Multiple myeloma (MM) accounts for 10% to 15% of all hematologic malignancies, and is the cause of 20% of the deaths that result from blood and bone cancers.1,2 In 2012, the American Cancer Society estimated that there would be 21,700 patients newly diagnosed with MM, and 10,710 who will die from this type of cancer.3 The median survival for patients with MM was less than 1 year before the introduction of alkylating agents in the 1960s, and that rate increased with the introduction of high-dose chemotherapy and autologous stem-cell transplant (ASCT) in the 1980s.4 The advent of hematologic cell growth factors, the use of bisphosphonates, and the improved treatment of fractures have also contributed to increased survival for patients with MM.2,4 This increase in survival since approximately the year 2000 can be largely attributed to the development of novel, targeted therapies, including the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, and the first-in-class proteasome inhibitor bortezomib (Velcade).4
Even with these new treatments, MM almost always relapses, and the duration of remission in patients with relapsed MM becomes shorter with each successive treatment regimen.5 Patients are likely to require treatment with one agent after another as their disease progresses and becomes resistant to chemotherapy.2 Therefore, there remains a need for additional therapies.
On July 20, 2012, the US Food and Drug Administration granted accelerated approval for carfilzomib (Kyprolis), which is indicated for the treatment of patients with MM who have received at least 2 previous therapies, including bortezomib and an IMiD (ie, thalidomide or lenalidomide), and have demonstrated disease progression on or within 60 days of completion of the last therapy.6,7 The approval of carfilzomib was based on the response rate determined in a single-arm, multicenter clinical trial, and was not based on survival.8 Furthermore, a clinical benefit (ie, increased survival or improved symptoms) has not been confirmed.6,7
Clinical Trial Updates on Carfilzomib-Based Treatment for Patients with MM
Oral presentations and posters based on carfilzomib clinical trials were presented at the 2012 American Society of Hematology meeting, which was held December 8-11, in Atlanta, GA. These presentations included reports on the safety and the efficacy of single-
agent carfilzomib; the use of carfilzomib as part of a combination therapy for patients who are newly diagnosed with MM, as well as those with relapsed and/or refractory disease; and dosing and administration modifications related to carfilzomib. In addition, interesting preclinical studies of carfilzomib were presented, as well as an initial report on oprozomib—an orally bioavailable structural analog of carfilzomib.
Carfilzomib Safety and Clinical Experience
Epidemiology of Cardiac Events in Patients with MM
Patients with MM are at risk for cardiac adverse events (AEs) as a result of their age, their disease, or their treatment regimen. Kristen D. Kistler, PhD, of United BioSource Corporation, Lexington, MA, and colleagues conducted a retrospective cohort study of commercial and Medicare supplemental insurance claims from January 1, 2006, through December 31, 2011, to determine the incidence and prevalence of cardiac AEs in US patients with MM.9 This analysis was presented in a poster and included 22,076 patients with newly diagnosed MM and 1723 patients with relapsed MM. Nearly 75% of the patients had a cardiac AE during the study period, most frequently arrhythmias (24% in patients with newly diagnosed MM, 29% in relapsed MM), congestive heart failure (15% in each group), and ischemic heart disease (19% and 14%, respectively), independent of anti-MM treatment and whether the MM was newly diagnosed or relapsed. Other cardiac events included cardiomyopathy and conduction disorders. The incidence of cardiac AEs was associated with older patient age (particularly those aged ≥75 years) and with a history of cardiac events.9
Cardiac and Pulmonary Safety
A poster presentation by Sagar Lonial, MD, Professor, Emory School of Medicine, Director, Translational Research, B-cell Malignancy Program, Winship Cancer Institute, Atlanta, GA, and colleagues summarized the cardiac and pulmonary events occurring in 526 patients with relapsed and/or refractory MM in 4 phase 2 trials of carfilzomib, including PX-171-003-A0 (N =46), PX-171-003-A1 (the pivotal registration trial; N =266), PX-171-004 (N = 164), and PX-171-005 (N = 50).10 Most patients received carfilzomib at the approved dose and schedule (20 mg/m2 for cycle 1, escalated to 27 mg/m2 for subsequent cycles, dosed on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle). The patients in the PX-171-005 study, who had various degrees of renal insufficiency, received carfilzomib 15 mg/m2 in cycle 1, 20 mg/m2 in cycle 2, and 27 mg/m2 in cycle 3 and beyond. At baseline, 70% of the patients had a cardiac risk factor, defined as taking ≥1 cardiac medication. As in the epidemiology study,9 the most common cardiac AEs were arrhythmias (13.3% overall of any grade), and these were mostly low-grade, benign events. Grade 3 cardiac AEs were primarily cardiac failure.10 The rates of cardiac AEs generally remained stable over time.
Overall, 1.1% of patients had their carfilzomib dose reduced and 4.4% of patients discontinued carfilzomib in response to cardiac AEs. There were 5 deaths resulting from cardiac events: 3 patients in the PX-171-003-A1 study died from cardiac arrest and 1 from dyspnea, and 1 patient in the PX-171-004 study died of a cardiac disorder. In addition, 3 patients in the PX-171-003-A1 study died of disease progression, which was considered to have a cardiac component.10
Respiratory AEs occurred in 69% of patients, most frequently dyspnea (42.2%), of which 4.8% had grade 3 dyspnea. This resulted in a dose reduction for 1.9% of patients, and for discontinuation in 2.3% of patients for all respiratory events and in 1.5% of patients with dyspnea. Dyspnea resolved in all but 1 patient and tended to occur in earlier cycles, with a median duration of 8 days. Respiratory infections occurred in 18.8% of patients, resulting in 2 deaths that were not considered to be related to carfilzomib. These rates of cardiac and pulmonary AEs are considered to be comparable to those reported for patients with relapsed and/or refractory MM. These events are being studied further in ongoing clinical trials.
Updated Analysis of Prolonged Carfilzomib Therapy
David S. Siegel, MD, PhD, Chief of the Division of Multiple Myeloma at John Theurer Cancer Center, Hackensack, NJ, and colleagues presented a poster of updated results from the phase 2 PX-171-010 extension study of prolonged carfilzomib therapy in patients with MM who were previously enrolled in phase 1 and 2 clinical trials.11 This study included 100 patients, of which 91 were diagnosed with MM and 9 with solid tumors. As of October 2012, 28 patients have remained in the study. Patients received a median of 22.5 cycles, with a maximum of 51 cycles. Carfilzomib was administered in combination with another drug (most frequently dexamethasone, lenalidomide, or cyclophosphamide) in 43% of patients. Although some patients required dose reductions or increases, overall response rates (ORRs) ranged from 24.2% to 45.2%, depending on the regimen; the clinical benefit responses (ie, ORR plus the minor response [MR]) ranged from 33.3% to 52.4%.11
Grade 3 or higher AEs occurred in 63% of patients, and were most frequently cytopenias and pneumonia. Serious AEs occurred in 53% of patients, most frequently pneumonia (9%), dyspnea (7%), and influenza (6%). Discontinuations resulting from AEs occurred in 11% of patients, most frequently as a result of myocardial infarction (MI) or dyspnea (2% each). Of the 6 deaths in the study, 3 were a result of AEs (1 MI, 1 pneumonia, 1 MI plus pneumonia), and 3 resulted from progressive disease. The incidence of peripheral neuropathy (PN) was low (12%) and grade 3 in 2 patients. Although these results are preliminary, the long-term safety, tolerability, and efficacy profiles of carfilzomib are promising.
Updated Results of Carfilzomib as a Replacement for Bortezomib
James R. Berenson, MD, Medical and Scientific Director, Institute for Myeloma & Bone Cancer Research, and Chief Executive Officer of Oncotherapeutics, both in West Hollywood, CA, and colleagues investigated the safety and efficacy of replacing bortezomib with carfilzomib in various regimens given to patients whose MM relapsed within 12 weeks of receiving a bortezomib-containing regimen or whose MM was refractory to the most recent bortezomib-containing regimen.12
This open-label, nonrandomized study has enrolled 33 patients, of whom 29 were evaluable for efficacy. Almost 66% of patients had a response of at least MR, almost 45% had at least MR for those receiving carfilzomib plus dexamethasone, and 75% had at least MR for those receiving carfilzomib with other agents, which included IMiDs, alkylating agents, and anthracyclines. The dose of carfilzomib was escalated and well tolerated up to 45 mg/m2. There were 2 hematologic serious AEs, 12 nonhematologic serious AEs, and 1 death that resulted from pneumonia. Future enrollment in this ongoing study will focus on IMiD-containing regimens and on establishing the maximum tolerated dose (MTD) for additional carfilzomib-containing regimens.
Table 1.
The carfilzomib combination therapy trials in patients with newly diagnosed MM are summarized in Table 1.
Carfilzomib, Lenalidomide, and Dexamethasone
Neha Korde, MD, Multiple Myeloma Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, gave an oral presentation on the first interim analysis of a phase 2 study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed patients with MM.13 Carfilzomib was administered at a dose of 20/36 mg/m2 on days 1, 2, 8, 9, 15, 16, 22, and 23 of a 28-day cycle, lenalidomide at 25 mg daily on days 1 to 21, and dexamethasone on days 1, 2, 8, 9, 15, and 16 at 20 mg for cycles 1 through 4, and at 10 mg thereafter. After at least 4 cycles, patients aged <70 years to 75 years could harvest stem cells. After 8 cycles, patients who had stable disease or better could receive extended-dose lenalidomide at 10 mg daily on days 1 to 21 for 12 cycles (ie, CRd-R). Correlative analyses included flow cytometry for minimal residual disease (MRD), positron emission tomography- computed tomography (PET-CT), proteasome assays, gene-expression profiling, and whole genome sequencing.
As of December 2012, 28 patients have been enrolled in the study, of whom 20 were evaluable. At a median of 7 cycles, no patients have developed grade ≥3 PN, and the second stage of accrual has begun. By cycle 2, mean M-protein levels dropped from approximately 2.75 g/dL to 0.5 g/dL. The best responses occurred after a median of 7 cycles, with ORR, 95%; ≥very good partial response (VGPR), 85%; and near-complete response (nCR)/stringent complete response (sCR), 75%. Response was not affected by fluorescence in situ hybridization or by cytogenetics. The median time to sCR was 4.5 cycles.
The most common nonhematologic toxicities were elevated liver function tests (LFTs), fatigue, and rash. Lymphopenia was the most common hematologic toxicity. Standardized uptake value by [18F]-fluorodeoxyglucose (FDG)-PET-CT declined 49.3% (mean) in 6 patients who had active lytic lesions. After receiving 1 dose of carfilzomib, gene-expression profiling analysis showed an increase in proteasome gene-expression, and proteasome activity in MM cells (20s CT-L) was inhibited by 80%.
Carfilzomib, Cyclophosphamide, Dexamethasone
Antonio Palumbo, MD, Chief, Myeloma Unit, Department of Oncology, University of Torino, Italy, gave an oral presentation on the initial results of a multicenter, phase 2 trial of carfilzomib, cyclophosphamide, and dexamethasone (CCd), which included 58 patients aged ≥65 years or those who were ineligible for ASCT.14 Patients received 9 cycles of CCd induction therapy with carfilzomib at 20/36 mg/m2 followed by carfilzomib maintenance therapy (infused on days 1, 2, 15, and 16 of a 28-day cycle) until disease progression. Of these patients, 28% were aged ≥75 years and 35% had an unfavorable cytogenetic profile (t[4;14] or t[14;16] or del[17p]). At this early follow-up point (approximately 1 year), the response rates increased from cycle 1 through cycle 9; at cycle 9, the response rates were sCR, 23%; sCR/nCR/CR, 53%; ≥VGPR, 77%; and ORR, 100%. The best response was slightly lower for patients with International Staging System stage 2 or 3 disease and for those with higher-risk cytogenetics.
The rates of grade ≥3 hematologic AEs were low. Nonhematologic grade ≥3 AEs included cardiac effects, fatigue, and infection. Dose reductions and discontinuations were approximately 10% to 12% each, and no difference was seen in AEs between patients who were aged ≤75 years and those aged >75 years. No thromboembolic events or PN were reported. The 1-year progression-free survival (PFS) and overall survival (OS) rates were projected to be 88% and 87%, respectively.
Cyclophosphamide, Carfilzomib, Thalidomide, and Dexamethasone
An update of the results of the dose expansion of the cyclophosphamide, carfilzomib, thalidomide (100 mg daily), and dexamethasone (CYCLONE) trial were discussed in an oral presentation by Joseph R. Mikhael, MD, FRCPC, a hematologist/oncologist at the Division of Hematology and Medical Oncology, Mayo Clinic Arizona, Scottsdale.15 A total of 3 dose-limiting toxicities (DLTs) have occurred with the 20/45-mg/m2 carfilzomib dose, and none with the 20/36-mg/m2 dose; therefore, additional patients are being accrued in the cohort receiving the 20/36-mg/m2 dose. This report included 38 patients, with a median follow-up of 11.6 months. One patient died of pneumonia during cycle 3; in 35 patients the disease has not progressed.
Overall, 27 patients were evaluable for response and received either 20/27 mg/m2 or 20/36 mg/m2 of carfilzomib. The ORR was 96%, and 74% of the patients reached ≥VGPR. As in the CRd and CCd trials,13,14 responses improved with increasing cycles of therapy.15 All 38 patients were evaluated for safety: 42% had grade 3 AEs, and 16% had grade 4 AEs. These included 4 patients with arrhythmia and 2 patients each with elevated LFTs, fatigue, or muscle weakness. Grade 4 thromboembolism occurred in 2 patients. Hematologic AEs included 18% grade 3 and 13% grade 4 events (eg, neutropenia and lymphopenia). Grade 1 PN occurred in 9 patients. Reductions in the dose of at least 1 drug occurred in 16% of the participants.
DLTs at the 20/45-mg/m2 carfilzomib dose that were possibly or probably drug-related included infusion reaction, heart failure, dyspnea, atrial fibrillation, fatigue, and increased alanine aminotransferase. Stem-cell mobilization and collection were successful in all patients in which they were attempted. The MTD cohort receiving the 20/36-mg/m2 carfilzomib dose will be completed with accrual of at least 20 additional patients.
Carfilzomib with Thalidomide and Dexamethasone
The updated results of a phase 2, open-label, dose- escalation trial combining carfilzomib, thalidomide, and dexamethasone (CTd) in transplant-eligible patients with MM were presented by Pieter Sonneveld, MD, PhD, Senior Staff Hematologist, Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands, in an oral presentation.16 This trial investigated 4 cycles of CTd as induction therapy followed by high-dose melphalan and ASCT as intensification, followed by 4 cycles of CTd at a lower dose of thalidomide for consolidation. The induction dose of thalidomide was twice that of the dose that was used in the CYCLONE trial.
The results from 50 patients who were evaluable for response, safety, and PFS in the first dose level were reported; 41 had completed stem-cell harvest, 40 had undergone ASCT, and 39 had received consolidation therapy. Grade 3 AEs included skin toxicities (12%), gastrointestinal (GI) and cardiac events (6% each), tumor lysis syndrome (4%), and PN (2%). The ORR was ≥90% in each phase of treatment; the number of CR and ≥VGPR increased after ASCT and consolidation. Responses for patients with standard-risk versus high-risk cytogenetics were similar. A dose escalation to 20/36-mg/m2 carfilzomib in induction and in consolidation has been completed; escalation to 20/45-mg/m2 carfilzomib is ongoing, and escalation to a 20/54-mg/m2 dose is planned. The median follow-up was 14 months, which is too short to assess PFS and OS.
Table 2.
Carfilzomib Dosing and Administration
Thirty-Minute Infusion and Dose Escalation
Ashraf Badros, MD, ChB, Professor of Medicine, Department of Hematology and Oncology at the University of Maryland Medical Center, Baltimore, presented a poster of a phase 1b study of 30-minute infusions of carfilzomib at doses of 20/45 mg/m2 and 20/56 mg/m2 in combination with weekly dexamethasone in patients with relapsed/refractory MM.17 The slower infusion rate was assessed as a means of increasing the tolerability of carfilzomib and of allowing a higher dose to be administered. Of the 14 patients receiving carfilzomib at 20/45 mg/m2, 4 had 7 serious AEs (ie, obstructive airway disorder, blood culture positive, spinal cord compression, pneumococcal bacteremia, pneumonia, hernia, and pulmonary embolism); of the 8 patients receiving carfilzomib at 20/56 mg/m2, 2 had 2 serious AEs (ie, diverticulitis and pneumonia).
The ORR was 55% in the 20 evaluable patients. The PFS was 5.4 months and 6.0 months, respectively, for the 2 dose groups at a median follow-up of 8.4 months and 6.6 months, respectively. The combination of a 30-minute infusion of 20/56-mg/m2 carfilzomib plus low-dose dexamethasone was at least as well tolerated and as effective as single-agent carfilzomib. This dose and regimen of carfilzomib is being tested in a phase 3 trial in combination with low-dose dexamethasone versus bortezomib plus low-dose dexamethasone in patients with relapsed MM.
Infusional Carfilzomib
An oral presentation by Nikoletta Lendvai, MD, PhD, Hematologist/Oncologist, Myeloma/Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY, summarized the results of a phase 2 study that was also based on the preclinical observations that slower infusion rates of carfilzomib permitted higher doses.18 This single-arm, open-label study included 41 patients with relapsed or refractory MM who had previously received bortezomib and an IMiD. The carfilzomib dose was 20/56 mg/m2, and low-dose (ie, 20 mg) dexamethasone was added for patients whose disease progressed after 2 cycles. Of the 38 evaluable patients, approximately 45% had MM refractory to bortezomib or to lenalidomide, and 39% had MM refractory to both of these agents. The ORR was 53% in 38 evaluable patients, with higher rates (71%) seen in patients with bortezomib-sensitive MM than in patients with double-refractory disease (39%). The median PFS was 7.6 months, the median duration of response was 10.0 months, and the median OS rate was not reached. Although the median PFS and the median duration of response were shorter in patients with bortezomib-refractory MM versus those with bortezomib-sensitive MM, these differences were not statistically significant.
Grades 3 and 4 hematologic AEs included anemia (20%) and thrombocytopenia (36%). Grades 3 and 4 nonhematologic AEs included hypertension (20%), pneumonia (15%), and pulmonary edema/congestive heart failure (CHF; 10%, occurring in the first cycle). Dose reduction occurred most frequently for hypertension, and 29 patients discontinued carfilzomib, mostly as a result of disease progression. As previously mentioned, this 20/56-mg/m2 dose of carfilzomib is under further investigation.
Carfilzomib Novel Combinations in Relapsed/Refractory MM
Table 2 lists carfilzomib combinations being tested in patients with relapsed and/or refractory MM.
Carfilzomib plus Panobinostat
Jesus G. Berdeja, MD, Director of Myeloma Research, Senior Investigator of Hematologic Malignancies, Sarah Cannon Research Institute, Nashville, TN, presented a poster describing a single-arm, open-label, multicenter, phase 1/2 study of combination carfilzomib plus panobinostat in patients with relapsed/refractory MM.19 Carfilzomib was administered at doses of 20/27 mg/m2, 20/36 mg/m2, and 20/45 mg/m2, and panobinostat was administered at doses of 20 mg and 30 mg. Of the 14 patients who were treated, none experienced DLTs or grade 4 AEs. A further expansion phase will assess the safety and efficacy of carfilzomib at a dose of 20/45 mg/m2 and panobinostat at a 30-mg dose.
Jatin J. Shah, MD, Assistant Professor of Lymphoma/Myeloma, Division of Cancer Medicine, M.D. Anderson Cancer Center, Houston, TX, presented another poster describing a phase 1/1b study of carfilzomib plus panobinostat in patients with relapsed and/or refractory MM.20 In this trial, panobinostat was administered at escalating doses of 15 mg, 20 mg, or 30 mg, and carfilzomib was administered at doses of 20/27 mg/m2, 20/36 mg/m2, and 20/45 mg/m2; unlike the other study of carfilzomib plus panobinostat,19 this study also included administration of dexamethasone 4 mg on the days of carfilzomib administration.21 Of the 21 patients enrolled in this study, 1 experienced a DLT of grade 4, which was thrombocytopenia with epistaxis. Other AEs included anemia and thrombocytopenia; no patients developed PN. The clinical benefit rate (response of ≥MR) was 38%. The MRD was 45 mg/m2 of carfilzomib plus 20 mg of panobinostat. This is a lower dose of panobinostat than that which is being tested in the expansion phase of the other trial of carfilzomib plus panobinostat by Dr Berdeja and colleagues.19 Additional patients, who have bortezomib-sensitive or refractory MM will be enrolled in this trial.
Carfilzomib plus Pomalidomide
In an oral presentation, Dr Shah discussed the results of a phase 1/2 trial of carfilzomib, pomalidomide, and dexamethasone (ie, Car-Pom-d).21 Cohort 1 included 3 mg of pomalidomide; all subsequent cohorts received 4 mg of pomalidomide on days 1 to 21 of
a 28-day cycle. Carfilzomib was escalated from 20/27 mg/m2 to 20/56 mg/m2, and patients received 40 mg of dexamethasone weekly for the first 4 cycles, followed by 20 mg for subsequent cycles. From cycle 7 and beyond, carfilzomib was dosed on days 1, 2, 15, and 16, and patients received pomalidomide and dexamethasone as in the previous cycle. All patients in this trial had to have MM that was refractory to lenalidomide; all but 2 of the enrolled patients also had MM refractory to previous therapy with bortezomib.
DLTs were reported in cohort level 1 (ie, febrile neutropenia [FN]) and cohort level 2 (ie, grade 4 thrombocytopenia and grade 3 rash). The MTD was established as 20/27-mg/m2 carfilzomib, 4-mg pomalidomide, and 40-mg dexamethasone; of the 32 patients who were enrolled, 20 were enrolled at the MTD. Hematologic AEs included FN (6%) and other cytopenias; nonhematologic AEs included fatigue, hypocalcemia, diarrhea, dyspnea, elevated creatinine, and rash. Serious AEs included grade 3 pneumonia, pulmonary emboli, and CHF. The ORR was 50%, and the clinical benefit response was 67%. The median PFS was 7.4 months, and the OS was estimated at 1 year to be 90%.
Patients with high-risk disease by the Mayo Stratification for Myeloma and Risk-Adapted Therapy (mSMART) responded similarly to those with standard or with intermediate risk, but the number of patients in all of these groups was small. Based on these results, enrollment is ongoing in a phase 2 clinical trial of 82 patients.
Carfilzomib plus ARRY-520
Dr Shah also presented a poster describing a phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 in combination with carfilzomib in patients with relapsed and/or refractory MM who have received previous ASCT and are intolerant of or whose MM is refractory to bortezomib and to lenalidomide.22 Carfilzomib was administered at a dose of 20/27 mg/m2, and ARRY-520 was dose-escalated from 0.5 mg/m2 (in cohort 1) to 1.5 mg/m2 (administered on days 1, 2, 15, and 16 of a 28-day cycle); dexamethasone 4 mg was administered on the same days as carfilzomib. Enrollment in the trial is ongoing. In the 9 patients enrolled so far, 1 DLT occurred, in cohort 2, which was influenza pneumonia (with 1.00-mg/m2 ARRY-520). Grade 3 or greater AEs included neutropenia, anemia, lung infection, diarrhea, fatigue, hyperglycemia, and hyponatremia. A preliminary clinical benefit response of 56% was reported.
Carfilzomib Preclinical Studies
Carfilzomib Induces Differentiation of Mesenchymal Stromal Cells
Yu Chen of the Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, presented a poster showing that carfilzomib induces differentiation of mesenchymal stromal cells toward osteoblasts via activation of the beta-catenin and T-cell factor pathway in patients with MM, the putative molecular mechanism that is underlying the bone anabolic effects of carfilzomib in myeloma bone disease.23
Antimyeloma Effects of Carfilzomib with Cyclophosphamide or Bendamustine
Eric Sanchez, Associate Director of Animal Research at the Institute for Myeloma and Bone Cancer Research, West Hollywood, CA, presented a poster describing the effects of carfilzomib administered with cyclophosphamide or with bendamustine in a xenograft model of mice bearing implanted MM tumors. Both carfilzomib combinations had anti-MM activity and provide the rationale for clinical trials evaluating these combinations in patients with MM.24
Figure
Oprozomib: Phase 1b Trial in Hematologic Malignancies
Michael Savona, MD, Director of Leukemia Research and Senior Investigator of Hematologic Malignancies and Drug Development at the Sarah Cannon Research Institute in Nashville, TN, gave an oral presentation of a phase 1b dose-escalation study of split-dose oprozomib (ONX 0912) in patients with hematologic malignancies.25 Oprozomib is an orally bioavailable structural analog of carfilzomib that similarly irreversibly and selectively inhibits the proteasome. Oprozomib was administered at a total daily dose of 120 mg and was escalated to 210 mg daily in 2 doses that were 4 to 6 hours apart with antiemetics and 4 mg of dexamethasone on days 1 to 5 of a 14-day cycle. The MTD was not reached at the highest dose (ie, cohort 4).
Of 13 patients receiving treatment, 11 had MM. The AEs that were reported for the first 3 cohorts included GI disturbances, cytopenias (including grade 4 thrombocytopenia), fatigue, pyrexia, hypoalbuminemia, and cognitive disorder. Some anti-MM was seen in 9 evaluable patients with MM, with partial response being the best response that was achieved. Dose-dependent proteasome inhibition was seen, as is shown in the Figure. Dose escalation will continue to MTD in a phase 2 expansion trial of patients with MM and Waldenström’s macroglobulinemia.
Conclusion
Ongoing trials of carfilzomib as a single agent and in combination therapies continue to define the role of this agent in the treatment of newly diagnosed patients and in patients with relapsed and/or refractory MM. The continued development of oprozomib may provide patients with a more convenient, oral option.
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