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April

Bortezomib (Velcade) Management for Multiple Myeloma and Mantle Cell Lymphoma

Written By: Joshua Nubla, PharmD, NCODA
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The purpose of this PQI is to discuss the option of using bortezomib for multiple myeloma (MM) and mantle cell lymphoma (MCL) patients.

Background:

Bortezomib is a reversible proteasome inhibitor of the chymotrypsin-like activity of the 26S proteasome and is approved for treatment of adult patients with multiple myeloma (MM) or mantle cell lymphoma (MCL). In a randomized, open-label study in patients with previously untreated MM, patients who received bortezomib, melphalan, and prednisone (Vc-MP) had a median time to progression of 20.7 months versus 15 months with melphalan and prednisone (MP) (HR=0.54); at a median follow-up of 60.1 months, the median overall survival (OS) was 56.4 months versus 43.1 months (HR 0.695). The bortezomib arm had complete and partial response rates of 30% and 40% respectively whereas the MP arm reported 4% and 30% complete and partial response rates.2,3 For newly diagnosed MCL, a phase 3, randomized, open-label study reported a median PFS of 25 months in the VcR-CAP regimen arm (bortezomib with rituximab, cyclophosphamide, doxorubicin, and prednisone) vs 14 months in the R-CHOP arm (HR=0.63); the median OS was 91 months versus 56 months at a median follow-up of 78.5 months (HR=0.66).4 In an integrated safety analysis of single agent bortezomib in 1163 patients with relapsed MM or relapsed MCL, the most commonly reported (>20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of ³ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

PQI Process:

Upon order of bortezomib:

  • Verify dosing of bortezomib is 1.3 mg/m2 with a concentration of 1 mg/mL intravenously or at a concentration of 2.5 mg/mL subcutaneously
    • Bortezomib is for intravenous or subcutaneous use only
    • When administered intravenously, administer as a 3 to 5 second bolus intravenous injection
    • Retreatment may be considered for patients with MM who had previously responded to treatment with bortezomib and who have relapsed at least six months after completing prior bortezomib treatment. Treatment may be started at the last tolerated dose
  • Bortezomib is available in single-dose vials containing 3.5 mg of lyophilized powder for reconstitution and withdrawal of the appropriate individual patient dose
  • Preparation: Bortezomib should only be reconstituted with 9% sodium chloride and should be a clear/colorless solution
Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration1
Route of AdministrationBortezomib (mg/vial)Diluent (0.9% Sodium Chloride)Final Bortezomib Concentration (mg/mL)
Intravenous3.5 mg3.5 mL1 mg/mL
Subcutaneous3.5 mg1.4 mL2.5 mg/mL

 

  • Dose Adjustment
    • No starting dosage adjustment of bortezomib is recommended for patients with mild hepatic impairment (tbili ≤1x ULN and AST > ULN, or tbili >1 to 1.5x ULN and any AST)
    • Consider reducing the starting dose in patients with moderate (tbili >1.5 to 3x ULN and any AST) or severe (tbili >3x ULN and any AST) hepatic impairment to 0.7 mg/m2 in the first cycle
      • Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability
    • No starting dose adjustment of bortezomib for patients with renal impairment
      • In patients requiring dialysis, bortezomib should be given after dialysis procedure
  • For Previously Untreated MM, bortezomib is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in Table 1
  • Prior to initiating any cycle of therapy with bortezomib in combination with melphalan and prednisone:
    • Platelet count should be at least 70 x 109/L and absolute neutrophil count (ANC) ³ 1 x 109/L
    • Nonhematological toxicities should have resolved to Grade 1 or baseline
    • If any of these requirements are not met, review prescribing information for dose modifications
Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma1
Twice Weekly Bortezomib (Cycles 1 to 4)
Week123456
Bortezomib

(1.3 mg/m2)

Day

1

Day

4

Day

8

Day

11

Rest

period

Day

22

Day

25

Day

29

Day

32

Rest

period

Melphalan (9 mg/m2)

Prednisone (60 mg/m2)

Day

1

Day

2

Day

3

Day

4

Rest

period

Rest

period

Once Weekly Bortezomib (Cycles 5 to 9 when used in combination with Melphalan and Prednisone)
Week123456
Bortezomib

(1.3 mg/m2)

Day

1

Day

8

Rest

period

Day

22

Day

29

Rest

period

Melphalan (9 mg/m2)

Prednisone (60 mg/m2)

Day

1

Day

2

Day

3

Day

4

Rest

period

Rest

period

  • For previously untreated MCL, bortezomib is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6, three week treatment cycles as shown in Table 2
    • Bortezomib is administered first followed by rituximab
    • If response first documented at cycle 6, two additional VcR-CAP cycles are recommended
    • At least 72 hours should elapse between consecutive doses of bortezomib
  • Prior to the first day of each cycle (other than Cycle 1):
    • Platelet count should be at least 100 x 109/L and ANC should be at least 1.5 x 109/L
    • Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L)
    • Nonhematologic toxicity should have recovered to Grade 1 or baseline
    • If any of these requirements are not met, review prescribing information for dose modifications
    • Hold at the onset of Grade 3 toxicities, excluding neuropathy managed without holding
Table 2: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma1
Twice Weekly Bortezomib (6, Three-Week Cycles)*
Week123
Bortezomib (1.3 mg/m2)Day 1Day 4Day 8Day 11Rest period
Rituximab (375 mg/m2)

Cyclophosphamide (750 mg/m2)

Doxorubicin (50 mg/m2)

Day 1 

 

 

 

Rest period
Prednisone (100 mg/m2)Day 1Day 2Day 3Day 4Day 5Rest period

*Dosing may continue for two more cycles (8 cycles total) if response is seen at cycle 6

  • Administration
    • When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site
    • If local injection site reactions occur following subcutaneous administration, a less concentrated solution (1 mg/mL) may be administered subcutaneously. Intravenous route can be considered

Patient Centered Activities:

  • Patient Education
    • Counsel patient on common side effects including peripheral neuropathy, headache, diarrhea, constipation, nausea/vomiting, and appropriate management of side effects
      • See Chemotherapy Induced Peripheral Neuropathy PQI
      • See Chemotherapy Induced Nausea and Vomiting PQI
      • See Chemotherapy, Oncolytic, Antiemetic Induced Constipation PQI
      • See Oncolytic Induced Diarrhea PQI
    • Velcade Reimbursement Assistance Program (VRAP)5
      • Takeda Oncology Here2Assist
      • View online at www.Here2Assist.com or by calling 1-844-817-6468, Option 2
      • Provide Velcade starter kit

References:

  1. Velcade (bortezomib) [prescribing information]. Cambridge, MA: Millennium Pharmaceuticals, Inc.; 2019.
  2. San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. N Engl J Med 2008; 359:906-917.
  3. 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(4):448-55.
  4. Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. The Lancet. Oncology. 2018;19(11):1449–1458.
  5. “VELCADE Reimbursement Assistance Program (VRAP)” https://www.velcade.com/paying-for-treatment.
Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional.  This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented.  NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.
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