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1.  Phase Ib Dose-escalation Study (PX-171-006) of Carfilzomib, Lenalidomide, and Low-dose Dexamethasone in Relapsed or Progressive Multiple Myeloma 
Carfilzomib, a selective proteasome inhibitor, has demonstrated safety and efficacy in relapsed and/or refractory multiple myeloma. This Phase I study in patients with relapsed or progressive multiple myeloma assessed the safety and tolerability of escalating doses of carfilzomib in combination with lenalidomide and low-dose dexamethasone (CRd) to identify the dose for a Phase II expansion study.
Experimental Design
Patients with multiple myeloma who relapsed after 1–3 prior regimens enrolled into dose-escalation cohorts. CRd was administered on 28-day dosing cycles: carfilzomib 15–27 mg/m2 on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10–25 mg on Days 1–21; and dexamethasone 40 mg weekly.
Forty patients enrolled in 6 cohorts. Prior treatment included bortezomib (75%) and lenalidomide (70%); 20% and 36% were refractory overall. The maximum tolerated dose was not identified, and the highest dose combination tested was recommended for the Phase II study. The most common toxicities of any grade were fatigue (62.5%), neutropenia (55.5%), and diarrhea (52.5%). Grade 3/4 toxicities included neutropenia (42.5%), thrombocytopenia (32.5%), and lymphopenia (27.5%), with no Grade 3/4 neuropathy reported. Proteasome inhibition 1 hour post-dose was >80% in Cycles 1 and 2. Among all patients, the overall response rate was 62.5%, the clinical benefit response rate was 75.0%, and median duration of response and progression-free survival were 11.8 and 10.2 months, respectively.
The maximum planned CRd dose—carfilzomib 27 mg/m2, lenalidomide 25 mg, and dexamethasone 40 mg—was recommended for further study, with promising safety and efficacy.
PMCID: PMC4149337  PMID: 23447001
Multiple myeloma; carfilzomib; lenalidomide; hematologic neoplasm; clinical trial; phase 1
2.  Incidence and management of adverse events in patients with relapsed and/or refractory multiple myeloma receiving single-agent carfilzomib 
Carfilzomib, a selective proteasome inhibitor approved in the USA in 2012, is a single agent for relapsed and refractory multiple myeloma. Carfilzomib is administered as a 2–10-minute infusion on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle at a starting dose of 20 mg/m2 for cycle 1 and a target dose of 27 mg/m2 thereafter. In the pivotal Phase II study (PX-171-003-A1), carfilzomib 20/27 mg/m2 provided durable responses in a heavily pretreated population with relapsed and refractory multiple myeloma (n=266), with an overall response rate of 22.9% and a median duration of response of 7.8 months. In an integrated safety analysis of four Phase II studies, common adverse events (32.7%–55.5%) included fatigue, anemia, nausea, thrombocytopenia, dyspnea, and diarrhea. Grade 3/4 adverse events were generally hematologic and included thrombocytopenia (23.4%), anemia (22.4%), and lymphopenia (18.1%). Serious adverse events included pneumonia (9.9%), acute renal failure (4.2%), pyrexia (3.4%), and congestive heart failure (3.4%). New or worsening peripheral neuropathy was infrequent (13.9% overall, 1.3% grade 3, no grade 4). This review discusses findings of the integrated safety analysis and provides practical experience from a single institution in managing treatment-related and disease-related adverse events. Individualized treatment with proactive management of side effects and complications allows patients with advanced multiple myeloma to remain on carfilzomib for extended periods.
PMCID: PMC4020895  PMID: 24855395
carfilzomib; relapsed; refractory; myeloma; safety; adverse events; toxicity
3.  A Phase 1 Dose Escalation Study of the Safety and Pharmacokinetics of the Novel Proteasome Inhibitor Carfilzomib (PR-171) in Patients with Hematologic Malignancies 
Carfilzomib (formerly PR-171) is a novel proteasome inhibitor of the epoxyketone class that is selective and structurally distinct from bortezomib. Proteasome inhibition by carfilzomib is mechanistically irreversible. Consequently, proteasome inhibition is more sustained with carfilzomib than with bortezomib.
Experimental Design
In a phase 1 trial evaluating the safety and efficacy of carfilzomib in relapsed or refractory hematologic malignancies, eight dose groups of three to six patients received 5 consecutive days of carfilzomib i.v. push at doses of 1.2, 2.4, 4, 6, 8.4, 11, 15, and 20 mg/m2 within 14-day cycles.
Twenty-nine patients enrolled that were relapsed or refractory after at least two prior therapies. Nonhematologic toxicities included fatigue, nausea, and diarrhea in more than one third of patients—mostly grade 1 or 2 in severity. At 20 mg/m2, grade 3 febrile neutropenia and grade 4 thrombocytopenia were reported, establishing 15 mg/m2 as the maximum tolerated dose. No grade 3 or 4 peripheral neuropathies were reported. Antitumor activity was observed at doses ≥11 mg/m2: one unconfirmed complete response (mantle cell), one partial response (multiple myeloma), and two minimal responses (multiple myeloma and Waldenström’s macroglobulinemia).
This is the first clinical use of carfilzomib that shows tolerability and clinical activity in multiple hematologic malignancies using consecutive-day dosing.
PMCID: PMC4019989  PMID: 19903785
4.  Carfilzomib: a novel treatment in relapsed and refractory multiple myeloma 
OncoTargets and therapy  2012;5:237-244.
Carfilzomib is a second-generation proteasome inhibitor with well-documented clinical activity as a single agent in patients with relapsed/refractory multiple myeloma. Carfilzomib can partially overcome resistance in bortezomib-refractory patients and has significant efficacy in bortezomib-naïve patients. Responses generally occur rapidly and are durable in the majority of cases. Carfilzomib can be safely administered in patients with renal failure and adverse cytogenetics do not seem to interfere with its activity. Moreover, carfilzomib has the advantage of a favorable safety profile, especially a low incidence of peripheral neuropathy, which is often the dose-limiting factor in thalidomide and bortezomib-based regimens. The most frequently observed high-grade adverse event is cytopenia. However, long-term tolerability is good with no cumulative toxicity. The place of carfilzomib in the treatment of the advanced and the newly diagnosed myeloma patient is currently under examination in several ongoing phase 3 clinical trials.
PMCID: PMC3463411  PMID: 23055749
relapsed; refractory; myeloma; carfilzomib; proteasome inhibitor
5.  Carfilzomib: a novel second-generation proteasome inhibitor 
Carfilzomib (formerly PR-171) is a novel epoxyketone-based irreversible proteasome inhibitor. In preclinical studies, carfilzomib demonstrated irreversible binding to the proteasome and minimal off-target inhibition of other proteases. In clinical studies carfilzomib has demonstrated substantial antitumor activity in hematologic malignancies while exhibiting a well-tolerated side-effect profile. Painful neuropathy was minimally reported, suggesting a possible advantage over other proteasome inhibitors. With single-agent carfilzomib, dose-limiting toxicity was hematologic and included thrombocytopenia and neutropenia. In patients with relapsed or refractory multiple myeloma, twice-weekly consecutive-day single-agent carfilzomib 20 mg/m2 for 3 weeks every 28 days, escalating to 27 mg/m2 the second cycle was associated with a 54% overall response rate in bortezomib-naive patients and a 26% overall response rate in bortezomib and immunomodulatory drug refractory patients.
PMCID: PMC3931449  PMID: 21568676
bortezomib; carfilzomib; chymotrypsin-like; multiple myeloma; PR-171; proteasome Inhibitor
6.  Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety 
Leukemia  2013;27(8):1707-1714.
This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80 ml/min, 50–80 ml/min, 30–49 ml/min, <30 ml/min and chronic hemodialysis. Carfilzomib was administered on days 1, 2, 8, 9, 15 and 16 in 28-day cycles: 15 mg/m2 (Cycle 1), 20 mg/m2 (Cycle 2) and 27 mg/m2 (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events (AEs) included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%) and fatigue (14.0%). AEs were similar among groups. At 15 mg/m2, proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.
PMCID: PMC3740399  PMID: 23364621
carfilzomib; myeloma; renal impairment; dialysis; proteasome inhibitor; relapsed
7.  Novel Agents for Multiple Myeloma to Overcome Resistance in Phase III Clinical Trials 
Seminars in oncology  2013;40(5):10.1053/j.seminoncol.2013.07.007.
The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free and overall survival in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next five years.
PMCID: PMC3819933  PMID: 24135408
8.  A phase I/II study of carfilzomib 2–10-min infusion in patients with advanced solid tumors 
Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2–10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study.
Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m2 in week 1 of cycle 1 and 20, 27, or 36 mg/m2 thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts.
Fourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m2 was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts.
Carfilzomib 20/36 mg/m2 was well tolerated when administered twice weekly by 2–10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.
PMCID: PMC3784064  PMID: 23975329
Proteasome inhibitor; Carfilzomib; Solid tumors; Pharmacokinetics; Pharmacodynamics
9.  From clinical trials to clinical practice: single-agent carfilzomib adverse events and their management in patients with relapsed and/or refractory multiple myeloma 
Multiple myeloma is characterized by periods of remission followed by relapse, and eventually the disease becomes refractory to treatment. While patients with multiple myeloma frequently receive multiple lines of treatment, antimyeloma agents are associated with a number of toxicities that can impact their use and influence future treatment options. Patients with relapsed and/or refractory multiple myeloma are particularly challenging to treat due to the advanced state of their disease, typically greater resistance to treatment, and the presence of disease- and treatment-related comorbidities. An understanding of the safety profile of the therapeutic agents used in treating multiple myeloma is thus crucial for appropriate patient management. Single-agent carfilzomib has been approved in the United States for the treatment of patients with relapsed and refractory multiple myeloma, and has been shown to be efficacious and well-tolerated in this setting. This review examines the frequency of common and significant hematologic and nonhematologic adverse events following administration of single-agent carfilzomib in four phase II trials in relapsed and/or refractory multiple myeloma, and provides practical recommendations for their management.
PMCID: PMC3854560  PMID: 24319571
carfilzomib; drug toxicity; multiple myeloma; proteasome inhibitors
10.  Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring 
BMC Cancer  2014;14(1):915.
Carfilzomib is a selective proteasome inhibitor approved in the United States in 2012 for the treatment of relapsed and refractory multiple myeloma. Although cardiopulmonary and vascular events have been reported infrequently, they can be potentially serious complications, and their incidence and pathophysiology following carfilzomib treatment remain poorly characterized in a real-world patient population.
We retrospectively reviewed the records of 67 patients with relapsed and/or refractory multiple myeloma treated at our institution.
We describe 12 patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib-based treatment (median age, 59 years [range, 49–77]). Nine patients had prior autologous stem cell transplant, and three had prior anthracycline exposure. Detailed case reports are provided for five representative patients: (1) systemic hypertension in a 65-year-old Caucasian female with a history of hypertension, hypothyroidism, and stage III chronic kidney disease; (2) pulmonary hypertension in a 72-year-old Caucasian male with a history of recurrent respiratory infections and chronic right lower extremity deep venous thrombosis; (3) acute renal insufficiency with increased blood pressure in a 50-year-old Caucasian male with a history of hypertension and stage IV chronic kidney disease; (4) heart failure in a 64-year-old African American female with a history of hypertension; and (5) dyspnea and lung disease in a 58-year-old Asian American male with a history significant for hepatitis B virus infection.
While cardiac and vascular-related adverse events were reported in patients with relapsed and/or refractory multiple myeloma who were treated with carfilzomib, most patients had a history of the specific cardiac or vascular adverse event they exhibited and demonstrated an improvement or resolution in symptoms after the discontinuation of therapy. Appropriate screening and monitoring could potentially allow at-risk patients to benefit fully from treatment with carfilzomib.
PMCID: PMC4289164  PMID: 25471129
Carfilzomib; Proteasome inhibitor; Cardiac toxicity; Vascular toxicity; Multiple myeloma
11.  Development of peptide-based reversing agents for P-glycoprotein-mediated resistance to carfilzomib 
Molecular pharmaceutics  2012;9(8):2197-2205.
Carfilzomib is a novel class of peptidyl epoxyketone proteasome inhibitor and has demonstrated promising activity in multiple clinical trials to treat patients with multiple myeloma and other types of cancers. Here, we investigated molecular mechanisms underlying acquired resistance to carfilzomib and a potential strategy to restore cellular sensitivity to carfilzomib. H23 and DLD-1 cells (human lung and colon adenocarcinomas cell lines) with acquired resistance to carfilzomib displayed marked cross-resistance to YU-101, a closely related proteasome inhibitor and paclitaxel, a known substrate of Pgp. However, carfilzomib-resistant cells remained sensitive to bortezomib, a clinically used dipeptide with boronic acid pharmacophore. In accordance with these observations, carfilzomib-resistant H23 and DLD-1 cells showed marked upregulation of P-glycoprotein (Pgp) compared to their parental controls and co-incubation with verapamil, a Pgp inhibitor, led to an almost complete restoration of cellular sensitivity to carfilzomib. These results indicate that Pgp upregulation plays a major role in the development of carfilzomib resistance in these cell lines. In developing a potential strategy to overcome carfilzomib resistance, we as a proof of concept prepared a small library of peptide analogs derived from the peptide backbone of carfilzomib and screened these molecules for their activity to restore carfilzomib sensitivity when co-treated with carfilzomib. We found that compounds as small as dipeptides are sufficient in restoring carfilzomib sensitivity. Taken together, we found that Pgp upregulation plays a major role in the development of resistance to carfilzomib in lung and colon adenocarcinomas cell lines and that small peptide analogs lacking the pharmacophore can be used as agents to reverse acquired carfilzomib resistance. Our findings may provide important information in developing a potential strategy to overcome drug resistance.
PMCID: PMC3473138  PMID: 22734651
acquired resistance; carfilzomib; P-glycoprotein; resistance reversal; small peptides
12.  Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study 
Leukemia  2013;27(12):2351-2356.
Several cytogenetic abnormalities are associated with poor outcomes in multiple myeloma (MM). We prospectively analyzed the impact of cytogenetic abnormalities on outcomes during the phase 2 PX-171-003-A1 study of single-agent carfilzomib for relapsed and refractory MM. In the response-evaluable population (257/266), fluorescence in situ hybridization (FISH)/conventional cytogenetic profiles were available for 229 patients; 62 (27.1%) had high-risk cytogenetics—del 17p13, t(4;14) or t(14;16) by interphase FISH or deletion 13 or hypodiploidy by metaphase cytogenetics—and 167 (72.9%) had standard-risk profiles. Generally, baseline characteristics were similar between the subgroups, but International Staging System stage III disease was more common in high- vs standard-risk patients (41.9% vs 27.5%) as was Eastern Cooperative Oncology Group performance status 1/2 (85.5% vs 68.3%). Overall response was comparable between the subgroups (25.8% vs 24.6%, respectively; P=0.85), while time-to-event end points showed a trend of shorter duration in high-risk patients, including median duration of response (5.6 months (95% confidence interval (CI) 3.7–7.8) vs 8.3 months (95% CI 5.6–12.3)) and overall survival (9.3 (95% CI 6.5–13.0) vs 19.0 months (95% CI 15.4–NE); P=0.0003). Taken together, these findings demonstrate that single-agent carfilzomib is efficacious and has the potential to at least partially overcome the impact of high-risk cytogenetics in heavily pre-treated patients with MM.
PMCID: PMC3865533  PMID: 23670297
multiple myeloma; cytogenetics; proteasome inhibitor; carfilzomib; relapsed; refractory
13.  Identification of an ABCB1 (P-glycoprotein)-positive carfilzomib-resistant myeloma subpopulation by the pluripotent stem cell fluorescent dye CDy1 
American journal of hematology  2013;88(4):265-272.
Multiple myeloma (MM) is characterized by the malignant expansion of differentiated plasma cells. Although many chemotherapeutic agents display cytotoxic activity toward MM cells, patients inevitably succumb to their disease because the tumor cells become resistant to the anticancer drugs. The cancer stem cell hypothesis postulates that a small subpopulation of chemotherapy-resistant cancer cells is responsible for propagation of the tumor. Herein we report that efflux of the pluripotent stem cell dye CDy1 identifies a subpopulation in MM cell lines characterized by increased expression of P-glycoprotein, a member of the ABC (ATP-binding cassette) superfamily of transporters encoded by ABCB1. We also demonstrate that ABCB1-overexpressing MM cells are resistant to the second-generation proteasome inhibitor carfilzomib that recently received accelerated approval for the treatment of therapy-refractive MM by the U.S. Food and Drug Administration. Moreover, increased resistance to carfilzomib in sensitive MM cells following drug selection was associated with upregulation of ABCB1 cell-surface expression which correlated with increased transporter activity as measured by CDy1 efflux. We further show that chemosensitization of MM cells to carfilzomib could be achieved in vitro by cotreatment with vismodegib, a hedgehog pathway antagonist which is currently in MM clinical trials. CDy1 efflux may therefore be a useful assay to determine whether high expression of ABCB1 is predictive of poor clinical responses in MM patients treated with carfilzomib. Our data also suggest that inclusion of vismodegib might be a potential strategy to reverse ABCB1-mediated drug resistance should it occur.
PMCID: PMC3608751  PMID: 23475625
CDy1; ABCB1; multiple myeloma; carfilzomib; vismodegib; ASPM; KIF14; TMPO
14.  The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide 
Leukemia & lymphoma  2013;55(2):337-341.
Patients with multiple myeloma who are refractory or intolerant to both bortezomib and lenalidomide have a poor prognosis. Next-generation therapies carfilzomib and pomalidomide have shown promising activity in this dual refractory population. Here we describe the clinical characteristics and ascertain the effects of carfilzomib and pomalidomide on survival in this patient cohort. We retrospectively reviewed the records of 65 dual refractory/intolerant myeloma patients diagnosed between January 2007 and May 2012 at a single institution. The median overall survival (OS) from the time patients became dual refractory/intolerant was 10.2 months. Patients who received carfilzomib or pomalidomide after they became dual refractory/intolerant had a better OS compared to those who did not (12.6 vs. 6.8 months, p=0.03 by Wilcoxon test). Prospective randomized control trials are needed for confirmation.
PMCID: PMC3951876  PMID: 23662990
multiple myeloma; lenalidomide; bortezomib; pomalidomide; carfilzomib
15.  New drugs in multiple myeloma – role of carfilzomib and pomalidomide 
Contemporary Oncology  2014;18(1):17-21.
Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with “older” IMIDs – thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future.
PMCID: PMC4037992  PMID: 24876816
multiple myeloma; treatment; carfilzomib; pomalidomide
16.  Targeted treatments for multiple myeloma: specific role of carfilzomib 
Carfilzomib is a selective, irreversible proteasome inhibitor, initially approved in the US in 2012 as single-agent therapy for relapsed and refractory multiple myeloma. Numerous Phase II studies have evaluated carfilzomib in the relapsed and refractory as well as the newly diagnosed setting, and Phase III studies are entering their final analysis. Data continue to grow to support its use as both single-agent therapy and in combination with immunomodulatory and other novel agents. This review discusses the role of carfilzomib in the treatment of multiple myeloma. Its mechanism of action, pharmacokinetics, and role in clinical management will be reviewed.
PMCID: PMC4325627
relapsed and refractory; targeted therapy; proteasome inhibitor; novel agents
17.  Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline 
Current Oncology  2006;13(5):160-172.
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?
What is the toxicity associated with the use of bortezomib?
Which patients are more or less likely to benefit from treatment with bortezomib?
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 of interest were overall survival, quality of life, response rates and duration, and rates of adverse events.
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.
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.
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.
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.
PMCID: PMC3394599  PMID: 22792013
Bortezomib; Velcade; multiple myeloma; lymphoma; clinical practice guideline; systematic review
18.  Renal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma 
BMC Nephrology  2014;15(1):156.
Proteasome inhibitors are a relatively new class of chemotherapeutic agents. Bortezomib is the first agent of this class and is currently being used for the treatment of multiple myeloma. However, recent reports have linked exposure to bortezomib with the development of thrombotic microangiopathy. A new agent in this class, carfilzomib, has been recently introduced as alternative therapy for relapsing and refractory multiple myeloma. We report a case of renal thrombotic microangiopathy associated with the use of carfilzomib in a patient with refractory multiple myeloma.
Case presentation
A 62 year-old Caucasian man with hypertension and a 4-year history of multiple myeloma, had been previously treated with lenalidomide, bortezomib and two autologous hematopoietic stem cell transplants. After the second hematopoietic stem cell transplant, he developed acute kidney injury secondary to septic shock and required dialysis for 4 weeks. Subsequently, his serum creatinine stabilized at 2.1 mg/dL (185.64 μmol/L). Seventeen months after the second hematopoietic stem cell transplant, he was initiated on carfilzomib for relapse of multiple myeloma. Six weeks later, he developed abrupt worsening of lower extremity edema and hypertension, and new onset proteinuria. His kidney function remained stable. Kidney biopsy findings were consistent with thrombotic microangiopathy. Eight weeks after discontinuation of carfilzomib, proteinuria and hypertension improved. Due to progression of multiple myeloma, he died a few months later.
In view of the previously reported association of bortezomib with thrombotic microangiopathy, the temporal association of the clinical picture with the initiation of carfilzomib, and the partial resolution of symptoms after discontinuation of the drug, we conclude that carfilzomib may have precipitated a case of clinically evident renal thrombotic microangiopathy in our patient.
PMCID: PMC4190298  PMID: 25267524
Thrombotic microangiopathy; Malignant hypertension; Proteasome inhibitor; Proteinuria
19.  Novel therapeutics in multiple myeloma 
Hematology (Amsterdam, Netherlands)  2012;17(0 1):S105-S108.
Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating agents, immune modulators (lenalidomide and thalidomide) or proteasome inhibitors such as bortezomib. Once this happens average survivals are less than one year. Progress has been made for such patients, however, with the demonstration of clinical benefit of novel proteasome inhibitors (carfilzomib) and immune modulators (pomalidomide). Pomalidomide when used with dexamethasone has activity in 30–60% of patients depending on disease stage. Carfilzomib is an irreversible proteasome inhibitor with favorable toxicity profile (minimal neuropathy) and response rates of 17–54% depending on the disease stage treated. Novel targets are also being explored. Histone deacetylase inhibitors such as vorinostat and panobinostat are in phase II testing although results from a randomized trial combining vorinostat with bortezomib were disappointing. Other small molecules or monoclonal antibodies with novel targets such as kinase inhibitors(AKT, CDK5) and cell surface receptors (e.g. elotuzumab) are undergoing active investigation.
PMCID: PMC3905954  PMID: 22507794
Myeloma; Therapy; Carfilzomib; Vorinostat; Pomalidomide; Novel agents
20.  Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma 
Core Evidence  2011;6:43-57.
Proteasome inhibition forms the cornerstone of antimyeloma therapy. The first-in-class proteasome inhibitor, bortezomib, either alone or in combination with other chemotherapeutic agents, induces high overall response rates and response qualities in patients with clinically and molecularly defined high-risk disease. However, resistance to bortezomib and neurotoxicity associated with the treatment remain challenging issues. Carfilzomib is a novel, well tolerated, irreversible proteasome inhibitor with minimal neurotoxicity. Carfilzomib demonstrates promising activity in myeloma patients who are refractory to bortezomib and immunomodulatory agents. This review focuses on the pharmacology, safety, and efficacy of carfilzomib for the treatment of multiple myeloma in bortezomib-naïve and bortezomib-exposed populations.
PMCID: PMC3102580  PMID: 21654882
carfilzomib; multiple myeloma; pharmacology; safety; efficacy
21.  Relapsed and refractory lymphoid neoplasms and multiple myeloma with a focus on carfilzomib 
Proteasomal inhibition revolutionized myeloma therapies in this decade of novel agents. The only US Food and Drug Administration approved proteasome inhibitor so far, bortezomib effectively targets the constitutive proteasome subunit β5 of the 26S proteasome. Bortezomib induces high and quality response rates that are durable. However, myeloma cells acquire resistance to bortezomib through various mechanisms. Further, grade 3/4 peripheral neuropathy is seen in up to a quarter of patients treated with bortezomib. While the recent change in the mode of administration via the subcutaneous route is associated with a lower incidence of grade 3/4 peripheral neuropathy, it remains a major concern. The second generation proteasome inhibitors are promising, with increased preclinical efficacy and a better administration schedule. The current review spotlights the second generation proteasome inhibitors with special focus on the safety and efficacy of carfilzomib, an epoxyketone with lesser peripheral neuropathy, which exhibits irreversible proteasome inhibition. In this article, we review the pharmacology and preclinical and clinical efficacy and safety of carfilzomib alone and in combination with other chemotherapeutic agents in the various lymphoid neoplasms and multiple myeloma as well as ongoing clinical trials.
PMCID: PMC3563316  PMID: 23386784
myeloma; carfilzomib; second generation; proteasome inhibitor; epoxyketone
22.  Novel Approaches to Treatment of “Double-Refractory” Multiple Myeloma 
Multiple myeloma refractory to both proteasome inhibitors and immunomodulatory agents (IMiDs) has a poor prognosis. With the increasing use of these agents as part of initial therapy, and then in the maintenance setting until disease progression, such drug resistance is an emerging problem of great significance. New therapeutic strategies are clearly needed for this patient population, including the development of more potent agents within existing anti-myeloma drug classes, exploration of rational combinations of both novel and conventional drugs, and validation of new myeloma drug targets. Several approaches have shown substantial promise, including use of the second-generation proteasome inhibitor carfilzomib and the third-generation IMiD pomalidomide, which led to the recent regulatory approval of both agents. In addition, the kinesin spindle protein inhibitor ARRY-520 has shown activity as a first-in-class drug in myeloma therapeutics, while the histone deacetylase inhibitors vorinostat and panobinostat have demonstrated efficacy when used in rational combinations. This overview provides a summary of novel agents that have shown activity in double-refractory myeloma in recent phase II and III clinical trials, and a framework for future studies that will help to improve outcomes in this patient population.
PMCID: PMC3762449  PMID: 23714530
23.  Molecular Mechanisms of Bortezomib Resistant Adenocarcinoma Cells 
PLoS ONE  2011;6(12):e27996.
Bortezomib (Velcade™) is a reversible proteasome inhibitor that is approved for the treatment of multiple myeloma (MM). Despite its demonstrated clinical success, some patients are deprived of treatment due to primary refractoriness or development of resistance during therapy. To investigate the role of the duration of proteasome inhibition in the anti-tumor response of bortezomib, we established clonal isolates of HT-29 adenocarcinoma cells adapted to continuous exposure of bortezomib. These cells were ∼30-fold resistant to bortezomib. Two novel and distinct mutations in the β5 subunit, Cys63Phe, located distal to the binding site in a helix critical for drug binding, and Arg24Cys, found in the propeptide region were found in all resistant clones. The latter mutation is a natural variant found to be elevated in frequency in patients with MM. Proteasome activity and levels of both the constitutive and immunoproteasome were increased in resistant cells, which correlated to an increase in subunit gene expression. These changes correlated with a more rapid recovery of proteasome activity following brief exposure to bortezomib. Increased recovery rate was not due to increased proteasome turnover as similar findings were seen in cells co-treated with cycloheximide. When we exposed resistant cells to the irreversible proteasome inhibitor carfilzomib we noted a slower rate of recovery of proteasome activity as compared to bortezomib in both parental and resistant cells. Importantly, carfilzomib maintained its cytotoxic potential in the bortezomib resistant cell lines. Therefore, resistance to bortezomib, can be overcome with irreversible inhibitors, suggesting prolonged proteasome inhibition induces a more potent anti-tumor response.
PMCID: PMC3245226  PMID: 22216088
24.  Nelfinavir augments proteasome inhibition by bortezomib in myeloma cells and overcomes bortezomib and carfilzomib resistance 
Blood Cancer Journal  2013;3(3):e103-.
HIV protease inhibitors (HIV-PI) are oral drugs for HIV treatment. HIV-PI have antitumor activity via induction of ER-stress, inhibition of phospho-AKT (p-AKT) and the proteasome, suggesting antimyeloma activity. We characterize the effects of all approved HIV-PI on myeloma cells. HIV-PI were compared regarding cytotoxicity, proteasome activity, ER-stress induction and AKT phosphorylation using myeloma cells in vitro. Nelfinavir is the HIV-PI with highest cytotoxic activity against primary myeloma cells and with an IC50 near therapeutic drug blood levels (8–14 μM), irrespective of bortezomib sensitivity. Only nelfinavir inhibited intracellular proteasome activity in situ at drug concentrations <40 μℳ. Ritonavir, saquinavir and lopinavir inhibited p-AKT comparable to nelfinavir, and showed similar synergistic cytotoxicity with bortezomib against bortezomib-sensitive cells. Nelfinavir had superior synergistic activity with bortezomib/carfilzomib in particular against bortezomib/carfilzomib-resistant myeloma cells. It inhibited not only the proteasomal β1/β5 active sites, similar to bortezomib/carfilzomib, but in addition the β2 proteasome activity not targeted by bortezomib/carfilzomib. Additional inhibition of β2 proteasome activity is known to sensitize cells for bortezomib and carfilzomib. Nelfinavir has unique proteasome inhibiting activity in particular on the bortezomib/carfilzomib-insensitive tryptic (β2) proteasome activity in intact myeloma cells, and is active against bortezomib/carfilzomib-resistant myeloma cells in vitro.
PMCID: PMC3615215  PMID: 23454896
proteasome; drug resistance; myeloma
25.  Novel agents in Waldenström macroglobulinemia 
Clinical investigation  2011;1(6):815-824.
Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow with lymphoplasmacytic cells and the detection of an IgM monoclonal gammopathy in the serum. WM is considered an incurable disease, with a median overall survival of 87 months. The success of targeted therapy in multiple myeloma has led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias, including WM, both in the preclinical settings and as part of clinical trials. Among therapeutic options, first-line therapies have been based on single-agent or combination regimens with alkylator agents, nucleoside analogues and the monoclonal antibody anti-CD20. Based on the understanding of the complex interaction between WM tumor cells and the bone marrow microenvironment, and the signaling pathways that are deregulated in WM pathogenesis, a number of novel therapeutic agents are now available and have demonstrated significant efficacy in WM. The range of the overall response rate for these novel agents is between 25 and 96%. Ongoing and planned future clinical trials include those using protein kinase C inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as LBH589, humanized CD20 antibodies such as ofatumumab and additional alkylating agents such as bendamustine. These agents, when compared with traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM. This article will mainly focus on those novel agents that have entered clinical trials for the treatment of WM.
PMCID: PMC3199976  PMID: 22034589
novel agents; targeted therapies; Waldenström macroglobulinemia

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