE, Kukreti V et al. Long-term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br J Haematol. 2014; 167:563-5. http://www.ncbi.nlm.nih.gov/pubmed/24974945?dopt=AbstractPlus

10023. Sonneveld P, Schmidt-Wolf IG, van der Holt B et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012; 30:2946-55. http://www.ncbi.nlm.nih.gov/pubmed/22802322?dopt=AbstractPlus

10024. Jakubowiak AJ, Kendall T, Al-Zoubi A et al. Phase II trial of combination therapy with bortezomib, pegylated liposomal doxorubicin, and dexamethasone in patients with newly diagnosed myeloma. J Clin Oncol. 2009; 27:5015-22. http://www.ncbi.nlm.nih.gov/pubmed/19738129?dopt=AbstractPlus

10025. Dytfeld D, Griffith KA, Friedman J et al. Superior overall survival of patients with myeloma achieving very good partial response or better to initial treatment with bortezomib, pegylated liposomal doxorubicin, and dexamethasone, predicted after two cycles by a free light chain- and M-protein-based model: extended follow-up of a phase II trial. Leuk Lymphoma. 2011; 52:1271-80. http://www.ncbi.nlm.nih.gov/pubmed/21699382?dopt=AbstractPlus

10026. Berenson JR, Yellin O, Chen CS et al. A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. Br J Haematol. 2011; 155:580-7. http://www.ncbi.nlm.nih.gov/pubmed/21950583?dopt=AbstractPlus

10027. Moreau P, Hulin C, Macro M et al. VTD is superior to VCD prior to intensive therapy in multiple myeloma: results of the prospective IFM2013-04 trial. Blood. 2016; 127:2569-74. http://www.ncbi.nlm.nih.gov/pubmed/27002117?dopt=AbstractPlus

10028. Mai EK, Bertsch U, Dürig J et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia. 2015; 29:1721-9. http://www.ncbi.nlm.nih.gov/pubmed/25787915?dopt=AbstractPlus

10029. Bensinger WI, Jagannath S, Vescio R et al. Phase 2 study of two sequential three-drug combinations containing bortezomib, cyclophosphamide and dexamethasone, followed by bortezomib, thalidomide and dexamethasone as frontline therapy for multiple myeloma. Br J Haematol. 2010; 148:562-8. http://www.ncbi.nlm.nih.gov/pubmed/19919652?dopt=AbstractPlus

10030. Merz M, Salwender H, Haenel M et al. Subcutaneous versus intravenous bortezomib in two different induction therapies for newly diagnosed multiple myeloma: an interim analysis from the prospective GMMG-MM5 trial. Haematologica. 2015; 100:964-9. http://www.ncbi.nlm.nih.gov/pubmed/25840597?dopt=AbstractPlus

10031. Lacy MQ, Gertz MA, Dispenzieri A et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc. 2007; 82:1179-84. http://www.ncbi.nlm.nih.gov/pubmed/17908524?dopt=AbstractPlus

10032. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10033. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with thalidomide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10034. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with doxorubicin and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

10035. AHFS final determination of medical acceptance: Off-label use of bortezomib in combination with cyclophosphamide and dexamethasone as induction therapy for newly diagnosed multiple myeloma in transplant-eligible patients. Published 17 May 2018.

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