Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2022029
Category:	Pharmacy
Initiated:	October 2022
Last Review:	July 2023

Bortezomib (e.g., Velcade)

Description:

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 vitro in nonclinical tumor models, including multiple myeloma. (FDA, 2021)

Regulatory Status

On May 13, 2003, the Food and Drug Administration approved the use of bortezomib (e.g., Velcade) for Injection for the treatment of multiple myeloma individuals who have received at least two prior therapies and have demonstrated disease progression on the last therapy.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Effective October 15, 2022, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service when rendered for oncologic indications and is managed through the oncology benefits management program.

Effective July 12, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Bortezomib meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following:

ADULTS:

Acute Lymphoblastic Leukemia (NCCN 2A)

a. Used in combination with chemotherapy for relapsed/refractory Philadelphia chromosome-negative T-ALL

2. Mantle Cell Lymphoma (FDA 2021) (NCCN 2A)

a. In the absence of a clinical trial*, consider as preferred less aggressive induction therapy for classical or symptomatic indolent TP53 mutated stage II bulky, III, or IV disease as a component of VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen.

*TP53 mutation has been associated with poor prognosis in individuals treated with conventional therapy, including transplant – clinical trial is strongly recommended.

b. Useful in certain circumstances as second-line and subsequent therapy as a single agent or in combination with rituximab for:

i. Stage I-II disease with partial response, progression, or relapse after prior treatment with chemoimmunotherapy

ii. Classical or symptomatic indolent stage II bulky, III, or IV disease in individuals who have stable or progressive disease or partial response with substantial disease after induction therapy.

iii. Relapsed or refractory disease (if not previously given)

c. Preferred less aggressive induction therapy as component of VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen.

i. As initial therapy for stage I-II disease

ii. As additional therapy for partial response, progression, or relapse after initial treatment with involved site radiation therapy alone in individuals who are not candidates for high-dose therapy/autologous stem cell rescue (HDT/ASCR)

iii. As re-indication therapy, in selected cases, for relapse after initial treatment with chemoimmunotherapy in individuals who are not candidates for HDT/ASCR

iv. For classical or symptomatic indolent TP53 wildtype stage II bulky, III, or IV disease in individuals who are not candidates for HDT/ASCR.

3. Castleman Disease (NCCN 2A)

a. Subsequent therapy with or without rituximab for multicentric CD that has progressed following treatment of relapsed/refractory or progressive disease (NCCN 2A)

4. Kaposi Sarcoma (NCCN 2A)

a. Subsequent systemic therapy, given alone (no HIV) or with antiretroviral therapy (ART) for people with HIV (PWH), for relapsed/refractory advanced cutaneous, oral, visceral, or nodal disease that has progressed on or not responded to first-line systemic therapy, and progressed on alternate first-line systemic therapy.

5. Multiple Myeloma (FDA 2021) (NCCN 1 and 2A)

a. Primary therapy for symptomatic multiple myeloma or for disease relapse after 6 months following primary induction therapy with the same regimen. (NCCN 1 for combination with dexamethasone and lenalidomide when used as primary therapy, or for combination dexamethasone in the relapse setting; NCCN 2A for all others)

i. in combination with dexamethasone and lenalidomide (preferred regimen)

ii. in combination with dexamethasone and cyclophosphamide (preferred primarily as initial treatment in individuals with acute renal insufficiency or those who have no access to bortezomib/lenalidomide/dexamethasone) (useful in certain circumstances when used as primary therapy; other recommended regimen when used in the relapse setting)

iii. in combination with dexamethasone, cyclophosphamide, and daratumumab (useful in certain circumstances for transplant candidates when used as primary therapy; other recommended regimen for non-transplant candidates when used as primary therapy or when used in the relapse setting)

iv. in combination with dexamethasone for non-transplant candidates (useful in certain circumstances)

v. in VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) regimen for transplant candidates (useful in certain circumstances, generally reserved for the treatment of aggressive multiple myeloma)

b. Therapy for previously treated multiple myeloma for relapse or progressive disease in (NCCN 1 in combination with dexamethasone with or without daratumumab, pomalidomide, liposomal doxorubicin or selinexor; NCCN 2A for all others)

i. combination with dexamethasone and lenalidomide (preferred regimen)

ii. combination with dexamethasone and daratumumab (preferred regimen)

iii. combination with pomalidomide and dexamethasone for individuals who have received at least two prior therapies, including an immunomodulatory agent and a proteasome inhibitor and who have demonstrated disease progression on or within 60 days of completion of the last therapy (preferred regimen)

iv. combination with dexamethasone and liposomal doxorubicin

v. combination with dexamethasone and cyclophosphamide

vi. combination with dexamethasone, cyclophosphamide, and daratumumab

vii. combination with elotuzumab and dexamethasone

viii. combination with selinexor and dexamethasone (once weekly)

ix. combination with dexamethasone (useful in certain circumstances)

x. VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) regimen (useful in certain circumstances, generally reserved for the treatment of aggressive multiple myeloma)

c. Primary therapy for symptomatic multiple myeloma (NCCN 2A for combination with dexamethasone and doxorubicin, or for combination with daratumumab, thalidomide, and dexamethasone, or for combination with dexamethasone, daratumumab and lenalidomide, or as part of VRd-lite regimen; NCCN 1 for all others)

i. in combination with dexamethasone, daratumumab and lenalidomide for transplant candidates

ii. in combination with daratumumab, melphalan hydrochloride, and prednisone for non-transplant candidates

iii. in combination with dexamethasone and doxorubicin for transplant candidates (useful in certain circumstances)

iv. in combination with dexamethasone and thalidomide for transplant candidates (useful in certain circumstances)

v. in combination with daratumumab, thalidomide, and dexamethasone for transplant candidates (useful in certain circumstances)

vi. as part of VRd-lite (bortezomib, lenalidomide, and dexamethasone) regimen for non-transplant candidates (useful in certain circumstances, for frail individuals)

d. Treatment in combination with dexamethasone for the management of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome (NCCN 2A)

i. as induction therapy for transplant eligible individuals

ii. for transplant ineligible individuals

e. Maintenance therapy for symptomatic multiple myeloma after response to primary myeloma therapy or for response or stable disease following autologous hematopoietic cell transplant. (NCCN 1 for maintenance therapy for response or stable disease following hematopoietic cell transplant; NCCN 2A for all others)

i. as a single agent

ii. in combination with lenalidomide (useful in certain circumstances; dual maintenance recommended for high-risk disease)

iii. in combination with lenalidomide and dexamethasone for transplant candidates (useful in certain circumstances, dual maintenance recommended for high-risk disease)

f. Therapy for previously treated multiple myeloma for late relapse or progressive disease (>3 prior therapies) in combination with bendamustine and dexamethasone. (NCCN 2A)

6. Systemic Light Chain Amyloidosis (NCCN 1 for combination with daratumumab and hyaluronidase-fihj, cyclophosphamide, and dexamethasone; NCCN 2A for all others)

a. Treatment for relapsed/refractory disease

i. as a single agent

ii. in combination with dexamethasone

iii. in combination with cyclophosphamide and dexamethasone.

iv. in combination with dexamethasone and melphalan

b. Treatment for newly diagnosed disease or consider for relapsed/refractory disease as a repeat of initial therapy if relapse-free for several years.

i. in combination with daratumumab and hyaluronidase-fihj, cyclophosphamide, and dexamethasone (preferred)

ii. in combination with cyclophosphamide and dexamethasone

iii. as a single agent

iv. in combination with dexamethasone

v. in combination with lenalidomide and dexamethasone

vi. in combination with dexamethasone and melphalan

7. Adult T-Cell Leukemia/Lymphoma (NCCN 2A)

a. Second-line or subsequent therapy as a single agent for nonresponders to first-line therapy for acute or lymphoma subtypes

8. Lymphoplasmacytic Lymphoma – Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma (NCCN 2A)

a. Used as primary therapy, or consider for relapse if previously used as primary therapy that was well tolerated and elicited a prolonged response, or as alternative therapy for previously treated disease that does not respond to primary therapy or for progressive or relapsed disease in combination with dexamethasone and rituximab (preferred)

Pediatrics:

9. Pediatric Acute Lymphoblastic Leukemia (NCCN 2A)

a. Therapy for relapsed/refractory Ph-negative B-ALL, or in combination with dasatinib or imatinib for relapsed/refractory Ph-positive B-ALL as a component of COG AALL07P1 regimen.

b. Therapy for T-LBL (T-lymphoblastic lymphoma) in combination with Berlin-Frankfurt-Munster (BFM) backbone chemotherapy.

c. Therapy for relapsed/refractory T-ALL as a component of a bortezomib-containing regimen (e.g., bortezomib, vincristine, doxorubicin, pegaspargase, and prednisone or dexamethasone)

10. Pediatric Hodgkin Lymphoma (NCCN 2A)

a. Subsequent therapy in combination with ifosfamide and vinorelbine for relapsed or refractory disease

The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Dosage and Administration

FDA dosing for Mantle Cell Lymphoma and Multiple Myeloma:

The recommended starting dose of bortezomib is 1.3 mg/ square meters administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection.
Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose.
Hepatic Impairment: Use a lower starting dose for individuals with moderate or severe hepatic impairment.
Dose must be individualized to prevent overdose.

Bortezomib is available in a single-dose vial containing of 3.5 mg lyophilized powder for reconstitution.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Bortezomib does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for any indication or circumstance other than those outlined above.

For members with contracts without primary coverage criteria, Bortezomib is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective October 15, 2022 to July 11, 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Bortezomib meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:

ADULTS:

1. Acute Lymphoblastic Leukemia (NCCN 2A)

a. Used in combination with chemotherapy for relapsed/refractory Philadelphia chromosome-negative T-ALL

2. Mantle Cell Lymphoma (FDA 2021) (NCCN 2A)

a. In the absence of a clinical trial*, consider as preferred less aggressive induction therapy for classical or symptomatic indolent TP53 mutated stage II bulky, III, or IV disease as a component of VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen

*TP53 mutation has been associated with poor prognosis in patients treated with conventional therapy, including transplant – clinical trial is strongly recommended.

b. Useful in certain circumstances as second-line and subsequent therapy as a single agent or in combination with rituximab for:

i. Stage I-II disease with partial response, progression, or relapse after prior treatment with chemoimmunotherapy

ii. Classical or symptomatic indolent stage II bulky, III, or IV disease in patients who have stable or progressive disease or partial response with substantial disease after induction therapy

iii. Relapsed or refractory disease (if not previously given)

c. Preferred less aggressive induction therapy as component of VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone) regimen

i. As initial therapy for stage I-II disease

ii. As additional therapy for partial response, progression, or relapse after initial treatment with involved site radiation therapy alone in patients who are not candidates for high-dose therapy/autologous stem cell rescue (HDT/ASCR)

iii. As re-indication therapy, in selected cases, for relapse after initial treatment with chemoimmunotherapy in patients who are not candidates for HDT/ASCR

iv. For classical or symptomatic indolent TP53 wildtype stage II bulky, III, or IV disease in patients who are not candidates for HDT/ASCR.

3. Castleman Disease (NCCN 2A)

a. Subsequent therapy with or without rituximab for multicentric CD that has progressed following treatment of relapsed/refractory or progressive disease (NCCN 2A)

4. Kaposi Sarcoma (NCCN 2A)

a. Subsequent systemic therapy, given alone (no HIV) or with antiretroviral therapy (ART) for people with HIV (PWH), for relapsed/refractory advanced cutaneous, oral, visceral, or nodal disease that has progressed on or not responded to first-line systemic therapy, and progressed on alternate first-line systemic therapy

5. Multiple Myeloma (FDA 2021) (NCCN 1 and 2A)

a. Primary therapy for symptomatic multiple myeloma or for disease relapse after 6 months following primary induction therapy with the same regimen

i. in combination with dexamethasone and lenalidomide (preferred regimen)

ii. in combination with dexamethasone and cyclophosphamide (preferred primarily as initial treatment in patients with acute renal insufficiency or those who have no access to bortezomib/lenalidomide/dexamethasone) (useful in certain circumstances when used as primary therapy; other recommended regimen when used in the relapse setting)

iii. in combination with dexamethasone, cyclophosphamide, and daratumumab (useful in certain circumstances for transplant candidates when used as primary therapy; other recommended regimen for non-transplant candidates when used as primary therapy or when used in the relapse setting)

iv. in combination with dexamethasone for non-transplant candidates (useful in certain circumstances)

v. in VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) regimen for transplant candidates (useful in certain circumstances, generally reserved for the treatment of aggressive multiple myeloma)

b. Therapy for previously treated multiple myeloma for relapse or progressive disease in

i. combination with dexamethasone and lenalidomide (preferred regimen)

ii. combination with dexamethasone and daratumumab (preferred regimen)

iii. combination with pomalidomide and dexamethasone for patients who have received at least two prior therapies, including an immunomodulatory agent and a proteasome inhibitor and who have demonstrated disease progression on or within 60 days of completion of the last therapy (preferred regimen)

iv. combination with dexamethasone and bendamustine

v. combination with dexamethasone and liposomal doxorubicin

vi. combination with dexamethasone and cyclophosphamide

vii. combination with dexamethasone, cyclophosphamide, and daratumumab

viii. combination with elotuzumab and dexamethasone

ix. combination with selinexor and dexamethasone (once weekly)

x. combination with dexamethasone (useful in certain circumstances)

xi. VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) regimen (useful in certain circumstances, generally reserved for the treatment of aggressive multiple myeloma)

c. Primary therapy for symptomatic multiple myeloma

i. in combination with dexamethasone, daratumumab and lenalidomide for transplant candidates

ii. in combination with daratumumab, melphalan hydrochloride, and prednisone for non-transplant candidates

iii. in combination with dexamethasone and doxorubicin for transplant candidates (useful in certain circumstances)

iv. in combination with dexamethasone and thalidomide for transplant candidates (useful in certain circumstances)

v. in combination with daratumumab, thalidomide, and dexamethasone for transplant candidates (useful in certain circumstances)

vi. as part of VRd-lite (bortezomib, lenalidomide, and dexamethasone) regimen for non-transplant candidates (useful in certain circumstances, for frail patients)

d. Treatment in combination with dexamethasone for the management of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) syndrome

i. as induction therapy for transplant eligible patients

ii. for transplant ineligible patients

e. Maintenance therapy for symptomatic multiple myeloma after response to primary myeloma therapy or for response or stable disease following autologous hematopoietic cell transplant

i. as a single agent

ii. in combination with lenalidomide (useful in certain circumstances; dual maintenance recommended for high-risk disease)

iii. in combination with lenalidomide and dexamethasone for transplant candidates (useful in certain circumstances, dual maintenance recommended for high-risk disease)

6. Systemic Light Chain Amyloidosis (NCCN 1 and 2A)

a. Treatment for relapsed/refractory disease

i. as a single agent

ii. in combination with dexamethasone

iii. in combination with dexamethasone and melphalan

b. Treatment for newly diagnosed disease or consider for relapsed/refractory disease as a repeat of initial therapy if relapse-free for several years

i. in combination with daratumumab and hyaluronidase-fihj, cyclophosphamide, and dexamethasone (preferred)

ii. in combination with cyclophosphamide and dexamethasone

iii. as a single agent

iv. in combination with dexamethasone

v. in combination with lenalidomide and dexamethasone

vi. in combination with dexamethasone and melphalan

7. Adult T-Cell Leukemia/Lymphoma (NCCN 2A)

a. Second-line or subsequent therapy as a single agent for nonresponders to first-line therapy for acute or lymphoma subtypes

8. Lymphoplasmacytic Lymphoma – Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma (NCCN 2A)

a. Used as primary therapy, or consider for relapse if previously used as primary therapy that was well tolerated and elicited a prolonged response, or as alternative therapy for previously treated disease that does not respond to primary therapy or for progressive or relapsed disease in combination with dexamethasone and rituximab (preferred)

Pediatrics:

9. Pediatric Acute Lymphoblastic Leukemia (NCCN 2A)

a. Therapy for relapsed/refractory Ph-negative B-ALL, or in combination with dasatinib or imatinib for relapsed/refractory Ph-positive B-ALL as a component of COG AALL07P1 regimen.

b. Therapy for relapsed/refractory T-ALL as a component of a bortezomib-containing regimen (e.g., bortezomib, vincristine, doxorubicin, pegaspargase, and prednisone or dexamethasone)

10. Pediatric Hodgkin Lymphoma (NCCN 2A)

a. Subsequent therapy in combination with ifosfamide and vinorelbine for relapsed or refractory disease

Dosage and Administration

FDA dosing for Mantle Cell Lymphoma and Multiple Myeloma:

· The recommended starting dose of bortezomib is 1.3 mg/m2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection.

· Retreatment for Multiple Myeloma: May retreat starting at the last tolerated dose.

· Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment.

· Dose must be individualized to prevent overdose.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Bortezomib does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any circumstance other than those outlined above .

Rationale:

Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance) were compared. A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in a retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m2); median dose intensity was lower (2.0 vs 5.1 mg/m2/month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen. (Mateos MV, Oriol A, Martínez-López J, et.al., 2016)

Bortezomib-dexamethasone is widely used for relapsed myeloma in routine clinical practice, but comparative data versus single-agent bortezomib are lacking. A retrospective analysis compared second-line treatment with bortezomib-dexamethasone and bortezomib using 109 propensity score-matched pairs of patients treated in three clinical trials: MMY-2045, APEX, and DOXIL-MMY-3001. Propensity scores were estimated using logistic regression analyses incorporating 13 clinical variables related to drug exposure or clinical outcome. Patients received intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, in 21-day cycles, alone or with oral dexamethasone 20 mg on the days of/after bortezomib dosing. Median bortezomib cumulative dose (27.02 and 28.60 mg/m(2)) and treatment duration (19.6 and 17.6 weeks) were similar with bortezomib-dexamethasone and bortezomib, respectively. The overall response rate was higher (75% vs. 41%; odds ratio=3.467; P<0.001), and median time-to-progression (13.6 vs. 7.0 months; hazard ratio [HR]=0.394; P=0.003) and progression-free survival (11.9 vs. 6.4 months; HR=0.595; P=0.051) were longer with bortezomib-dexamethasone versus bortezomib, respectively. Rates of any-grade adverse events, most common grade 3 or higher adverse events, and discontinuations due to adverse events appeared similar between the groups. Two patients per group died of treatment-related adverse events. These data indicate the potential benefit of bortezomib-dexamethasone compared with single-agent bortezomib at first relapse in myeloma. (Dimopoulos MA, Orlowski RZ, Facon T, et.al., 2015)

Bortezomib is approved for both subcutaneous (SC) and IV administration. Approval of SC administration was based on the phase III MMY-3021 study in 222 patients with relapsed MM, which demonstrated non-inferiority of SC versus IV bortezomib in terms of response rates after four cycles, similar efficacy, and an improved systemic safety profile. To confirm these findings in the setting of renal impairment, a post hoc subanalysis was conducted to compare activity, response kinetics, long-term outcomes, and safety with SC versus IV bortezomib in patients with moderate-to-severe (CrCl 20–50 mL/min) or mild/no renal impairment (baseline CrCl >50 mL/min).

Patients were randomized 2:1 to receive up to eight 21-day cycles of SC or IV bortezomib 1.3 mg/m2 on days 1, 4, 8, and 21. Two additional cycles were permitted for patients with evolving response. Dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 could be added from cycle 5 onwards. All patients required adequate hematologic, hepatic, and renal function (baseline CrCl ≥20 mL/min).

Response rates were generally similar between SC and IV bortezomib in patients with CrCl more than 50 mL/min; the relative risk of response was 0.92 (95%CI: 0.69, 1.22; unstratified Mantel-Haenszel estimate). Overall response rate also appeared to be similar with SC bortezomib in patients with CrCl 20–50 mL/min and CrCl more than 50 mL/min (53% and 52%, respectively). In the patient population with CrCl 20–50 mL/min, time to response was rapid via both routes of bortezomib administration; a finding also seen in the subgroups of patients with CrCl more than 50 mL/min. In addition, among patients with baseline CrCl 20–50 mL/min, clinical benefit in terms of renal impairment reversal (to CrCl >60 mL/min) was reported in 10 (30%) SC bortezomib patients and 2 (15%) IV bortezomib patients.

Overall median follow up was 17.3 months in the SC arm and 17.8 months in IV arm. In the subgroups of patients with CrCl more than 50 mL/min, long-term outcomes including time to progression (TTP), progression-free survival (PFS), and overall survival (OS) were generally similar between SC and IV bortezomib (Table 2). Median TTP (10.5 and 9.7 months) and median PFS (8.6 and 9.5 months) also appeared to be similar between patients with CrCl 20–50 mL/min and CrCl more than 50 mL/min who received SC bortezomib. However, OS with SC bortezomib appeared somewhat shorter in patients with CrCl 20–50 mL/min compared with patients with CrCl more than 50 mL/min (1-year OS: 69.7% and 78.3%, respectively). These data suggest that SC bortezomib may possibly partly overcome the negative prognostic impact of renal impairment, while the apparent trend to shorter OS may be influenced by the use of subsequent therapies that do not sustain the effect of SC bortezomib in renally impaired patients.

Findings showed an improved systemic safety profile with SC versus IV bortezomib in patients with CrCl more than 50 mL/min, with the most common AEs including PN not elsewhere classified (NEC; high-level term) (36% vs. 57%), anemia (33% vs. 38%), and thrombocytopenia (33% vs. 41%). Overall, 54% versus 69% of patients with CrCl more than 50 mL/min receiving SC versus IV bortezomib reported grade 3 or more AEs, which included 5% versus 18% PN NEC. Serious AEs were reported in 35% versus 33% of patients, 22% versus 28% of patients discontinued due to AEs, and 3% versus 7% of patients died due to AEs with SC versus IV bortezomib. In patients with CrCl 20–50 mL/min, comparisons of the safety profiles of SC and IV bortezomib are confounded; the relative safety profiles differed compared with in the overall study population, likely associated with the difference in treatment exposure.

The findings of the subanalysis indicate that SC bortezomib appears effective in patients with renal impairment, resulting in a beneficial impact in terms of response rates and long-term outcomes, including TTP, PFS, and OS. Of clinical importance, SC bortezomib resulted in a 30% rate of renal impairment reversal in this patient population. Moreover, across renal subgroups, SC bortezomib resulted in a rapid onset of response. Notably, the activity and safety of SC bortezomib in MM patients with renal impairment demonstrated in these analyses appear to reflect previously reported data on IV bortezomib-based therapy in this setting. Furthermore, the findings from this post hoc subgroup analysis of the MMY-3021 study add to the increasing level of recent data on SC bortezomib in previously untreated and relapsed/refractory MM that support the feasibility and utility of this route of administration. For example, similar efficacy and a substantially lower rate of PN were seen with SC compared with IV bortezomib in the bortezomib-thalidomide-dexamethasone regimen when used as pre-transplant induction therapy in previously untreated patients.

In conclusion, the findings from the subgroup analysis, combined with data from other recent studies, support the use of SC bortezomib across the MM treatment algorithm in settings in which bortezomib use is established, including as a feasible and effective treatment that can enable renal function reversal in relapsed MM patients with moderate-to-severe renal impairment. (Moreau P, Pylypenko H, Grosicki S, et.al., 2015)

An open-label, multicenter study randomized 54 patients with multiple myeloma who had progressed or relapsed on or after front-line therapy to receive VELCADE 1 mg/m2 or 1.3 mg/m2 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 VELCADE 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/m2 and 38% (10/26) at 1.3 mg/m2. (FDA 2021)

Patients from the two Phase 2 studies, who in the investigators’ opinion would experience additional clinical benefit, continued to receive VELCADE 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 VELCADE 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 VELCADE treatment. (FDA 2021)

A single-arm, open-label trial (NCT00431769) was conducted to determine the efficacy and safety of retreatment with VELCADE. One hundred and thirty patients (≥18 years of age) with multiple myeloma who previously had at least partial response on a VELCADE-containing regimen (median of two prior lines of therapy [range: 1 to 7]) were retreated upon progression with VELCADE 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 VELCADE therapy, VELCADE was restarted at the last tolerated dose of 1.3 mg/m2 (n=93) or ≤1 mg/m2 (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 VELCADE to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of VELCADE 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. (FDA 2021)

In a randomized, open-label, phase 3 study done at 128 clinical centers in 28 countries in Asia, Europe, North America, and South America. adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomization was done according to a computer-generated randomization schedule prepared by the sponsor; permuted blocks central randomization was used (block size of 4) and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analyzed in the intention-to-treat population.

Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease.

Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. ( Robak T, Jin J, Pylypenko H, et. al., 2018)

The safety and efficacy of VELCADE in relapsed or refractory mantle cell lymphoma were evaluated in an open-label, single-arm, multicenter study (NCT00063713) of 155 patients with progressive disease who had received at least one prior therapy. The median age of the patients was 65 years (42, 89), 81% were male, and 92% were Caucasian. Of the total, 75% had one or more extra-nodal sites of disease, and 77% were Stage 4. In 91% of the patients, prior therapy included all of the following: an anthracycline or mitoxantrone, cyclophosphamide, and rituximab. A total of thirty-seven percent (37%) of patients were refractory to their last prior therapy. An intravenous bolus injection of VELCADE 1.3 mg/m2/dose was administered twice weekly for two weeks on Days 1, 4, 8, and 11 followed by a ten-day rest period (Days 12 to 21) for a maximum of 17 treatment cycles. Patients achieving a CR or CRu were treated for four cycles beyond first evidence of CR or CRu. The study employed dose modifications for toxicity [see Dosage and Administration (2.6, 2.7)]. Responses to VELCADE are shown in Table 19. Response rates to VELCADE were determined according to the International Workshop Response Criteria (IWRC) based on independent radiologic review of CT scans. The median number of cycles administered across all patients was four; in responding patients the median number of cycles was eight. The median time to response was 40 days (range: 31 to 204 days). The median duration of follow-up was more than 13 months. (FDA 2021)

2023 Update

Children and young adults with T-ALL/T-LL were randomly assigned to a modified augmented Berlin-Frankfurt-Münster chemotherapy regimen with/without bortezomib during induction and delayed intensification. Multiple modifications were made to the augmented Berlin-Frankfurt-Münster backbone used in the predecessor trial, AALL0434, including using dexamethasone instead of prednisone and adding two extra doses of pegaspargase in an attempt to eliminate CRT in most patients.

AALL1231 accrued 824 eligible and evaluable patients from 2014 to 2017. The 4-year event-free survival (EFS) and overall survival (OS) for arm A (no bortezomib) versus arm B (bortezomib) were 80.1% ± 2.3% versus 83.8% ± 2.1% (EFS, P = .131) and 85.7% ± 2.0% versus 88.3% ± 1.8% (OS, P = .085). Patients with T-LL had improved EFS and OS with bortezomib: 4-year EFS (76.5% ± 5.1% v 86.4% ± 4.0%; P = .041); and 4-year OS (78.3% ± 4.9% v 89.5% ± 3.6%; P = .009). No excess toxicity was seen with bortezomib. In AALL0434, 90.8% of patients with T-ALL received CRT. In AALL1231, 9.5% of patients were scheduled to receive CRT. Evaluation of comparable AALL0434 patients who received CRT and AALL1231 patients who did not receive CRT demonstrated no statistical differences in EFS (P = .412) and OS (P = .600).

Patients with T-LL had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. Systemic therapy intensification allowed elimination of CRT in more than 90% of patients with T-ALL without excess relapse. (Teachey DT, Devidas M, Wood BL, et.al., 2022)

CPT/HCPCS:

References:

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