The Health Burden of Multiple Myeloma: Subcutaneous Bortezomib a New, Convenient Route of Administration Option

Rhonda Williams

February 2012, Vol 3, No 1 - Cancer Drugs

In 2011, the American Cancer Society projected there would be 20,520 cases of newly diagnosed multiple myeloma (MM) and 10,610 deaths from the disease that year.1 MM is an incurable hematologic cancer marked by great heterogeneity, in terms of its biology and clinical course. Morbidity and survival rates vary widely, even in the age of novel, molecularly based targeted therapies. Many factors account for differences in prognoses among patients with MM, including genomic aberrations in the plasma cells of the myeloma neoplasm. Survival outcomes range from <1 year in patients with aggressive disease to >10 years in those with indolent disease.2

A variety of patient-, disease-, and therapy-related characteristics have been identified to predict the disease course and outcomes among patients with MM. Evaluation of prognostic factors and risk stratification is important in defining appropriate treatment strategies and comparing therapeutic outcomes, to predict survival.2

The Approach to Therapy in MM
Use of the proteasome inhibitor bortezomib (Velcade), the immuno­modulatory agents lenalidomide (Rev­li­mid) and thalidomide (Thalomid), and bisphosphonates such as zoledronic acid (Zometa) and pami­dronate (Aredia) has revolutionized the management of patients with MM. These therapies, however, are all associated with potentially serious side effects, which can negatively affect a patient’s quality of life.

The majority of preferred regimens for initial therapy are 3-drug combinations, although some 2-drug combinations are also recommended in the current guidelines from the National Com­prehensive Cancer Network, be­cause these multidrug regimens are associated with the best response rates.3

New Treatment Option
The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins that control the cell cycle and cellular processes. By blocking the proteasome, bortezomib disrupts biologic pathways related to the growth and survival of cancer cells.4

Bortezomib was approved by the US Food and Drug Administration (FDA) in 2003 for intravenous (IV) injection for the treatment of patients with MM who had received at least 2 previous therapies and had demonstrated disease progression on their last therapy.4

In 2008, the FDA approved an expanded indication for bortezomib for the first-line treatment of patients with previously untreated MM. The approval was based on data from the VISTA trial, which compared the addition of bortezomib to melphalan plus prednisone (MP) versus MP without bortezomib (ie, control group) in 682 patients with newly diagnosed MM. At a median follow-up of 16.3 months, the addition of bortezomib to the MP regimen resulted in significantly improved outcomes, including improved re­sponse rates, increased time to disease progression, overall survival (OS), and progression-free survival.5 The trial was stopped early and patients in the control group were permitted to cross over to the bortezomib regimen.

In December 2011, results of 5-year median follow-up of the VISTA trial con­firmed a >13-month OS advantage of the bortezomib plus MP regimen for patients with previously untreated MM. Bortezomib is also indicated for the treatment of patients with mantle-cell lymphoma who have received at least 1 previous therapy.5

In January 2012, the FDA approved a new route of administration for bor­tezomib; the new subcutaneous (SC) form of bortezomib for injection offers patients an easier mode of administration, with a safety profile comparable to the IV form but with significantly reduced peripheral neuropathy (6% vs 16%, respectively),5 providing patients with MM a new option in the choice of the route of administration.  

Clinical Pharmacology of Bortezomib

Mechanism of action. Bortezomib is a reversible inhibitor of the chymo­trypsin-like activity of the 26S pro­tea­some in mammalian cells; the 26S proteasome degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concen­tration of specific proteins, thereby maintaining homeo­stasis within cells. Inhibition of this pathway can therefore affect multiple signaling cascades within the cell and can lead to cell death.5

Pharmacodynamics. After twice-weekly administration of bortezomib 1 mg/m2 and 1.3 mg/m2, the maximum inhibition of 20S proteasome activity, relative to baseline, occurred 5 minutes after drug administration.5

Pharmacokinetics. After IV admin­istration of bortezomib 1 mg/m2 and bortezomib 1.3 mg/m2 in 24 patients with MM, the maximum plasma concentrations (Cmax) of bortezomib were 57 ng/mL and 112 ng/mL, respectively. The mean elimination half-life of bortezomib with multiple dosing ranged from 40 to 193 hours after administration of the 1-mg/m2 dose and 76 to 108 hours after ad­ministration of the 1.3-mg/m2 dose.

After an IV or a SC bolus injection of a 1.3-mg/mL dose in patients with MM, the total systemic exposure with a repeat-dose administration was equivalent for the SC and the IV routes of administration. The Cmax after SC administration (20.4 ng/mL) was lower than that after IV administration (223 ng/mL).5

In vitro studies suggest that bortez­omib is primarily oxidatively metabolized via the cytochrome P450 enzymes 3A4, 2C19, and 1A2.5

Phase 3 Clinical Trials: Bortezomib SC versus IV
The FDA approval of SC bortezomib was based on a randomized, open-label, phase 3, noninferiority trial that compared the efficacy and safety of SC versus IV administration of bortezomib in patients with relapsed MM.

A total of 222 bortezomib-naïve patients were randomly assigned, in a 2:1 ratio, to receive bortezomib 1.3 mg/m2 by either SC injection (N = 148) or IV infusion (N = 74) for 8 cycles. Patients were stratified according to the number of lines of previous therapy they had received (1 previous line vs >1 previous line of therapy) and stage of disease, using International Staging System (ISS) stage I, II, or III.

The primary study end point was to demonstrate noninferiority of single-agent SC bortezomib with respect to overall response rate (ORR)—complete response (CR) plus partial response. In this study, noninferiority was defined as retaining at least 60% of the ORR relative to single-agent IV bor­tezomib after 4 cycles of therapy.5

Patients who did not obtain an optimal response (less than CR) to treatment with bortezomib alone after 4 cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after bortezomib administration (N = 82 in the SC treatment group; N = 39 in the IV treatment group). Patients with baseline grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/L, were excluded from trial participation. A total of 218 patients were evaluable for response.5

The baseline demographic and other characteristics of the 2 treatment groups were similar. The median patient age was approximately 64 years (range, 38-88 years), and the majority of patients were male (SC, 50%; IV, 64%). The primary type of myeloma was immunoglobulin G. ISS stage I/II/III was 27%, 41%, and 32%, respectively, with both SC and IV routes of administration.

The Karnofsky performance status score was ≤70% in 22% of SC-treated patients and 16% of IV-treated pa­tients. Creatinine clearance was 67.5 mL/min in the SC group and 73 mL/min in the IV group. The median years from diagnosis were 2.68 years and 2.93 years in the SC and IV groups, respectively. The proportion of patients with >1 prior line of therapy was 38% with SC treatment versus 35% with IV treatment.5

Table 1
Summary of Efficacy Analyses in the Relapsed MM Study of Bortezomib SC versus IV
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This study met its primary (nonin­feriority) objective that treatment with single-agent SC bortezomib retains at least 60% of the ORR after 4 cycles relative to IV bortezomib (Table 1).5


Safety Profile: Reduced Peripheral Neuropathy with SC Option
The safety data reported herein are from the randomized, open-label study that compared the SC administration of bortezomib with IV administration of bortezomib at the recommended dose of 1.3 mg/m2 in 222 patients with relapsed MM.

Table 2
 Most Common Adverse Events (? 10%) in the Relapsed MM Study of Bortezomib SC versus IV
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Overall, the safety data were similar between the SC and IV treatment groups (Table 2), but with significant differences in some adverse events (AEs) favoring the SC form of bortez­omib. Differences of ≥5% between the 2 groups favoring the SC administration were reported for neuralgia (3% SC vs 9% IV), peripheral neuropathy grade ≥3 (6% SC vs 16% IV) and all grades (38% vs 53%), and thrombocytopenia (13% SC vs 19% IV).5


In the SC treatment group, local reactions, primarily redness, were reported in 6% of patients; 2 patients (1%) experienced local reactions that were considered severe (1 case of pruritus and 1 case of redness). These reactions resolved in a median of 6 days. Local reaction led to study discontinuation in 1 patient and reduction in dose concentration in 1 patient.5

Dose reductions associated with drug-related AEs were reported in 31% of patients in the SC group compared with 43% of patients in the IV group. The most common AEs leading to dose reduction included sensory peripheral neuropathy (17% SC vs 31% IV) and neuralgia (11% SC vs 19% IV).5

Warnings and Precautions

Peripheral neuropathy. Peripheral neuropathy has long been recognized as a problem, because it is frequently associated with both MM and its treatment. The peripheral neuropathy associated with bortezomib use is primarily sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported with use of the agent. Patients with such pre­existing symptoms as numbness, pain, or a burning sensation in the feet or hands, and/or signs of peripheral neu­r­op­athy, may experience worsening of peripheral neuropathy, including grade ≥3, during treatment with bortezomib.5

A paradigm shift regarding bortez­omib use currently exists, with recent data suggesting that changing the mode of administration or dosing schedule can substantially impact the incidence of neuropathy. The results of a phase 3 study by Moreau and colleagues, which included patients with relapsed MM who had received 1 to 3 previous lines of therapy, concluded that SC administration of bortezomib 1.3 mg/m2 twice weekly significantly reduced the incidence of peripheral neuropathy compared with IV administration at the same dose and schedule, with no deleterious effect on efficacy.6

The protocol of this study provided for a robust comparison of the 2 routes of administration, since it specified 4 cycles of single-agent bortezomib with the addition of oral dexamethasone 20 mg to enhance response at the end of cycle 4 in patients who achieved a suboptimum response.6 In this trial, the incidence of grade ≥2 peripheral neuropathy was 24% in patients who received SC bortezomib and 41% in those who received IV bortezomib (a significant difference).5,6 Also in this trial, grade ≥3 peripheral neuropathy occurred in 6% of patients in the SC treatment group and 16% of those in the IV treatment group.5,6

When initiating bortezomib therapy, SC administration may be considered for patients with preexisting peripheral neuropathy or those who are at high risk for developing peripheral neuropathy. In patients with preexisting, severe peripheral neuropathy, the risk-benefit should be carefully assessed prior to beginning bortezomib therapy.5

Table 3
Recommended Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy
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Prevention is the best approach to use when addressing bortezomib-related neuropathy. One advantage of bortezomib is that most episodes of grade 3/4 neuropathy can be prevented by closely adhering to the algorithm for dose modification and interruption provided in the prescribing information (Table 3). By following these recommendations, the severity of peripheral neuropathy can usually be decreased to grade 1 or 2, and in many cases, patients may resume bortezomib therapy.5


Hypotension. The incidence of hy­po­tension, which included postural hypo­­tension, orthostatic hypotension, and hypotension not otherwise specified, reported with the use of bortezomib was 13%. These events occurred throughout treatment. Caution should be used when administering bortezomib to patients with a history of syncope, those receiving medications known to be associated with hypo­tension (eg, antihypertensive agents), and persons who are dehy­drated.5

Cardiac disorders. Exacerbation or acute development of congestive heart failure and new onset of decreased left ventricular ejection fraction (LVEF) have been reported in patients receiving treatment with bortezomib, including those with no known risk factors for decreased LVEF. Thus, patients at risk for the development of heart disease or those with a history of existing heart disease should be monitored closely.5

Pulmonary disorders. Reports of acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, acute respiratory distress syndrome, and lung infiltration, have been noted among patients receiving treatment with bortezomib.5

Reversible posterior leukoen­cepha­lopathy syndrome. Reversible pos­terior leukoencepha­lopathy syn­drome (RPLS), a rare, reversible neu­rologic disorder that can present with seizure, hypertension, lethargy, head­ache, blindness, confusion, and other visual and neurologic dis­turbances, has been reported in pa­tients receiving bortezomib therapy. Bortezomib should be discontinued in patients who develop RPLS that has been confirmed by brain imaging, pre­ferably magnetic resonance imaging.5

Gastrointestinal events. Nausea, diarrhea, constipation, and vomiting, at times requiring the use of antiemetic therapy and antidiarrheal agents, have been reported in patients receiving bortezomib. In order to prevent de­hy­dration, fluid and electrolyte replace­ment should be administered to these patients.5  

Thrombocytopenia and neutro­penia. Bortezomib is associated with the development of thrombocytopenia and neutropenia that follows a cyclical pattern, with nadirs that generally occur following the last dose of each cycle and typically recover prior to initiation of the next cycle of therapy. This cyclical pattern remained con­sistent over 8 cycles of twice-weekly therapy, with no evidence of cumu­lative thrombocytopenia or neu­tro­­­­­penia observed. In patients exper­iencing throm­b­ocytopenia, platelet counts should be monitored prior to the administration of each dose; an adjustment in dose and/or schedule may be required. There have been reports of gastro­intestinal and intra­cerebral hemorrhage associated with the use of bortezomib.5   

Tumor lysis syndrome. Tumor lysis syndrome may occur with the use of bortezomib because the agent is cytotoxic and can rapidly kill ma­lignant cells. Patients with a high tumor burden prior to therapy may be at a higher risk for the development of tumor lysis syndrome.5

Hepatic events. Acute liver failure has occurred in bortezomib-treated pa­tients receiving multiple conco­m­itant medications and in those with serious underlying medical con­ditions. Other hepatic events reported with the use of bor­tezomib include elevations in liver en­zymes, hyper­bilirubinemia, and hepatitis.5

Hepatic Impairment
Because bortezomib is metabolized by the liver, exposure is increased in patients with moderate or severe hepatic impairment. Therefore, such patients should be started on reduced doses of bortezomib and closely monitored for the development of toxicities.5

Use in Pregnancy
Women of childbearing potential should avoid becoming pregnant while being treated with bortezomib.5

Bortezomib is for IV or SC administration only and should not be administered by any other route. The recommended starting dose of bortezomib is 1.3 mg/m2 for both SC and IV forms of administration. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume of drug to be administered. With IV administration, the recommended con­centration of bortezomib is 1 mg/mL; with SC administration, the recommended concentration of bortezomib is 2.5 mg/mL.5

Patients with pre­viously un­treated MM. In patients with pre­viously untreated MM, bortezomib is admin­istered in combi­nation with oral melphalan and oral prednisone for a total of nine 6-week treatment cycles. In cycles 1 through 4, bortezomib is administered twice weekly (on days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 through 9, bortezomib is administered once weekly (on days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of bortezomib.5

Patients with relapsed MM or mantle-cell lymphoma. In patients with relapsed MM or mantle-cell lymphoma, bortezomib 1.3 mg/m2 per dose is administered twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12-21). For extended therapy of more than 8 cycles, bortezomib may be admin­istered according to the standard schedule or on a maintenance, once-weekly schedule for 4 weeks (days 1, 8, 15, and 22), followed by a 13-day rest period.5

Dose modifications. A patient’s platelet count should be ≥70 x 109/L and his or her absolute neutrophil count should be ≥1.0 x 109/L before receiving any cycle of therapy with bortezomib in combination with melphalan and pred­nisone. All nonhematologic toxicities should have resolved to grade 1 or to baseline level.5 Dose modification guidelines for patients with relapsed MM or mantle-cell lymphoma state that bortezomib therapy should be withheld at the onset of any grade 3 nonhematologic or grade 4 hema­tologic toxicities excluding neuropathy, which is discussed separately. Once the symptoms of the toxicity have resolved, bortez­omib therapy may be reinitiated at a 25% reduced dose.5

Administration Precautions
When the SC route of administration is used, the site for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.5

If local injection-site reactions occur after SC bortezomib administration, a less-concentrated bortezomib solution (1 mg/mL instead of 2.5 mg/mL) may be used for SC administration. Alternatively, the IV route of administration may be considered.5


  1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011.
  2. Munshi NC, Anderson AC, Bergsagel PL, et al; for the International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the Inter­national Myeloma Workshop Consensus Panel 2. Blood. 2011;117:4696-4700.
  3. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Multiple Myeloma, Version 1. 2012. February 5, 2012.
  4. CenterWatch. Drug information. Velcade (bortezo­mib). Accessed February 5, 2012.
  5. VELCADE prescribing information. Cambridge, MA: Millennium Pharmaceuticals, Inc; 2012.
  6. 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;12:431-440.