A phase 2 trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303)

BACKGROUND:

Bortezomib, an inhibitor of the 26S proteasome and NF‐κB, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin.

METHODS:

Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0‐2, and ejection fraction within normal limits. Patients with stable disease for ≥9 months were excluded. Patients received bortezomib 1.3 mg/m² by intravenous (IV) push on Days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20 mg/m² IV on Days 1 and 8 was added at the time of progression.

RESULTS:

Twenty‐five patients were enrolled, of whom 24 were eligible; the most common distant metastatic sites were the lung (n = 22) and the liver (n = 7). There was no objective response with single‐agent bortezomib; best response was stable disease in 15 (71%) of 21 evaluable patients. The median progression‐free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response, and 6 had stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin, serious toxicities seen more than once were grade 3‐4 neutropenia (n = 3) and grade 3 anorexia (n = 2).

CONCLUSIONS:

Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC. Cancer 2011. © 2011 American Cancer Society.     

Bortezomib,thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma

BACKGROUND:

This single‐center retrospective study determined the efficacy of bortezomib, thalidomide, and dexamethasone (BTD) as induction for patients with multiple myeloma (MM) who were eligible for autologous stem cell transplantation (ASCT).

METHODS:

Patients with symptomatic MM who had received BTD induction before stem cell collection at Winship Cancer Institute were included. BTD induction comprised up to 8 3‐week cycles of bortezomib 1.3 mg/m² on Days 1, 4, 8, and 11; thalidomide 100 mg daily; and dexamethasone 40 mg on Days 1 through 4 and Days 9 through 12. Stem cell mobilization involved granulocyte‐colony–stimulating factor and/or cyclophosphamide. Response was assessed according to European Group for Blood and Marrow Transplantation criteria.

RESULTS:

Review of medical records identified 44 eligible patients (34 patients who were treated in the front‐line setting and 10 patients who were treated for recurrent disease) who received a median of 4 BTD cycles. The overall response rate (ORR) was 91%, which included a greater than or equal to very good partial response (≥VGPR) rate of 57% (including 20% stringent complete responses/complete response [sCR/CR] rate). In front‐line patients, the ORR was 94%, which included a 56% ≥VGPR rate (24% sCR/CR). The median CD34‐positive stem cell collection was 10.67 × 10⁶/kg. The ORR after ASCT in 34 patients who were evaluable for response was 100%, including a 76% ≥VGPR rate (53% sCR/CR). Among all 44 patients, the median progression‐free survival (PFS) was 27.4 months. The median overall survival (OS) was not reached after a median follow‐up of 25 months, and the 2‐year OS rate was 82%. There were no significant differences in PFS (27.4 months vs 23.5 months) or in 2‐year survival (80% vs 90%) between patients who did and did not undergo ASCT, respectively. Twenty patients (45%) developed neuropathy, including 4 (9%) with grade 3 neuropathy episodes, and 1 patient developed deep vein thrombosis.

CONCLUSIONS:

BTD was highly effective and well tolerated as induction for MM patients who were eligible for ASCT. Long‐term outcomes appeared to be similar with or without ASCT consolidation. Cancer 2010. © 2010 American Cancer Society.     

Bortezomib,melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma

BACKGROUND:

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event‐free survival compared with MP alone.

METHODS:

In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose‐intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m² on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28‐day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled.

RESULTS:

After a median follow‐up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles.

CONCLUSIONS:

A weekly infusion of bortezomib associated with lower dose‐intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM. Cancer 2013. © 2012 American Cancer Society.     

A study of paclitaxel,carboplatin, and bortezomib in the treatment of metastatic malignant melanoma

BACKGROUND:

Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3‐drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma).

METHODS:

A 2‐stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3‐agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m² intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m²; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21‐day cycle. The primary endpoint of this trial was tumor response rate (TRR).

RESULTS:

Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1‐7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade ≥3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression‐free survival was 3.2 months, and the median overall survival was 7.0 months.

CONCLUSIONS:

Due to insufficient clinical efficacy, this trial did not proceed to second‐stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity. Cancer 2010. © 2010 American Cancer Society.     

Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia

BACKGROUND:

Dose intensification of chemotherapy has improved outcome for younger adults with de novo acute lymphoblastic leukemia (ALL). Novel formulations of standard chemotherapy agents may further reduce the incidence of disease recurrence after frontline chemotherapy. Vincristine (VCR) sulfate liposomes injection (VSLI) is a sphingomyelin/cholesterol nanoparticle encapsulated VCR formulation that improves the pharmacokinetic profile of VCR without augmenting neurotoxicity.

METHODS:

A phase 1 trial of weekly, intravenous VSLI at 1.5 mg/m², 1.825 mg/m², 2.0 mg/m², 2.25 mg/m², or 2.4 mg/m² was conducted to determine the maximum tolerated dose (MTD) using a standard, 3 + 3 dose‐escalation design. Dexamethasone (40 mg) was given on Days 1 through 4 and on Days 11 through 14 of each 4‐week cycle.

RESULTS:

Thirty‐six adults with relapsed/refractory ALL, all previously treated with conventional VCR, received at least 1 dose of VSLI. The MTD of VSLI was 2.25 mg/m² based on dose‐limiting toxicities of grade 3 motor neuropathy, grade 4 seizure, and grade 4 hepatotoxicity in 1 patient each at the 2.4 mg/m² dose level. The most common toxicities attributed to VSLI included peripheral neuropathy (55%) and constipation (53%). A complete response (CR) was achieved in 7 of 36 patients (19%) based on an intent‐to‐treat analysis; the CR rate was 29% for the 14 patients who underwent therapy as their first salvage attempt. Four of 7 patients who achieved a CR underwent subsequent allogeneic stem cell transplantation in remission.

CONCLUSIONS:

In this study, VSLI plus dexamethasone appeared to be an effective salvage therapy option for relapsed/refractory ALL. A phase 2, international, multicenter clinical trial assessing the efficacy of single‐agent VSLI as second salvage therapy for patients with previously treated ALL is underway. Cancer 2009. © 2009 American Cancer Society.     

Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma

BACKGROUND:

In vitro studies in mantle cell lymphoma (MCL) cell lines and patient‐derived cells have demonstrated synergistic apoptosis with combined rituximab and bortezomib (R‐bortezomib) compared with single‐agent bortezomib. Therefore, the authors of this report evaluated R‐bortezomib in a preclinical model and in a phase 2 clinical trial.

METHODS:

A Hu‐MCL‐severe combined immunodeficiency (SCID) model engrafted with the Jeko cell line was treated with R‐bortezomib, bortezomib, or rituximab. Twenty‐five patients with relapsed follicular lymphoma (n = 11) and MCL (n = 14) received 375 mg/m² rituximab on Days 1 and 8 and 1.3 to 1.5 mg/m² bortezomib on Days 1, 4, 8, and 11 every 21 days for a median of 3 cycles (range, 1‐5 cycles).

RESULTS:

R‐bortezomib resulted in a statistically significant improvement in overall survival in Hu‐MCL‐SCID mice. In the clinical trial, the overall response rate was 40% in all 25 patients, 55% in patients with follicular lymphoma, and 29% in patients with MCL. The estimated 2‐year progression‐free survival (PFS) rate was 24% (95% confidence interval [CI], 10%‐53%) in all patients and 60% (95% CI, 20%‐85%) in responding patients. Thirteen patients (52%) developed grade 3 neurotoxicity, which consisted of constipation/ileus, sensory or motor neuropathy, or orthostatic hypotension. Patients who were heterozygous for the CD32a (Fcγ receptor IIa) 131 histidine (H) to arginine (R) polymorphism had a significantly decreased PFS (P = .009) after R‐bortezomib compared with HH and RR homozygotes.

CONCLUSIONS:

R‐bortezomib had significant activity in patients with relapsed or refractory follicular lymphoma and MCL, although an unexpectedly high incidence of grade 3 neurologic toxicity was a potential limiting factor with this combination. Cancer 2011. © 2010 American Cancer Society.     

Oxaliplatin‐based chemotherapy (dexamethasone,high‐dose cytarabine,and oxaliplatin) ± rituximab is an effective salvage regimen in patients with relapsed or refractory lymphoma

BACKGROUND:

Patients affected by relapsed or primary refractory lymphomas currently have a poor prognosis and no standard salvage treatment options. This study was carried out to assess the efficacy and safety of a dexamethasone, high‐dose cytarabine, and oxaliplatin as salvage therapy in those patients, replacing cisplatin with oxaliplatin in the standard dexamethasone, cytarabine, and cisplatin scheme.

METHODS:

Seventy patients with relapsed or refractory aggressive non‐Hodgkin or Hodgkin lymphoma were treated from September 2001 to September 2007. The median age of patients was 51 years (range, 19‐75 years). Histological subtypes were: diffuse large B‐cell lymphoma (n = 47) and Hodgkin lymphoma (n = 23). The overall response rate was 73% (51 of 70), with 30 (43%) complete remissions and 21 (30%) partial remissions. Fifty‐two patients were treated with dexamethasone, high‐dose cytarabine, and oxaliplatin as second‐line chemotherapy. Forty‐eight patients were enrolled in an autologous stem cell transplantation program; forty (83%) finally proceeded to high‐dose consolidation and autografting.

RESULTS:

No grade 3 or 4 nonhematological toxicity was demonstrated; in particular, no renal or neurotoxicity was reported. After a median follow‐up period of 21 months (range, 2‐87 months), 22 (31%) patients had died. Probabilities of 2‐year progression‐free survival (PFS) and overall survival (OS) were 44% and 71%, respectively. In the chemosensitive patients, the PFS and OS were 52% and 83%, respectively. The only factor that significantly correlated with better OS was the response to therapy.

CONCLUSIONS:

This study confirms that dexamethasone, high‐dose cytarabine, and oxaliplatin ± rituximab is an effective and feasible outpatient regimen for salvage therapy in patients affected by relapsed or refractory lymphoma. Moreover, the feasibility and efficacy of this scheme as an in vivo chemosensitive test in patients in autotransplantation programs was confirmed. Cancer 2010. © 2010 American Cancer Society.     

Efficacy and toxicity of 2 schedules of frontline rituximab plus cyclophosphamide,doxorubicin, vincristine,and prednisone plus bortezomib in patients with B‐cell lymphoma

BACKGROUND:

Bortezomib demonstrated promising activity in lymphomas. The authors conducted a randomized phase 2 trial of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) with the addition of bortezomib in patients with B‐cell lymphoma.

METHODS:

Patients were randomized between 2 schedules of bortezomib, Arm A (Days 1, 4, 8, and 11) and Arm B (Days 1 and 8), combined with 6 cycles of R‐CHOP. For the first patients (Step 1), bortezomib was given at a dose of 1 mg/m² in Arm A and 1.3 mg/m² in Arm B. For the next patients (Step 2), doses were increased to 1.3 mg/m² and 1.6 mg/m² in Arms A and B, respectively. The primary endpoint was the rate of complete response (CR) and unconfirmed CR (CR/CRu) after 6 cycles.

RESULTS:

Forty‐nine patients were included in the study, and 41 patients (84%) achieved a CR/CRu, ie, 18 of 20 patients (90%) in Arm A and 23 of 29 patients (79%) in Arm B. There were 6 partial responses and 2 patients with progressive disease. Neurologic toxicity occurred in 21 patients (43%) and was grade 2 in 11 patients (7 patients in Step 2) and grade 3 in 10 patients (9 patients in Step 2). Other grade 3 and 4 toxicities included constipation (n = 1), infections (n = 3), and cardiac events (n = 2). Grade 3 and 4 thrombocytopenia and leucopenia occurred in 14% and 41% of cycles, respectively.

CONCLUSIONS:

R‐CHOP + bortezomib was an effective regimen and produced an 84% CR rate. However, the dose‐limiting neurotoxicity should be kept in mind for further trials with vinca alkaloids or other potentially neurotoxic drugs combination therapies. Cancer 2009. © 2009 American Cancer Society.     

A phase 2 pilot trial of low‐dose,continuous infusion,or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma

BACKGROUND:

Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX‐2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression. Thus, the authors tested the safety and efficacy of a low dose of paclitaxel and celecoxib in patients with MM.

METHODS:

Patients received paclitaxel 10 mg/m² for 96 hours weekly as a continuous intravenous infusion and oral celecoxib 400 mg twice daily. Systemic tumor response was assessed at 6‐week intervals. Tumor measurements at the end of Cycle 1 were used as the baseline for assessment of tumor progression. Patients with unacceptable toxicity or disease progression after Cycle 2 relative to the end of Cycle 1 were taken off study.

RESULTS:

Twenty patients were enrolled. Twelve of 20 patients (60%) had received ≥2 previous systemic therapies. Three patients did not receive treatment because of rapid disease progression. Treatment‐related grade 3/4 toxicities were limited to catheter‐related complications. One patient achieved a partial response, and 3 of 20 patients (15%) had stable disease for >6 months. The median time to progression was 57 days (95% confidence interval, 43‐151 days), and the median overall survival was 212 days (95% confidence interval, 147‐811 days).

CONCLUSIONS:

Low‐dose, continuous intravenous infusion paclitaxel and oral celecoxib produced disease stabilization in a significant proportion of heavily pretreated patients with MM. These findings support a role for metronomic therapy in patients with this disease. Cancer 2010. © 2010 American Cancer Society.     

An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Previously Treated Myeloma

Background

Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received ≥ 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability.

A phase 2 clinical trial of nab‐paclitaxel in previously treated and chemotherapy‐naive patients with metastatic melanoma

BACKGROUND:

nab‐Paclitaxel (ABI‐007, Abraxane), a 130‐nM, albumin‐bound (nab) particle form of Cremophor‐free paclitaxel, is approved for metastatic breast cancer. In the current study, the efficacy and safety of nab‐paclitaxel were evaluated in previously treated and chemotherapy‐naive patients with metastatic melanoma (MM).

METHODS:

Patients with histologically or cytologically confirmed, measurable MM were enrolled. nab‐Paclitaxel was administered intravenously weekly for 3 of 4 weeks at a dose of 100 mg/m² (in previously treated patients) or 150 mg/m² (in chemotherapy‐naive patients).

RESULTS:

Thirty‐seven patients were treated in each cohort. The response rate was 2.7% in the previously treated cohort and 21.6% in the chemotherapy‐naive cohort; the response plus stable disease rate was 37.8% and 48.6% in the previously treated and chemotherapy‐naive cohorts, respectively. The median progression‐free survival (PFS) was 3.5 months and 4.5 months, and the median survival was 12.1 months and 9.6 months, respectively. The probability of being alive and free of disease progression at 6 months was 27% for the previously treated cohort and 34% for the chemotherapy‐naive cohort; the probability of surviving 1 year was 49% and 41%, respectively, for the previously treated and chemotherapy‐naive cohorts. Approximately 78% of the previously treated patients and 49% of the chemotherapy‐naive patients were treated without dose reduction. Eight (22%) chemotherapy‐naive patients discontinued therapy because of toxicities. Drug‐related toxicities included grade 3 to 4 (graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neuropathy, alopecia, neutropenia, and fatigue.

CONCLUSIONS:

nab‐Paclitaxel was found to be well tolerated and demonstrated activity in both previously treated and chemotherapy‐naive patients with MM. The response rate, PFS, and survival compared favorably with current standard dacarbazine therapy and combination therapies for melanoma. nab‐Paclitaxel therapy of MM should be investigated further in controlled clinical trials. Cancer 2010. © 2010 American Cancer Society.     

A randomized phase 2 trial of a preparative regimen of bortezomib, high-dose melphalan, arsenic trioxide, and ascorbic acid

BACKGROUND:

Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and it has synergistic activity with melphalan. The authors of this report conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA), and melphalan.

METHODS:

Among 60 patients who enrolled between October 2006 and September 2007, 58 patients underwent autologous transplantation with a preparative regimen of melphalan 200 mg/m² intravenously, AA 1000 mg daily intravenously for 7 days, and ATO 0.25 mg/kg intravenously for 7 days. Patients were randomized to receive no bortezomib (Group 1), bortezomib 1 mg/m² × 3 doses (Group 2), and bortezomib 1.5 mg/m² × 3 doses (Group 3). Primary endpoints were complete response (CR), grade IV toxicity, and 90‐day treatment‐related mortality (TRM). Secondary endpoints were progression‐free survival (PFS) and overall survival (OS).

RESULTS:

The median follow‐up of all surviving patients was 36 months (range, 20‐43 months). The CR rates in Groups 1, 2, and 3 were 20%, 10%, and 10%, respectively. Grade 3 and 4 nonhematologic toxicities and TRM were comparable. The median OS was not reached in the groups, whereas the median PFS in Groups 1, 2, and 3 was 17.8 months, 17.4 months, and 20.7 months, respectively. PFS and OS were significantly shorter in patients who had high‐risk cytogenetics (P = .016 and P = .0001, respectively) and relapsed disease (P = .0001 and P = .0001, respectively) regardless of the treatment group.

CONCLUSIONS:

Adding bortezomib to a preparative regimen of ATO, AA, and high‐dose melphalan was safe and well tolerated in patients with multiple myeloma. There was no significant improvement in the CR rate, PFS, or OS in the bortezomib groups. Cancer 2012;. © 2011 American Cancer Society.     

Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline

Questions

1. In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate?
2. What is the toxicity associated with the use of bortezomib?
3. Which patients are more or less likely to benefit from treatment with bortezomib?

Perspectives

Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidence-based Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback.

Outcomes

Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events.

Methodology

A systematic search was conducted of the medline, embase, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc.

Results

The literature review found one randomized controlled trial (rct)—the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma.The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation.

Practice Guideline

This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status.

Recommendations

Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations:

• For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.
• Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline.
• For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent–based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent–based chemotherapy is recommended.
• Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials.

Qualifying Statements

Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg.For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes.

Dosage

Bortezomib 1.3,g/m² is given as a rapid intravenous bolus over 3–5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed.

Response to Treatment

Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone.The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent–based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.     

Bortezomib in combination with dexamethasone and subsequent thalidomide for newly-diagnosed multiple myeloma: A Chinese experience

ObjectiveBortezomib–dexamethasone–thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology 2007;12(3):235–9), but this regimen has not been tested in the Chinese patients. We report here our results testing with this combination in the Chinese population and to investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM.MethodsBetween June 2006 and March 2008, 20 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3 mg/m² IV on days 1, 4, 8 and 11 and dexamethasone at 20 mg/m² IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100 mg to 200 mg. Fourteen patients were male and 6 were female. Median age was 59 years (range 43–86 years). 11 patients were stage 2 according to the International Staging System, 8 were stage 3, only 1 patient was stage 1. All patients received a median of two cycles of therapy (range 1–6). The EBMT criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3.Results16 out of 20 patients (80%) achieved PR and 3 (15%) achieved CR; therefore the overall response rate was 95%. With a median follow-up duration of 7.8 months (4–22 months), no patients died. Grade 3–4 toxicities included fatigue (3/20), thrombocytopenia (10/20) diarrhea (5/20) and orthostatic hypotension (3/20) Grade 2 neuropathy occurred in four out of 20 patients and herpes zoster occurred in four out of 20 patients. Routine anticoagulation or anti-thrombosis was not used. Only 1 patient suffered from DVT/PE.ConclusionsOur preliminary experience in Chinese patients indicated that bortezomib–dexamethasone–thalidomide is highly effective in newly-diagnosed MM. Grade three and 4 toxicities are rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in the Chinese patients with MM are being cautiously observed.     

Gemcitabine alone or combined with cisplatin in relapsed or refractory multiple myeloma

Gemcitabine is a pyrimidine nucleoside analog with antitumor activity against solid tumor malignancies and leukemia. We evaluated its activity as a single agent and combining it with cisplatin in relapsed-refractory multiple myeloma (MM). Sixteen patients with advanced MM received intravenous gemcitabine 1250 mg/mq (days 1, 8 and 15) as a single agent for a total of 3 monthly courses. The responders received another three courses, and the non-responders received three courses of gemcitabine 1000 mg/mq (days 1, 8 and 15) plus cisplatin 80 mg/mq (day 1). No grade 4 hematological toxicity was seen after gemcitabine treatment, whereas > or = 3 grade neutropenia and thrombocytopenia were seen in 21 and 13% of the gemcitabine-cisplatin infusions, respectively. Non-hematological toxicity was negligible for both the regimens. After three courses of gemcitabine as a single agent, th e response rate was 31% (1 complete response, 1 partial response and 3 minimal response). Eight patients (50%) achieved stable disease and 3 (19%) had disease progression. Ten patients received gemcitabine-cisplatin and were evaluable for the response. Two patients progressed, four maintained stable disease whereas four patients, unresponsive to gemcitabine, obtained a response (3 partial response and 1 minimal response). With a median follow-up of 13 months (range 8-17.5), 7 patients (44%) died, 5 (31%) had disease progression, 1 (6%) relapsed, 1 was still in partial response (+11 months) and 2 (13%) had a stable disease. Median time to treatment failure (TTF) was 8 months (CI95%: 7.6-8.4) and median overall survival (OS) was 16 months (CI95%: 10-22). These results showed that gemcitabine and gemcitabine-cisplatin were feasible regimens and well tolerated in advanced relapsed-refractory MM. The response rates, the TTF and OS were similar to other salvage chemotherapy regimens; nevertheless, the quality of response was modest particularly after gemcitabine alone. Better results might be obtained combining gemcitabine with other chemotherapy compounds or with biologically based therapies.     

A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies

BACKGROUND:

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies.

METHODS:

Eligible patients had CNS malignancies that required a (minimum) 2‐week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3.

RESULTS:

Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8‐3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow‐up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6‐month progression‐free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT.

CONCLUSIONS:

Continuous 37.5‐mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial. Cancer 2011;. © 2011 American Cancer Society.     

A phase 1 dose escalation study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone for untreated follicular lymphoma and other low-grade B-cell lymphomas

BACKGROUND:

Bortezomib has demonstrated efficacy in patients with relapsed B‐cell non‐Hodgkin lymphoma (NHL) both alone and in combination with other agents; however, limited data exist regarding its toxicity in combination with common frontline therapies for indolent NHL. A phase 1 study of bortezomib combined with rituximab, cyclophosphamide, doxorubicin, modified vincristine, and prednisone (R‐CHOP) was conducted in patients with untreated follicular lymphoma (FL) and other indolent NHLs.

METHODS:

Nineteen patients, including 10 patients with FL, were enrolled. The median patient age was 59 years (range, 29‐71 years). Seven patients had a FL International Prognostic Index score ≥3. R‐CHOP with the vincristine dose capped at 1.5 mg was administered on a 21‐day cycle for 6 to 8 cycles, and 1 of 3 dose levels of bortezomib (1.0 mg/m² [n = 1], 1.3 mg/m² [n = 6], or 1.6 mg/m² [n = 12]) was administered on days 1 and 8 of each cycle using a Bayesian algorithm for dose escalation.

RESULTS:

The maximum tolerated dose (MTD) of bortezomib with modified R‐CHOP was reached at 1.6 mg/m². Dose‐limiting toxicity was observed in 5 patients (1 patient at a bortezomib dose of 1.0 mg/m², 1 patient at a bortezomib dose of 1.3 mg/m², and 3 patients at a bortezomib dose of 1.6 mg/m²). Neuropathy occurred in 16 patients (84%), including 2 patients (11%) who experienced grade 3 sensory neuropathy. Grade 4 hematologic toxicity occurred in 4 patients. Of 19 evaluable patients, 100% responded, and the complete response rate was 68%. At a median follow‐up of 32 months, the 3‐year progression‐free survival rate was 89.5%.

CONCLUSIONS:

Bortezomib combined with modified R‐CHOP produced high response rates without substantial increases in toxicity. A phase 2 study of R‐CHOP and bortezomib given at this established MTD is currently ongoing. Cancer 2012;3538–3548. © 2012 American Cancer Society.     

Panobinostat: A Review in Relapsed or Refractory Multiple Myeloma

Oral panobinostat (Farydak®), a potent nonselective histone deacetylase inhibitor, is approved in several countries for use in combination with bortezomib and dexamethasone in patients with multiple myeloma (MM) [USA] or relapsed and/or refractory MM (EU) who have received at least two prior treatment regimens, including bortezomib and an immunomodulatory drug (IMiD). In a pivotal phase III trial (PANORAMA 1) in patients with relapsed or relapsed and refractory MM who had received one to three previous lines of therapy, progression-free survival (PFS) was significantly prolonged with panobinostat plus bortezomib and dexamethasone compared with placebo plus bortezomib and dexamethasone. The significantly favourable effect of panobinostat- versus placebo-based treatment on PFS was also observed in a subgroup analysis of patients who had previously received an IMiD, bortezomib plus an IMiD, or at least two lines of treatment including bortezomib and an IMiD. Panobinostat plus bortezomib and dexamethasone had a generally manageable tolerability profile, with the most frequent grade 3–4 adverse events being myelosuppression, diarrhoea, asthenia or fatigue, peripheral neuropathy and pneumonia. Thus, panobinostat, in combination with bortezomib and dexamethasone, is a useful addition to the available treatment options for patients with relapsed or refractory MM.     

Long-Term Disease Control by Pomalidomide-/Dexamethasone-Based Therapy in a Patient with Advanced Multiple Myeloma: A Case Report and Review of the Literature

Background

Therapy for multiple myeloma (MM) has substantially improved in the era of immunomodulatory drugs and bortezomib. However, the prognosis of patients with progressive disease despite treatment with these ‘novel agents’ remains poor. Recently, pomalidomide was approved in this setting, but a median progression-free survival of <4 months still leaves room for improvement. Pomalidomide-based combination therapies are currently under investigation, but data on long-term treatment are lacking.

Case Report

We present the case of a 68-year-old woman with refractory MM who received pomalidomide in combination with various drugs including anthracyclines, alkylators and proteasome inhibitors. Initially, major hematological toxicities and infectious complications including a hepatitis B virus reactivation were encountered. With careful dose adjustments and selection of combination partners, pomalidomide treatment was maintained for over 4 years and led to a sustained partial remission. In particular, the well-tolerated regimen of bortezomib, cyclophosphamide and dexamethasone together with pomalidomide was administered for >30 cycles.

Conclusion

This case illustrates the value of an individualized approach to myeloma care given an increasing availability of ‘novel agents’. Tailored treatment using these drugs as a backbone is essential to achieve long-lasting responses and minimize side effects.Key Words: Multiple myeloma, Combination therapy, Pomalidomide, Hepatitis B virus reactivation