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Why do you consider VELCADE (bortezomib) for the treatment of previously untreated multiple myeloma?

Efficacy and safety experience with subcutaneous administration of VELCADE

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Aids in the identification of peripheral neuropathy (PN) symptoms

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A well-characterized safety profile in previously untreated multiple myeloma

The safety profile of VELCADE® (bortezomib)+MP is consistent with the known safety profiles of both VELCADE and MP.

Safety Profile in Previously Untreated Multiple Myeloma

  • Results achieved with VELCADE (bortezomib) twice-weekly followed by once-weekly administration
  • The incidence of new-onset ARs was defined as the number of patients who remained in the trial having a new onset of an event within weeks 1-24 and weeks 25-541
  • 36% of patients treated with VELCADE had 1 dose reduction during the study and 18% required 2 dose reductions2
  • A total of 25% of patients in the treatment group receiving VELCADE+MP experienced serious adverse reactions (ARs) vs 18% in the treatment group receiving MP. The most commonly reported serious ARs with VELCADE+MP vs MP alone included pneumonia (5% vs 4%), diarrhea (4% vs 0%), thrombocytopenia (3% vs 1%), vomiting (3% vs <1%), nausea (2% vs <1%), anemia (2% vs 2%), herpes zoster (2% vs <1%) and dehydration (2% vs <1%)3
  • Discontinuations due to adverse reactions were 11% for VELCADE combination and 10% for MP alone4
  • Treatment-related deaths were similar between VELCADE combination and MP treatment groups (1% and 2%, respectively)5

Early Detection and Management of PN May Help Patients Stay on VELCADE (bortezomib)

Characteristics of Peripheral Neuropathy in VISTA Trial

In multiple myeloma, VELCADE (bortezomib)-associated peripheral neuropathy was reversible or completely resolved in the majority of patients with dose modification or discontinuation.6

  • In the VISTA trial, 47% of patients experienced treatment-emergent peripheral neuropathy (PN)6
    • Of the patients who experienced PN, 91% experienced onset by week 246
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  • In the VISTA trial, 11% of patients discontinued treatment with VELCADE (bortezomib) due to peripheral neuropathy (PN) and continued melphalan+prednisone (MP); 3% of patients discontinued treatment with VELCADE+MP due to PN6
  • PN, including severe cases, may occur—manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment
  • Treatment with VELCADE may cause PN that is predominantly sensory. However, cases of severe sensory and motor PN have been reported. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness

Dose modification guidelines available for peripheral neuropathy, moderate to severe hepatic impairment, and other hematologic and nonhematologic toxicities

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Neurotoxicity Assessment Tool
Aids in the identification of peripheral neuropathy symptoms

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Additional Safety Considerations for VELCADE (bortezomib)

  • Antiviral prophylaxis should be considered for patients treated with VELCADE (bortezomib). Herpes zoster reactivation was more common in patients treated with VELCADE
  • Thrombocytopenia and neutropenia were predictable, transient, and cyclical
    • Complete blood counts should be monitored regularly throughout treatment
  • Low incidence of thromboembolic events with VELCADE combination3
    • DVT 1%
    • Pulmonary embolism <1%
  • Incidence of febrile neutropenia with VELCADE+MP was 2%8

Next: Trial Design

Indications and Important Safety Information for VELCADE® (bortezomib)

  • INDICATIONS: VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma and patients with mantle cell lymphoma.

  • 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. Fatal events have occurred with intrathecal administration of VELCADE.

  • 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 (including ≥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. Support with transfusions and supportive care, according to published guidelines.

    • 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 subcutaneous vs IV: In the phase 3 study of VELCADE (bortezomib) 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.

    • Previously untreated mantle cell lymphoma (MCL): In a phase 3 study of VELCADE administered intravenously with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) vs vincristine, rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), the most commonly reported ARs were neutropenia (87% vs 71%), thrombocytopenia (72% vs 17%), leukopenia (48% vs 36%), anemia (44% vs 29%), lymphopenia (28% vs 12%), peripheral neuropathy (30% vs 27%), diarrhea (25% vs 5%), nausea (23% vs 12%), and pyrexia (20% vs 10%).

    • Relapsed MM and MCL: In the integrated analysis of 1163 patients in phase 2 and 3 studies of VELCADE 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%).

  • Please see full Prescribing Information available at www.VELCADE.com

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*VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with melphalan+prednisone (MP) vs MP in previously untreated multiple myeloma. After progressive disease was established, all patients were eligible to receive subsequent therapies.7 The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted, and patients receiving MP were offered VELCADE in addition. Updated analyses were performed.
Based on a total plan of nine 6-week cycles.
A cumulative VELCADE (bortezomib) dose of approximately 45 mg/m2 is equivalent to approximately four 6-week cycles of VELCADE+MP.6
§Improvement by at least 1 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade.
||Return to PN baseline in those people with preexisting grade 1 PN and a complete absence of PN in all other patients.

References: 1. Data on file 60, Millennium Pharmaceuticals, Inc. 2. Data on file 61, Millennium Pharmaceuticals, Inc. 3. Data on file 48, Millennium Pharmaceuticals, Inc. 4. Data on file 53, Millennium Pharmaceuticals, Inc. 5. San Miguel JF, Schlag R, Khuageva NK, et al. VISTA Trial Investigators. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917. 6. Dimopoulos MA, Mateos M-V, Richardson PG, et al. Risk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone in newly diagnosed patients with multiple myeloma: subanalysis of the phase 3 VISTA study. Eur J Haematol. 2011;86(1):23-31. 7. Mateos M-V, 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(13):2259-2266. 8. Data on file 49, Millennium Pharmaceuticals, Inc.

Important Safety Information for VELCADE® (bortezomib)