VELCADE® (bortezomib) was studied in a non-inferiority, phase 3, randomized (2:1), open-label trial that compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed multiple myeloma. Patients who did not obtain a CR after 4 cycles were allowed oral dexamethasone. The primary endpoint was ORR at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival, and safety.
Efficacy
The study met its primary non-inferiority objective that single-agent subcutaneous VELCADE (bortezomib) retained at least 60% of the ORR after 4 cycles relative to single-agent IV VELCADE
Other secondary endpoints in relapsed multiple myeloma: Subcutaneous and IV
| 11.8-Month Median Follow-up2 | Subcutaneous (n=148) | IV (n=74) |
| 1-Year Overall Survival, % | 72.6 | 76.7 |
| Median PFS, mo | 10.2 | 8.0 |
| Median TTP, mo | 10.4 | 9.4 |
Safety and Tolerability
Subcutaneous VELCADE (bortezomib) has a safety profile similar to IV but a different incidence of peripheral neuropathy
- Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment
- Treatment with VELCADE may cause peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. 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 during therapy with VELCADE may require a decrease in the dose, a less-dose-intense schedule, or discontinuation. Please see dose modification guidelines for peripheral neuropathy
Adverse Reactions: Subcutaneous and IV
| Adverse Reactions: Subcutaneous and IV | ||||||
| Most Commonly Reported (≥20%) Adverse Reactions | Subcutaneous VELCADE (bortezomib) (n=147), % |
IV VELCADE (n=74), % | ||||
| All Events | Grade 3 Events | Grade ≥4 Events | All Events | Grade 3 Events | Grade ≥4 Events | |
| Peripheral Neuropathies NEC | 37 | 5 | 1 | 50 | 14 | 1 |
| Thrombocytopenia | 30 | 5 | 3 | 34 | 9 | 7 |
| Neutropenia | 23 | 10 | 3 | 27 | 14 | 4 |
| Neuralgia | 23 | 3 | 0 | 23 | 9 | 0 |
| Anemia | 19 | 5 | 0 | 23 | 4 | 0 |
| Diarrhea | 19 | 1 | 0 | 28 | 4 | 0 |
| Leukopenia | 18 | 5 | 0 | 20 | 5 | 1 |
- In general, safety data were similar for the subcutaneous and IV treatment groups. Differences were observed in grade ≥3 adverse reactions (ARs) (≥5% difference) for:
- Neutropenia (13% subcutaneous vs 18% IV)
- Neuralgia (3% subcutaneous vs 9% IV)
- Peripheral neuropathies, NEC (6% subcutaneous vs 15% IV)
- Thrombocytopenia (8% subcutaneous vs 16% IV)
- The incidence of serious adverse reactions (ARs) was similar in the subcutaneous and IV treatment groups (20% vs 19%, respectively). The most commonly reported serious ARs in the subcutaneous treatment group were pneumonia and pyrexia (2% each); in the IV treatment group, pneumonia, diarrhea, and peripheral sensory neuropathy (3% each)
- Dose reductions due to adverse reactions (ARs) occurred in 31% of patients in the subcutaneous group vs 43% in the IV group
- The most common ARs leading to a dose reduction included:
- Peripheral sensory neuropathy (17% subcutaneous vs 31% IV)
- Neuralgia (11% subcutaneous vs 19% IV)
- In the subcutaneous vs IV trial, discontinuations due to adverse reactions were 18% and 23%, respectively
- Treatment-related deaths were similar between the subcutaneous and IV treatment groups (1% each)
Additional Safety Considerations
- Injection site reactions with subcutaneous administration: In the clinical trial, the most common reaction was redness, occurring in 57% of patients.1 Injection site reactions were reported in 6% of patients as an adverse reaction, with 1% being serious and leading to dose modification or discontinuation. All events resolved in a median of 6 days
- Antiviral prophylaxis should be considered for patients treated with VELCADE (bortezomib). Herpes zoster reactivation was more common in patients treated with VELCADE
Reconstitution and Administration
A vial of VELCADE (bortezomib) can be used for either subcutaneous or IV administration, but reconstitution is different.
- The volume of 0.9% sodium chloride solution used to reconstitute VELCADE (bortezomib) for subcutaneous administration is different from the volume for IV administration
- The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL)
- Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered
- VELCADE contains no antimicrobial preservative
- Reconstituted VELCADE should be administered within 8 hours of preparation
Administration of Subcutaneous VELCADE
- VELCADE (bortezomib) is for subcutaneous or intravenous use only. VELCADE should not be administered by any other route
- Before VELCADE administration, visually inspect the solution for particulate matter and discoloration. If any discoloration or particulate matter is observed, do not use the reconstituted product. File a product complaint by calling 1-866-VELCADE
- Verify that the volume in the syringe is correct (refer to figure below)
Volume calculation for subcutaneous administration
The amount (in mg) of VELCADE to be administered is based on body surface area (BSA) calculations using a standard nomogram or according to institutional policy.
VELCADE (bortezomib) can be administered subcutaneously in all indications
- Before VELCADE administration, visually inspect the solution for particulate matter and discoloration. If any discoloration or particulate matter is observed, do not use the reconstituted product. File a product complaint by calling 1-866-VELCADE
- Verify that the dose in the syringe is correct
- VELCADE is for subcutaneous or IV use only. VELCADE should not be administered by any other route
- Administer VELCADE (bortezomib) (1.3 mg/m2) as a subcutaneous injection
- Use the abdomen or thighs as sites for subcutaneous injections
- Rotate injection sites
- Administer new injections at least 1 inch from an old site and never into areas where the skin is tender, bruised, erythematous, or indurated
Click here to download an editable pdf to track injection sites for your patients receiving subcutaneous VELCADE
- Please see Administration Precautions in the full Prescribing Information
†SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial that compared the efficacy and safety of VELCADE (bortezomib) administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed multiple myeloma. Patients who did not obtain a CR after 4 cycles were allowed oral dexamethasone. The primary endpoint was ORR at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival, and safety.
VELCADE (bortezomib) was studied in a non-inferiority, phase 3, randomized (2:1), open-label trial that compared the efficacy and safety of VELCADE administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed multiple myeloma. Patients who did not obtain a CR after 4 cycles were allowed oral dexamethasone. The primary endpoint was ORR at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival, and safety.
Subcutaneous vs IV Trial Design
Indications and Important Safety Information for VELCADE® (bortezomib)
INDICATIONS: VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.
WARNINGS AND PRECAUTIONS
VELCADE (bortezomib) is for subcutaneous or IV administration only. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.Peripheral neuropathy, including severe cases, may occur. Patients should be monitored for symptoms and managed with dose modification or discontinuation. Patients with preexisting symptoms may experience worsening peripheral neuropathy (includingâ„grade 3). Starting with VELCADE subcutaneously may be considered for patients who either have preexisting or are at high risk for peripheral neuropathy.
Hypotension: Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated.
Cardiac toxicity, including acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction, has occurred. Isolated cases of QT-interval prolongation have been reported. Patients with risk factors for, or existing, heart disease should be closely monitored.
Pulmonary toxicity: Acute respiratory distress syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology have occurred (sometimes fatal). Pulmonary hypertension, in the absence of left heart failure or significant pulmonary disease, has been reported. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt and comprehensive diagnostic evaluation is conducted.
Posterior reversible encephalopathy syndrome has occurred. Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected.
Gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting, has occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement. Interrupt VELCADE (bortezomib) for severe symptoms.
Thrombocytopenia/Neutropenia: Manage with dose and/or schedule modifications. Complete blood counts should be monitored frequently during treatment. There have been reports of gastrointestinal and intracerebral hemorrhage. Transfusions may be considered.
Tumor lysis syndrome: Closely monitor patients with high tumor burden and take appropriate precautions.
Hepatic toxicity: Monitor hepatic enzymes during treatment. Upon occurrence, interrupt therapy with VELCADE to assess reversibility.
Embryo-fetal risk: Women should avoid breast-feeding or becoming pregnant while on VELCADE.
Patients with diabetes may require close monitoring and adjustment of the antidiabetic medications.
DRUG INTERACTIONS: Closely monitor patients receiving VELCADE (bortezomib) in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.
ADVERSE REACTIONS
Previously untreated multiple myeloma (MM): In the phase 3 study of VELCADE administered intravenously with melphalan and prednisone (MP) vs MP alone, the most commonly reported adverse reactions (ARs) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), and leukopenia (32% vs 28%).
Relapsed MM and mantle cell lymphoma: In the integrated analysis of 1163 patients in phase 2 and 3 studies of VELCADE (bortezomib) administered intravenously, the most commonly reported ARs were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathy NEC (38%), and thrombocytopenia (32%). A total of 26% of patients experienced serious ARs. The most commonly reported serious ARs included diarrhea, vomiting, and pyrexia (each 3%); nausea, dehydration, and thrombocytopenia (each 2%); and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (each 1%).
Relapsed MM subcutaneous vs IV: In the phase 3 study of VELCADE administered subcutaneously vs intravenously in relapsed MM, safety data were similar between the two treatment groups. The most commonly reported ARs in the subcutaneous vs IV treatment groups were peripheral neuropathy (37% vs 50%) and thrombocytopenia (30% vs 34%). The incidence of serious ARs was similar in the subcutaneous treatment group (20%) and the IV treatment group (19%). The most commonly reported serious ARs were pneumonia and pyrexia (each 2%) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (each 3%) in the IV treatment group.
- Please see full Prescribing Information available at www.VELCADE.com
View full U.S. Prescribing Information
*Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.1
†SUBCUTANEOUS VS IV TRIAL: a non-inferiority, phase 3, randomized (2:1), open-label trial that compared the efficacy and safety of VELCADE (bortezomib) administered subcutaneously (n=148) with VELCADE administered intravenously (n=74) in patients with relapsed multiple myeloma. Patients who did not obtain a CR after 4 cycles were allowed oral dexamethasone. The primary endpoint was ORR at 4 cycles. Secondary endpoints included response rate at 8 cycles, median TTP and PFS (months), 1-year overall survival, and safety.
‡82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone.
References: 1. 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(5):431-440. 2. Data on file 46, Millennium Pharmaceuticals, Inc.
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