Bortezomib and Dexamethasone (BD) Regimen for Multiple Myeloma

Abstract

The complexity of cancer chemotherapy requires that pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparing, dispensing, and administering antineoplastic therapy, and to the agents, commercially available and investigational, used to treat malignant diseases.

Regimen Name : Bortezomib and dexamethasone (BD)

Origin of Name : The BD regimen is named for the medications it contains: bortezomib and dexamethasone.

Indication(s)

The bortezomib and dexamethasone (BD) regimen has been used as initial therapy for multiple myeloma^1-6,11 and relapsed or refractory multiple myeloma.^7-10,12-13 BD is recommended as a treatment option for primary induction therapy for autologous peripheral stem cell transplants, or salvage therapy for multiple myeloma.¹⁴

Drug Preparation

Bortezomib 1.

Follow institutional policies for preparation of hazardous medications when preparing bortezomib.

Bortezomib is available as a powder for injection.

Reconstitute with 0.9% sodium chloride injection to a concentration of 1 mg/mL.

Dexamethasone 1.

No special dispensing precautions are required.

Dexamethasone is available in 0.25, 0.5, 0.75, 1, 1.5, 2, 4, and 6 mg tablets, and as a 0.5 mg per 5 mL and 1 mg/mL oral solution.

Drug Administration

Bortezomib is administered as a rapid IV push over 3 to 5 seconds.

Dexamethasone 1.

Dexamethasone is usually given orally as a single daily dose.

To avoid gastric irritation, the drug should be taken with food or after a meal.

Supportive Care

Acute Emesis Prophylaxis: The BD regimen is predicted to cause acute emesis in 10% to 30% of patients.^15–17 The studies reviewed reported grade 1 or 2 nausea or vomiting in 1% to 12% of patients.^1,4,6,8 Harrousseau et al reported 2% each grade 3 and grade 4 nausea or vomiting.¹ Jagannath et al reported nausea (all grades) in 13% of patients receiving 1 mg/m² and 21% of patients receiving 1.3 mg/m² bortezomib respectively.⁹ Suvannasankha et al reported gastrointestinal (GI) toxicity (all grades) in 3% of patients.¹² Yuan et al reported nausea and vomiting (all grades) in 75% of patients.¹³

Prophylactic antiemetic therapy with one of the following regimens may be given 30 minutes before each dose of bortezomib¹⁵: 1.

Dexamethasone 8 to 20 mg orally (PO), given 30 minutes before bortezomib on day 1, 4, 8, and 11. Because dexamethasone is 1 of the components of the BD regimen, additional dexamethasone, or an additional antiemetic may not be necessary.

Metoclopramide 10 to 40 mg PO or IV ± lorazepam 0.5 to 2 mg PO or IV ± H₂ blocker or proton pump inhibitor.

Prochlorperazine 10 mg PO or IV ± lorazepam 0.5 to 2 mg PO or IV ± H₂ blocker or proton pump inhibitor.

Promethazine 25 to 50 mg orally ± lorazepam 0.5 to 2 mg PO or IV ± H₂ blocker or proton pump inhibitor.

On days when dexamethasone is given alone, the expected emetogenicity is minimal¹⁵; most patients will not require prophylactic antiemetic therapy.^15–17

Patients who do experience significant nausea or vomiting with one of the above regimens should receive an agent from a different pharmacologic category.^15–17

Breakthrough Nausea and Vomiting^15–17: Patients should receive an antiemetic prescription to treat breakthrough nausea. One of the following regimens is suggested: 1.

Metoclopramide 0.5 to 2 mg/kg PO every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 6 hours if needed.

Prochlorperazine 10 mg PO every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 6 hours if needed.

Prochlorperazine 25 mg rectally every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 4 to 6 hours if needed.

Promethazine 25 to 50 mg PO every 4 to 6 hours if needed, ± diphenhydramine 25 to 50 mg PO every 4 to 6 hours if needed.

Hydration¹⁸: No special precautions are required.

Hypersensitivity Precautions¹⁸: No special precautions are required.

Hematopoietic Growth Factors: Accepted practice guidelines and pharmacoeconomic analysis suggest that an antineoplastic regimen have a greater than 20% incidence of febrile neutropenia before prophylactic use of colony-stimulating factors is warranted. For regimens with an incidence of febrile neutropenia between 10% and 20%, use of colony-stimulating factors should be considered. For regimens with an incidence of febrile neutropenia of less than 10%, routine prophylactic use of colony-stimulating factors is not recommended.^19,20 Febrile neutropenia was not reported in the studies reviewed; however, (grade 3 or 4) neutropenia was reported in 3% to 50% of patients.^2,3,6-8 Prophylactic use of colony-stimulating factors is not recommended.

Extravasation: No special precautions required.

Pulmonary: No special precautions required.

Major Toxicities

Most of the toxicities listed below are presented according to their degree of severity. Higher grades represent more severe toxicities. Although there are several grading systems for cancer chemotherapy toxicities, all are similar. One of the frequently used systems is the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events. (For more information, visit http://ctep.info.nih.gov.) Oncologists generally do not adjust doses or change therapy for grade 1 or 2 toxicities, but they make or consider dosage reductions or therapy changes for grade 3 or 4 toxicities. Incidence values are rounded to the nearest whole percent, unless the incidence was 0.5% or less. A.

Dermatologic: Skin rash (unspecified grade) 2%¹; (grade 3) 3% to 6%.^4,11

Gastrointestinal: Nausea (all grades) 12% to 21%^6,9; constipation (all grades) 14% to 31%^6,9,13; (grade 3) 5%²; diarrhea (all grades) 19% to 22%^9,13; (grade 3) 6% to 14%^2,3,7; (grade 4) 1%⁷; abdominal pain/cramping (grade 3) 9%²; 1 report of grade 3 Ileus¹⁰; unspecified toxicity 2% to 75%^1,13; (grade 3/4) 3% to 8%.^4,12 Harousseau et al reported a single (grade 4) transient intestinal obstruction.¹

Hematologic: Anemia (grade 3) 11%⁷; (grade 4) 2%⁷; (all grades) 13% to 14%⁹; neutropenia (grade 3) 11% to 50%,^2-3,7,8,11 (grade 4) 3%,^3,6,7 (all grades) 12% to 35%^6,11; lymphopenia (grade 3) 19% to 25%⁸; thrombocytopenia (all grades) 2% to 50%.^1,9,11,13 (grade 3) 22% to 50%^7,8; (grade 4) 3% to 18%^6,7,8; deep vein thrombosis (DVT) 3%.⁵

Hepatic: Transient elevation of alkaline phosphatases in 2% and alkaline phosphatases and transaminases 2%¹; (grade 3) 3% to 8%.^4,11

Infection: Unspecified infection (all grades) 17%⁷; herpes zoster infection (grade 3) 6%^1,4; other unspecified infection (grade 3) 6% to 10%.^11,13

Neurologic: Peripheral neuropathy (all grades) 3% to 26%^1,5,11; (grade 3) 5% to 33%^4,7,8,12; (grade 4) 1% to 6%^7,8; sensory neuropathy (all grades) 37%⁶; (grade 3) 8% to 23%^2,3; neuropathic pain (grade 3) 6%³; bone pain (all grades) 6% to 8%⁹; (grade 3) 14% to 19%^2,8; myalgia/arthralgia (all grades) 13% to 50%⁹; (grade 3) 18%³; weakness (grade 3) 6% to 25%⁸; back pain (all grades) 6% to 13%⁹; insomnia (all grades) 19% to 31%⁹; fatigue (all grades) 2% to 25%.^1,6,9,13 (grade 3) 2% to 9%.^2,4,7

Pulmonary: Pneumopathy (all grades) 4%⁵; pneumonia 4% to 33%.^1,8 Acute respiratory distress syndrome (ARDS) resulted in discontinuation of treatment in 2% of patients and toxic death in 3%.^1,4 Ozaki et al indicated severe lung injury had been reported among Japanese patients treated with bortezomib; however, no pulmonary complications were observed in their study.¹⁰

Other: Hyponatremia (grade 3) 17% to 19%⁸; pyrexia (all grades) 12% to 25%⁹; peripheral edema (all grades) 3% to 6%.⁹

Treatment-Related Deaths: Harousseau reported 3% caused by ARDS.⁴

Table 1.

Bortezomib and Dexamethasone Chemotherapeutic Regimens

Drug	Dose	Route of Administration	Administered on Day(s)	Total Dose/Cycle
Bortezomib^1,4,5	1.3 mg/m²	IV	1, 4, 8, 11	5.2 mg/m²
Dexamethasone	40 mg	PO	1 through 4 and 9 through 12^a	320 mg
OR
Bortezomib^2,3,6	1.3 mg/m²	IV	1, 4, 8, 11	5.2 mg/m²
Dexamethasone	40 mg	PO	1, 2, 4, 5, 8, 9, 11, 12	320 mg
Cycle repeats every 3 weeks.
Variations
1. Bortezomib 1.3 mg/m² IV day 1, 4, 8, and 11; dexamethasone 20 mg/day orally on day of and day after bortezomib every 21 days.^7,8,9,10
2. Bortezomib 1 mg/m² IV day 1, 4, 8, and 11; dexamethasone 20 mg/day orally on day of and day after bortezomib every 21 days.^8,9
3. Bortezomib 1.3 mg/m² IV days 1, 4, 8, and 11 (cycles 1, 3, and 5) and dexamethasone 40 mg orally on days 1 through 4, 9 through 12, and 17 through 20 (cycles 2, 4, and 6) every 28 days.¹¹
4. Bortezomib 1.3 mg/m² IV and methylprednisolone 500 mg to 2,000 mg IV on days 1, 8, and 15 every 28 days.¹²
5. Bortezomib 3.5 mg and dexamethasone 30 mg to 40 mg IV on days 1 and 8 every 21 days.¹³

Dexamethasone was given on days 1 through 4 and days 9 through 12 in cycles 1 and 2, and on days 1 through 4 only in cycles 3 and 4.^1,4,5; IV = intravenous; PO = oral.

Pretreatment Laboratory Studies Needed

Baseline 1.

Aspartate aminotransferase/alanine aminotransferase (AST/ALT)

Total bilirubin

Serum creatinine

Complete blood cell count (CBC) with differential

Before Each Treatment 1.

CBC with differential

Recommended Pretreatment Values: The minimally acceptable pretreatment laboratory values required to begin a cycle with full dose therapy in the protocols reviewed were: 1.

Absolute neutrophil count (ANC) a.

Greater than 1,000 cells/mcL.^1,4

Greater than 500 cells/mcL.^2,7-8

Hemoglobin a.

Greater than or equal to 8 g/dL.^2,8

Greater than 7 g/dL.⁷

Platelet count a.

Greater than 30,000 cells/mcL.^1,4,7-8

Greater than or equal to 50,000 cells/mcL.²

Greater than or equal to 30,000 cells/mcL—if there was extensive marrow infiltration.²

Serum creatinine: less than 200 mcmol/L.^1,4

Creatinine clearance (CrCl) a.

Greater than 20 mL/min.²

Greater than or equal to 30 mL/min.⁸

ALT/AST a.

Less than 3 times the upper limit of normal (ULN).^1,4

Less than or equal to 3 times the ULN.^2,8

Gamma-glutamyl transpeptidase: less than 3 times the ULN.⁴

Alkaline phosphatase: less than 3 times the ULN.¹

Serum bilirubin a.

Less than 3 times the ULN.^1,4

Less than or equal to 2 times the ULN.^2,8

In clinical practice, a pretreatment ANC of 1,000 cells/mcL and platelet count of 75,000 cells/mcL are usually considered acceptable.

Dosage Modifications

Renal Function: 1.

Bortezomib: No adjustment required.^18,21

Dexamethasone: No adjustment required.^21,22

Hepatic Function: 1.

Bortezomib a.

Dose adjustment may be required in patients with impaired liver function; specific guidelines are not available.²³

Some clinicians recommend no dose adjustment.²¹

Dexamethasone: No adjustment required.^21,23,24

Myelosuppression: Bortezomib: Any grade 4 hematological toxicity or febrile neutropenia: a.

Delay therapy, reduce dose 25%.^1,2,4,8

If therapy is delayed more than 2 weeks, discontinue the drug.^1,2,4

Neurologic: Grade 4 peripheral neuropathy—discontinue bortezomib.^1,4

Other: 1.

Dexamethasone—Any grade 3 or 4 adverse event related to dexamethasone: a.

Reduce dose to 20 mg.²

Delay therapy up to 2 weeks: (1)

If symptoms resolve to grade 2 or less, reduce dose 25%.¹¹

(2)

If symptoms do not resolve to grade 2 or less, reduce dose another 25%.¹¹

Bortezomib—Any grade 3 nonhematological toxicity, reduce dose 25%.^1,2,4,8

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the US Department of the Army or the Department of Defense.

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