DailyMed Label: Bortezomib

DailyMed Label: BORTEZOMIB

2022

DailyMed Prescription

BORTEZOMIB

bortezomib

Baxter Healthcare Corporation

NDC: 10019-991

NDC: 10019-991

Bortezomib for Injection, a proteasome inhibitor, contains bortezomib which is an antineoplastic agent. Bortezomib is a modified dipeptidyl boronic acid. The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. Bortezomib has the following chemical structure: The molecular weight is 384.24. The molecular formula is C 19 H 25 BN 4 O 4 . The solubility of bortezomib, as the monomeric boronic acid, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5. Bortezomib for Injection is available for intravenous injection or subcutaneous use. Each single-dose vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. It also contains the inactive ingredient: 35 mg mannitol, USP. The product is provided as a mannitol boronic ester which, in reconstituted form, consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine.

Bortezomib for Injection is a proteasome inhibitor indicated for: • treatment of adult patients with multiple myeloma ( 1.1 ) • treatment of adult patients with mantle cell lymphoma ( 1.2 )

• For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration. Exercise caution when calculating the volume to be administered. ( 2.1 , 2.10 ) • The recommended starting dose of Bortezomib for Injection is 1.3 mg/m 2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. ( 2.2 , 2.4 , 2.6 ) • Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose. ( 2.6 ) • Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. ( 2.8 ) • Dose must be individualized to prevent overdose. ( 2.10 )

For injection: Each single-dose vial of Bortezomib for Injection contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder for reconstitution and withdrawal of the appropriate individual patient dose [see Dosage and Administration (2.10 )] .

Bortezomib for Injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see Adverse Reactions (6.1 )] . Bortezomib for Injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Bortezomib for Injection.

• Peripheral Neuropathy: Manage with dose modification or discontinuation. ( 2.7 ) Patients with pre-existing severe neuropathy should be treated with Bortezomib for Injection only after careful risk-benefit assessment. ( 2.7 , 5.1 ) • Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ( 5.2 ) • Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ( 5.3 ) • Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting Bortezomib for Injection therapy. ( 5.4 ) • Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib for Injection if suspected. ( 5.5 ) • Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ( 5.6 ) • Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment. ( 5.7 ) • Tumor Lysis Syndrome: Closely monitor patients with high tumor burden. ( 5.8 ) • Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt Bortezomib for Injection therapy to assess reversibility. ( 5.9 ) • Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue Bortezomib for Injection if suspected. ( 5.10 ) • Embryo-Fetal Toxicity: Bortezomib for Injection can cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.11 )

The following clinically significant adverse reactions are also discussed in other sections of the labeling:

• Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. ( 7.1 ) • Strong CYP3A4 Inducers: Avoid concomitant use. (7.3)

Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. ( 8.8 )

Bortezomib for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder.   NDC 10019-991-01 3.5 mg single-dose vial Unopened vials may be stored at controlled room temperature 25ºC (77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Retain in original package to protect from light. Follow guidelines for handling and disposal for hazardous drugs, including the use of gloves and other protective clothing to prevent skin contact 1 .

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that 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 the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro . Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.

Carcinogenicity studies have not been conducted with bortezomib. Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice. Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the six month rat toxicity study, degenerative effects in the ovary were observed at doses ≥0.3  mg/m 2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2  mg/m 2 .

Randomized, Open-Label Clinical Study in Patients with Previously Untreated Multiple Myeloma A prospective, international, randomized (1:1), open-label clinical study (NCT00111319) of 682 patients was conducted to determine whether Bortezomib for Injection administered intravenously (1.3 mg/m 2 ) in combination with melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of nine cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. Antiviral prophylaxis was recommended for patients on the Bortezomib for Injection study arm. The median age of the patients in the study was 71 years (48;91), 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80 (60;100). Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/L (64;165), and a median platelet count of 221,500/microliter (33,000;587,000). Efficacy results for the trial are presented in Table 14 . At a prespecified interim analysis (with median follow-up of 16.3 months), the combination of Bortezomib for Injection, melphalan and prednisone therapy resulted in significantly superior results for time to progression, progression-free survival, overall survival and response rate. Further enrollment was halted, and patients receiving melphalan and prednisone were offered Bortezomib for Injection in addition. A later, prespecified analysis of overall survival (with median follow-up of 36.7 months with a hazard ratio of 0.65, 95% CI: 0.51, 0.84) resulted in a statistically significant survival benefit for the Bortezomib for Injection, melphalan and prednisone treatment arm despite subsequent therapies including Bortezomib for Injection based regimens. In an updated analysis of overall survival based on 387 deaths (median follow-up 60.1 months), the median overall survival for the Bortezomib for Injection, melphalan and prednisone treatment arm was 56.4 months and for the melphalan and prednisone treatment arm was 43.1 months, with a hazard ratio of 0.695 (95% CI: 0.57, 0.85). Table 14: Summary of Efficacy Analyses in the Previously Untreated Multiple Myeloma Study Efficacy Endpoint Bortezomib for Injection, Melphalan and Prednisone (n=344) Melphalan and Prednisone (n=338) Time to Progression Events n (%) 101 (29) 152 (45) Median Kaplan-Meier estimate (months) (95% CI) 20.7 (17.6, 24.7) 15.0 (14.1, 17.9) Hazard ratio Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors: beta 2 ‑ microglobulin, albumin, and region. A hazard ratio less than one indicates an advantage for Bortezomib for Injection, melphalan and prednisone (95% CI) 0.54 (0.42, 0.70) p-value p-value based on the stratified log-rank test adjusted for stratification factors: beta 2 -microglobulin, albumin, and region 0.000002 Progression-Free Survival Events n (%) 135 (39) 190 (56) Median (months) (95% CI) 18.3 (16.6, 21.7) 14.0 (11.1, 15.0) Hazard ratio (95% CI) 0.61 (0.49, 0.76) p-value 0.00001 Response Rate CR EBMT criteria n (%) 102 (30) 12 (4) PR n (%) 136 (40) 103 (30) nCR n (%) 5 (1) 0 CR + PR n (%) 238 (69) 115 (34) p-value p-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors <10 -10 Overall Survival at Median Follow-Up of 36.7 Months Events (deaths) n (%) 109 (32) 148 (44) Median (months) (95% CI) Not Reached (46.2, NR) 43.1 (34.8, NR) Hazard ratio (95% CI) 0.65 (0.51, 0.84) p-value 0.00084 Note: All results are based on the analysis performed at a median follow-up duration of 16.3 months except for the overall survival analysis. TTP was statistically significantly longer on the Bortezomib for Injection, melphalan and prednisone arm (see Figure 1 ). (median follow-up 16.3 months) Figure 1: Time to Progression Bortezomib for Injection, Melphalan and Prednisone vs Melphalan and Prednisone Figure 1: Time to Progression Bortezomib for Injection, Melphalan and Prednisone vs Melphalan and Prednisone Overall survival was statistically significantly longer on the Bortezomib for Injection, melphalan and prednisone arm (see Figure 2 ). (median follow-up 60.1 months) Figure 2: Overall Survival Bortezomib for Injection, Melphalan and Prednisone vs Melphalan and Prednisone Randomized, Clinical Study in Relapsed Multiple Myeloma of Bortezomib for Injection vs Dexamethasone A prospective Phase 3, international, randomized (1:1), stratified, open-label clinical study (NCT00048230) enrolling 669 patients was designed to determine whether Bortezomib for Injection resulted in improvement in time to progression (TTP) compared to high-dose dexamethasone in patients with progressive multiple myeloma following 1 to 3 prior therapies. Patients considered to be refractory to prior high-dose dexamethasone were excluded as were those with baseline Grade ≥2 peripheral neuropathy or platelet counts <50,000/µL. A total of 627 patients were evaluable for response. Stratification factors were based on the number of lines of prior therapy the patient had previously received (one previous line vs more than one line of therapy), time of progression relative to prior treatment (progression during or within six months of stopping their most recent therapy vs relapse >6 months after receiving their most recent therapy), and screening beta 2 -microglobulin levels (≤2.5 mg/L vs >2.5 mg/L). Baseline patient and disease characteristics are summarized in Table 15 . Table 15: Summary of Baseline Patient and Disease Characteristics in the Relapsed Multiple Myeloma Study Patient Characteristics Bortezomib for Injection (N=333) Dexamethasone (N=336)   Median age in years (range) 62.0 (33, 84) 61.0 (27, 86)   Gender: Male/female 56%/44% 60%/40%   Race: Caucasian/black/other 90%/6%/4% 88%/7%/5%   Karnofsky performance status score ≤70 13% 17%   Hemoglobin <100 g/L 32% 28%   Platelet count <75 x 10 9 /L 6% 4% Disease Characteristics   Type of myeloma (%): IgG/IgA/Light chain 60%/23%/12% 59%/24%/13%   Median beta2-microglobulin (mg/L) 3.7 3.6   Median albumin (g/L) 39.0 39.0   Creatinine clearance ≤30 mL/min [n (%)] 17 (5%) 11 (3%) Median Duration of Multiple Myeloma Since Diagnosis (Years) 3.5 3.1 Number of Prior Therapeutic Lines of Treatment   Median 2 2   1 prior line 40% 35%   >1 prior line 60% 65% Previous Therapy   Any prior steroids, e.g., dexamethasone, VAD 98% 99%   Any prior anthracyclines, e.g., VAD, mitoxantrone 77% 76% 77% 76%   Any prior alkylating agents, e.g., MP, VBMCP 91% 92%   Any prior thalidomide therapy 48% 50%   Vinca alkaloids 74% 72%   Prior stem cell transplant/other high-dose therapy 67% 68%   Prior experimental or other types of therapy 3% 2% Patients in the Bortezomib for Injection treatment group were to receive 8, three week treatment cycles followed by 3, five week treatment cycles of Bortezomib for Injection. Patients achieving a CR were treated for four cycles beyond first evidence of CR. Within each three week treatment cycle, Bortezomib for Injection 1.3 mg/m 2 /dose alone was administered by intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten day rest period (Days 12 to 21). Within each five week treatment cycle, Bortezomib for Injection 1.3 mg/m 2 /dose alone was administered by intravenous bolus once weekly for four weeks on Days 1, 8, 15, and 22 followed by a 13 day rest period (Days 23 to 35) [see Dosage and Administration (2.2 )] . Patients in the dexamethasone treatment group were to receive 4, five week treatment cycles followed by 5, four week treatment cycles. Within each five week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4, 9 to 12, and 17 to 20 followed by a 15 day rest period (Days 21 to 35). Within each four week treatment cycle, dexamethasone 40 mg/day PO was administered once daily on Days 1 to 4 followed by a 24 day rest period (Days 5 to 28). Patients with documented progressive disease on dexamethasone were offered Bortezomib for Injection at a standard dose and schedule on a companion study. Following a preplanned interim analysis of time to progression, the dexamethasone arm was halted and all patients randomized to dexamethasone were offered Bortezomib for Injection, regardless of disease status. In the Bortezomib for Injection arm, 34% of patients received at least one Bortezomib for Injection dose in all eight of the three week cycles of therapy, and 13% received at least one dose in all 11 cycles. The average number of Bortezomib for Injection doses during the study was 22, with a range of 1 to 44. In the dexamethasone arm, 40% of patients received at least one dose in all four of the five week treatment cycles of therapy, and 6% received at least one dose in all nine cycles. The time to event analyses and response rates from the relapsed multiple myeloma study are presented in Table 16 . Response and progression were assessed using the European Group for Blood and Marrow Transplantation (EBMT) criteria. Complete response (CR) required <5% plasma cells in the marrow, 100% reduction in M-protein, and a negative immunofixation test (IF - ). Partial response (PR) requires ≥50% reduction in serum myeloma protein and ≥90% reduction of urine myeloma protein on at least two occasions for a minimum of at least six weeks along with stable bone disease and normal calcium. Near complete response (nCR) was defined as meeting all the criteria for complete response including 100% reduction in M-protein by protein electrophoresis; however, M- protein was still detectable by immunofixation (IF + ). Table 16: Summary of Efficacy Analyses in the Relapsed Multiple Myeloma Study Efficacy Endpoint All Patients 1 Prior Line of Therapy >1 Prior Line of Therapy Bortezomib for Injection Dex Bortezomib for Injection Dex Bortezomib for Injection Dex (n=333) (n=336) (n=132) (n=119) (n=200) (n=217) Time to Progression Events n (%) 147 (44) 196 (58) 55 (42) 64 (54) 92 (46) 132 (61) Median Kaplan-Meier estimate (95%CI) 6.2 mo (4.9, 6.9) 3.5 mo (2.9,4.2) 7.0 mo (6.2, 8.8) 5.6 mo (3.4,6.3) 4.9 mo (4.2, 6.3) 2.9 mo (2.8,3.5) Hazard ratio Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than one indicates an advantage for Bortezomib for Injection (95%CI) 0.55 (0.44, 0.69) 0.55 (0.38, 0.81) 0.54 (0.41, 0.72) p-value p-value based on the stratified log-rank test including randomization stratification factors <0.0001 0.0019 <0.0001 Overall Survival Events (deaths) n (%) 51 (15) 84 (25) 12 (9) 24(20) 39 (20) 60 (28) Hazard ratio (95% CI) 0.57 (0.40, 0.81) 0.39 (0.19, 0.81) 0.65 (0.43, 0.97) p-value , Precise p-value cannot be rendered <0.05 <0.05 <0.05 Response Rate Population Response population includes patients who had measurable disease at baseline and received at least one dose of study drug n=627 n=315 n=312 n=128 n=110 n=187 n=202 CR EBMT criteria; nCR meets all EBMT criteria for CR but has positive IF. Under EBMT criteria nCR is in the PR category n (%) 20 (6) 2 (<1) 8 (6) 2 (2) 12 (6) 0 (0) PR n(%) 101 (32) 54 (17) 49 (38) 27 (25) 52 (28) 27 (13) nCR , In two patients, the IF was unknown n(%) 21 (7) 3 (<1) 8 (6) 2 (2) 13 (7) 1 (<1) CR + PR n (%) 121 (38) 56 (18) 57 (45) 29 (26) 64 (34) 27 (13) p-value p-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors <0.0001 0.0035 <0.0001 TTP was statistically significantly longer on the Bortezomib for Injection arm (see ). Figure 3: Time to Progression Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study) As shown in Bortezomib for Injection had a significant survival advantage relative to dexamethasone (p <0.05). The median follow-up was 8.3 months. Figure 4: Overall Survival Bortezomib vs Dexamethasone (Relapsed Multiple Myeloma Study) For the 121 patients achieving a response (CR or PR) on the Bortezomib for Injection arm, the median duration was 8.0 months (95% CI: 6.9, 11.5 months) compared to 5.6 months (95% CI: 4.8, 9.2 months) for the 56 responders on the dexamethasone arm. The response rate was significantly higher on the Bortezomib for Injection arm regardless of beta 2 -microglobulin levels at baseline. Randomized, Open-Label Clinical Study of Bortezomib for Injection Subcutaneous vs Intravenous in Relapsed Multiple Myeloma An open-label, randomized, Phase 3 noninferiority study (NCT00722566) compared the efficacy and safety of the subcutaneous administration of Bortezomib for Injection vs the intravenous administration. This study included 222 bortezomib naïve patients with relapsed multiple myeloma, who were randomized in a 2:1 ratio to receive 1.3 mg/m 2 of Bortezomib for Injection by either the subcutaneous (n=148) or intravenous (n=74) route for eight cycles. Patients who did not obtain an optimal response (less than Complete Response (CR)) to therapy with Bortezomib for Injection alone after four cycles were allowed to receive oral dexamethasone 20 mg daily on the day of and after Bortezomib for Injection administration (82 patients in subcutaneous treatment group and 39 patients in the intravenous treatment group). Patients with baseline Grade ≥2 peripheral neuropathy or neuropathic pain, or platelet counts <50,000/µL were excluded. A total of 218 patients were evaluable for response. Stratification factors were based on the number of lines of prior therapy the patient had received (one previous line vs more than one line of therapy), and international staging system (ISS) stage (incorporating beta 2 -microglobulin and albumin levels; Stages I, II, or III). The baseline demographic and other characteristics of the two treatment groups are summarized as follows: the median age of the patient population was approximately 64 years of age (range: 38 to 88 years), primarily male (subcutaneous: 50%, intravenous: 64%); the primary type of myeloma is IgG (subcutaneous: 65% IgG, 26% IgA, 8% light chain; intravenous: 72% IgG, 19% IgA, 8% light chain), ISS staging I/II/III (%) was 27, 41, 32 for both subcutaneous and intravenous, Karnofsky performance status score was ≤70% in 22% of subcutaneous and 16% of intravenous, creatinine clearance was 67.5 mL/min in subcutaneous and 73 mL/min in intravenous, the median years from diagnosis was 2.68 and 2.93 in subcutaneous and intravenous respectively and the proportion of patients with more than one prior line of therapy was 38% in subcutaneous and 35% in intravenous. This study met its primary (noninferiority) objective that single agent subcutaneous Bortezomib for Injection retains at least 60% of the overall response rate after four cycles relative to single agent intravenous Bortezomib for Injection. The results are provided in Table 17 . Table 17: Summary of Efficacy Analyses in the Relapsed Multiple Myeloma Study of Bortezomib for Injection Subcutaneous vs Intravenous Subcutaneous Bortezomib for Injection Intravenous Bortezomib for Injection Intent to Treat Population (n=148) (n=74) Primary Endpoint Response Rate at 4 Cycles ORR (CR + PR) n (%) 63 (43) 31 (42) Ratio of Response Rates (95% CI) 1.01 (0.73, 1.40) CR n (%) 11 (7) 6 (8) PR n (%) 52 (35) 25 (34) nCR n (%) 9 (6) 4 (5) Secondary Endpoints Response Rate at 8 Cycles ORR (CR + PR) 78 (53) 38 (51) CR n (%) 17 (11) 9 (12) PR n (%) 61 (41) 29 (39) nCR n (%) 14 (9) 7 (9) Median Time to Progression, months 10.4 9.4 Median Progression-Free Survival, months 10.2 8.0 1 Year Overall Survival (%) Median duration of follow-up is 11.8 months 72.6 76.7 A Randomized, Phase 2 Dose-Response Study in Relapsed Multiple Myeloma An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive Bortezomib for Injection 1 mg/m 2 or 1.3 mg/m 2 intravenous bolus twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten day rest period (Days 12 to 21). The median duration of time between diagnosis of multiple myeloma and first dose of Bortezomib for Injection on this trial was two years, and patients had received a median of one prior line of treatment (median of three prior therapies). A single complete response was seen at each dose. The overall response rates (CR + PR) were 30% (8/27) at 1 mg/m 2 and 38% (10/26) at 1.3 mg/m 2 . A Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma Patients from the two Phase 2 studies, who in the investigators’ opinion would experience additional clinical benefit, continued to receive Bortezomib for Injection beyond 8 cycles on an extension study. Sixty-three (63) patients from the Phase 2 multiple myeloma studies were enrolled and received a median of seven additional cycles of Bortezomib for Injection therapy for a total median of 14 cycles (range: 7 to 32). The overall median dosing intensity was the same in both the parent protocol and extension study. Sixty-seven percent (67%) of patients initiated the extension study at the same or higher dose intensity at which they completed the parent protocol, and 89% of patients maintained the standard three week dosing schedule during the extension study. No new cumulative or new long-term toxicities were observed with prolonged Bortezomib for Injection treatment [see Adverse Reactions (6.1 )] . A Single-Arm Trial of Retreatment in Relapsed Multiple Myeloma A single-arm, open-label trial (NCT00431769) was conducted to determine the efficacy and safety of retreatment with Bortezomib for Injection. One hundred and thirty patients (≥18 years of age) with multiple myeloma who previously had at least partial response on a Bortezomib for Injection-containing regimen (median of two prior lines of therapy [range: 1 to 7]) were retreated upon progression with Bortezomib for Injection administered intravenously. Patients were excluded from trial participation if they had peripheral neuropathy or neuropathic pain of Grade ≥2. At least six months after prior Bortezomib for Injection therapy, Bortezomib for Injection was restarted at the last tolerated dose of 1.3 mg/m 2 (n=93) or ≤1 mg/m 2 (n=37) and given on Days 1, 4, 8 and 11 every three weeks for maximum of eight cycles either as single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with Bortezomib for Injection to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of Bortezomib for Injection retreatment cycles. The primary endpoint was best confirmed response to retreatment as assessed by European Group for Blood and Marrow Transplantation (EBMT) criteria. Fifty of the 130 patients achieved a best confirmed response of Partial Response or better for an overall response rate of 38.5% (95% CI: 30.1, 47.4). One patient achieved a Complete Response and 49 achieved Partial Response. In the 50 responding patients, the median duration of response was 6.5 months and the range was 0.6 to 19.3 months.

Vial Label NDC 10019-991-01 Bortezomib for Injection 3.5 mg/vial FOR INTRAVENOUS OR SUBCUTANEOUS USE Single Dose Vial Discard Unused Portion CONTENTS: Lyophilized vial contains 3.5 mg bortezomib and 35 mg mannitol. USUAL DOSE: See accompanying Package Insert for dosage information. Rx ONLY STORAGE: Store at 25ºC (77ºF); excursions permitted from 15º to 30ºC (59º to 86ºF) [See USP Controlled Room Temperature]. Protect from light (see Package Insert). For bar code position only LOT: EXP: Baxter Logo Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015, USA Made in Germany USA HA-65-01-792 C 22 barcode Vial Intravenous Use Label Bortezomib for Injection INTRAVENOUS INJECTION ONLY 0.9% NaCI symbol ADD 3.5 mL 0.9% Sodium Chloride To make 1 mg / mL final concentration Place sticker on vial Intravenous Bortezomib Place sticker on syringe Intravenous Bortezomib See Package Insert (Section 2) for full Instructions USA HA-65-01-801 C150 Vial Subcutaneous Use Label Bortezomib for Injection SUBCUTANEOUS INJECTION ONLY 0.9% NaCI Add 1.4 mL 0.9% Sodium Chloride To make 2.5 mg / mL final concentration Place sticker on vial Subcutaneous Bortezomib Place sticker on syringe Subcutaneous Bortezomib See Package Insert (Section 2) for full Instructions USA HA-65-01-800 C148 Carton Label GTIN: SN: LOT: EXP: Bortezomib for Injection Barcode NDC 10019-991-01 See Reconstitution Information on Back Bortezomib for Injection 3.5 mg/vial FOR INTRAVENOUS OR SUBCUTANEOUS USE Single Dose Vial – Discard Unused Portion Baxter Logo HA-80-03-191 USA CONTENTS: Lyophilized vial contains 3.5 mg bortezomib and 35 mg mannitol. RECONSTITUTION: See back of this carton or Package Insert, Section 2. USUAL DOSE: See accompanying Package Insert for dosage information. Rx ONLY STORAGE: Store at 25° C (77° F); excursions permitted from 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature]. Protect from light (see Package Insert). C 501 NDC 10019-991-01 Bortezomib for Injection 3.5 mg/vial Reconstitution Information SUBCUTANEOUS INJECTION ONLY 0.9% NaCI Add 1.4 mL 0.9% Sodium Chloride To make 2.5 mg / mL final concentration INTRAVENOUS INJECTION ONLY 0.9% NaCI Add 3.5 mL 0.9% Sodium Chloride To make 1 mg / mL final concentration 2347B0016 Barcode (01) 20310019991010 Baxter is a registered trademark of Baxter International Inc. Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015, USA Made in Germany Reconstitution Information SUBCUTANEOUS INJECTION ONLY 0.9% NaCI Add 1.4 mL 0.9% Sodium Chloride To make 2.5 mg / mL final concentration INTRAVENOUS INJECTION ONLY 0.9% NaCI Add 3.5 mL 0.9% Sodium Chloride To make 1 mg / mL final concentration