Liposomal Doxorubicin and Bortezomib for Relapsed or Refractory Multiple Myeloma

Bortezomib

Liposomal Doxorubicin

Bortezomib is administered as a rapid intravenous (IV) injection over 3 to 5 seconds.

Liposomal doxorubicin should be administered at an initial rate of 1 mg/min. If no infusion-related adverse effects are observed, the infusion rate may be increased to complete administration of the drug in 1 hour.

Acute Emesis Prophylaxis: The LD-B regimen is predicted to cause acute emesis in 10% to 30% of patients on days when both liposomal doxorubicin and bortezomib are given. ^{9 11} The studies reviewed reported grade 1 or 2 nausea in 64%, ⁶ grade 3 nausea in 2% to 5%,^1,7 and grade 3 vomiting in 4% of patients. ¹ Prophylactic antiemetic therapy with one of the following regimens may be given 30 minutes prior to therapy on days when both liposomal doxorubicin and bortezomib are given ^{9 11} :

On days when bortezomib alone is administered, patients usually will not require prophylactic antiemetic therapy. ^{9 11} If antiemetic prophylaxis is required on bortezomib-only days, then one of the regimens above may be used.

Patients who do experience significant nausea or vomiting with one of the above regimens should receive an agent from a different pharmacologic category.^11–12

Breakthrough Nausea and Vomiting ^{10 12} : Patients should receive an antiemetic prescription to treat breakthrough nausea. One of the following regimens is suggested:

A few small studies suggest that higher doses of granisetron (3 mg IV or 40 to 240 mcg/kg) may be effective in treating breakthrough nausea; however none of these reports found the improvement to be statistically significant. ^{13 16}

Hydration: No special precautions are required.

Hypersensitivity Precautions:

Hematopoietic Growth Factors: Accepted practice guidelines and pharmacoeconomic analysis suggest that an antineoplastic regimen have a greater than 20% incidence of febrile neutropenia before primary prophylactic use of colony-stimulating factors is warranted. For regimens with an incidence of febrile neutropenia between 10% and 20%, primary prophylactic use of colony-stimulating factors should be considered. For regimens with an incidence of febrile neutropenia less than 10%, primary prophylactic use of colony-stimulating factors is not recommended.^18–19 In the LD-B studies reviewed, grade 3 or 4 febrile neutropenia was reported in 2% to 6%,^1,2,6,7 grade 3 neutropenia in 6% to 20%,^1,6,7 and grade 4 neutropenia in 2% to 9% of patients.^1,7 Prophylactic use of colony-stimulating factors is not recommended. Use of colony-stimulating factors may be considered if a patient experiences febrile neutropenia or grade 4 neutropenia in a prior cycle of LD-B.

Extravasation: No special precautions required. ^{20 22}

Cardiovascular: Congestive heart failure (all grades) 3% ¹ ; cardiac event (all grades) 2% ¹ ; hemorrhage (grade 3 or 4) 4%^1,2; hypotension (grade 3) 5% to 6%^6,7; coronary ischemic disease (all grades) 1% ¹ ; symptomatic arrhythmia (all grades) 3% ¹ ; dyspnea (grade 3) 5% to 6%^6,7; deep vein thrombosis (grade 3 or 4) 1%^1,2; unspecified cardiac event (ungraded) 2%. ¹

Dermatologic: Alopecia 1% ¹ ; hand foot syndrome (grade 3) 5% to 9%,^1,7 (grade 3 or 4) 5% ² ; skin rash (grade 3) 7%. ⁷

Gastrointestinal: Bowel obstruction 6% ⁶ ; constipation (grade 3) 1% ¹ ; diarrhea (grade 3) 5% to 7%^1,6,7; nausea (grade 1 or 2) 64%, ⁶ (grade 3) 2% to 5%^1,7; mucositis/stomatitis (grade 3) 2%, ¹ (grade 3 or 4) 2% ² ; vomiting (grade 3) 4%. ¹

Hematologic: Anemia (grade 3) 7%,^1,7 (grade 4) 2%^1,7; febrile neutropenia (grade 3) 6%, ⁶ (grade 3 or 4) 2% to 3%^1,2,7; neutropenia (grade 3) 6% to 20%,^1,6,7 (grade 4) 2% to 9%,^1,7 (grade 3/4) 30% ² ; lymphopenia (grade 3) 11% to 44%,^6,7 (grade 4) 2% ⁷ ; thrombocytopenia (grade 3) 9% to 50%,^1,6,7 (grade 4) 5% to 12%.^1,7

Infection: Unspecified infection (grade 3) 5% ⁷ ; pneumonia (grade 3) 13% ⁶ ; sinusitis (grade 3) 6%. ⁶

Metabolic: Anorexia (grade 3) 2% to 13%^1,6; dehydration (grade 3) 7% ⁷ ; fatigue (grade 3) 5% to 16%,^1,6,7 (grade 4) 1% ¹ ; pyrexia (grade 3) 1% to 6%^1,6; syncope (grade 3) 9% ⁷ ; weight loss (grade 3) 5%. ⁷

Neurologic: Asthenia (grade 3) 6% ¹ ; headache (grade 3) 1%, ¹ (grade 4) 0.3% ¹ ; motor neuropathy (grade 3) 7% ⁷ ; neuralgia (grade 3) 3% ¹ ; peripheral neuropathy (grade 3) 6%, ⁶ (grade 3 or 4) 4%^1,2; sensory neuropathy (grade 3) 11%, ⁷ (grade 4) 2%. ⁷

Treatment-Related Deaths. Unspecified 3%. ¹

Baseline

Prior to Each Treatment: 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:

Left ventricular ejection fraction:

Prothrombin time and activated partial thromboplastin time less than 1.5 times the ULN. ⁶

Previous doxorubicin exposure:

Renal Function:

Hepatic Function:

Myelosuppression: Grade 3 or 4 myelosuppression, including neutropenia and thrombocytopenia, was managed via unspecified dose reductions. ¹

Neurologic: Specific dose modifications were not reported in the studies reviewed.