Novel therapies for patients with multiple myeloma (MM) continue to show improved outcomes for a population that as little as 8 years ago had few options. The evolution of new targets for therapy and improved agents in established classes shows that continued investigation into the mechanisms of inhibiting plasma-cell proliferation and activity yields better medications for patients across the disease spectrum.1 Traditionally, new drugs are introduced to the field in the relapsed and/or refractory setting, which has recently become a more difficult endeavor because of the availability of multiple lines of effective therapies that are approved for use.
Despite this evolving and challenging drug development landscape, carfilzomib (Kyprolis) data showing improved response rates in patients with MM led to the US Food and Drug Administration’s accelerated approval of the drug in 2012.2 The current use and evolution of carfilzomib’s place in therapy, along with other agents and combinations, are important for pharmacists to follow to ensure that we are knowledgeable and prepared to help patients with MM achieve maximum benefit from therapy.
Current and Future Safety Considerations for Carfilzomib Use
Patients with MM who are eligible for carfilzomib therapy will likely be at greater risk for selected adverse events (AEs), such as myelosuppression, because of previous treatment and their disease status compared with newly diagnosed patients. It is, therefore, reasonable to assume that single-agent and combination trials in patients with newly diagnosed MM will show reduced toxicity rates compared with previous and ongoing trials in relapsed and/or refractory disease. Cardiac events in patients receiving carfilzomib are of particular interest, because these AEs were seen in patients receiving this agent in phase 2 trials. As in the case of neuropathy or thrombotic events, it is helpful to understand the pretreatment frequency of cardiac events to differentiate drug- versus disease-related causes. The data presented by Kistler and colleagues at the 2012 American Society of Hematology meeting helped to contextualize cardiac events in >23,000 patients with MM.3
Of note, the rates in newly diagnosed and relapsed disease were similar, with arrhythmias being the most common cardiac event for both groups (24% and 29%, respectively), followed by ischemic heart disease (19% and 14%, respectively) and cardiomyopathy (5% each). All AEs were more common in patients aged ≥75 years. The clinical implications of these data are that cardiac events are common in MM, and that causality may be difficult to assign. If an event should occur, the timing, relevant history (eg, smoking, hypercholesterolemia), subsequent therapy for the event, and overall tolerability and response to anti-MM therapy should be taken into consideration when deciding how to proceed.
With carfilzomib, cardiac and pulmonary safety was summarized and described in >500 patients with MM across 4 trials by Lonial and colleagues.4 More than 66% of the patients were receiving cardiovascular medications in these trials, and, although arrhythmias were the most common event, they were less frequent than the rate seen in the Kistler review.3 Fewer than 5% of the patients required discontinuation or dose reduction, suggesting that continued therapy is both safe and feasible. Dyspnea may occur in patients receiving carfilzomib; however, it is short-lived and has been shown to be associated with other clinical events (eg, pulmonary embolism, heart failure).
The safety of prolonged exposure was also reported by Siegel and colleagues,5 who suggested that in patients who continue to respond, the rate of neuropathy remains low, and most grade 3 or 4 AEs are either a result of cytopenias or pneumonia. These data indicate that carfilzomib therapy as a long-term strategy is worth pursuing because of its promising efficacy and safety profile.
Prolonged infusion strategies may also allow higher doses to be given while maximizing safety when compared with the current 2- to 10-minute recommended administration. The approved carfilzomib dose of 20/27 mg/m2 has been surpassed in many clinical trials, and an evaluation of the specific tolerability of 30-minute infusions of higher doses was presented by Badros and colleagues in a phase 1b trial, in which the dose of 20/56 mg/m2 was established as safe and will be compared with bortezomib in a phase 3 clinical trial setting.6 Additional efficacy data in 20 patients with MM showed that carfilzomib 20/40 and 20/56 mg/m2 infused over 30 minutes with dexamethasone was beneficial and had an overall response rate of 55%.
The Evolution of Carfilzomib Use in Relapsed/Refractory MM and in Newly Diagnosed Patients
When considering the safety profile and previous efficacy data, the most intriguing application of carfilzomib and other novel agents is in combination. Building on single-agent activity, further studies of carfilzomib combinations with novel agents were presented at the meeting. Combination data from phase 1/2 clinical trials on the histone deacetylase inhibitor panobinostat, pomalidomide, and the kinesin spindle protein inhibitor ARRY-520 provided insight into the next generation of MM regimens.7-10 Each trial defined recommended (phase 2) doses and demonstrated activity in heterogeneous populations, while validating the benefit of combination approaches with novel agents.
When evaluating data with carfilzomib in the initial treatment setting, we must carefully review the regimens and schedules used. Many new regimens are reassessing the optimal dose of carfilzomib with the understanding that higher doses in patients with newly diagnosed MM may be well tolerated, with improved efficacy compared with the relapsed and/or refractory setting. When comparing these regimens, we have to be mindful of the carfilzomib dose and the schedule, as well as any concurrent agents. The doses and schedules of agents such as dexamethasone, lenalidomide, and cyclophosphamide may be unique and regimen-specific. The trial by Korde and Landgren (N = 20) showed that a cycle 2 and beyond dose of carfilzomib 36 mg/m2, along with 21 days of lenalidomide and dexamethasone 20 mg on the day that carfilzomib was administered every 28 days, produced near complete remission (CR)/stringent CR in 75% of the patients, with most of the responses occurring by cycle 5.11 The regimen was generally well tolerated, with a median of 7 cycles delivered at the time of evaluation and no grade ≥3 neuropathy. This combination is based on previous data with the bortezomib, lenalidomide, and dexamethasone regimen, and an ECOG trial (E1A11) comparing the 2 regimens is planned.
Other carfilzomib-containing regimens may hold promise in patients with newly diagnosed MM, including combinations with the oral alkylating agent cyclophosphamide plus thalidomide. Palumbo and colleagues presented data of transplant-ineligible patients with MM (35% of whom had unfavorable cytogenetics) with accelerated carfilzomib (20 mg/m2 cycle 1, days 1 and 2, 36 mg/m2 thereafter) with weekly oral cyclophosphamide and dexamethasone.12 The rates of all CR categories were 53%, and the responses generally improved over time. The 4-drug phase 1 combination of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone was also presented, with updated results from the 20/27-mg/m2 carfilzomib cohort showing a 29% CR rate, with ongoing accrual to the 20/36-mg/m2 cohort.13
Back to the Future
As MM therapy evolves, it is clear that orally based regimens have shifted drug development. Much like the historical melphalan–prednisone regimen, we can envision standard therapy of an oral proteasome inhibitor, an immunomodulatory drug (IMiD), and a corticosteroid as initial therapy in many patients, regardless of their transplant eligibility. The remaining questions are—which proteasome inhibitor and which IMiD agent? Novel agents, including pomalidomide, ixazomib (MLN 9708), oprozomib (ONX 0912), and the humanized monoclonal antibody elotuzumab continue to show promising activity and predict a future of effective, convenient regimens for patients with MM.
Conclusion
Carfilzomib data continue to evolve, showing promise across all categories of MM treatment. Contextualizing the safety information in different populations, while expanding efficacious options for patients with MM, is critical to ensuring optimal outcomes. Pharmacists can continue to provide needed education and input on carfilzomib-based treatment strategies for other clinicians and patients.
Author Disclosure Statement Dr Harvey has received research support from Acetylon Pharmaceuticals, Celgene, Genzyme, Millennium Pharmaceuticals, Onyx Pharmaceuticals, and Synta Pharmaceuticals.
References
1. Kumar SK, Rakjumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.
2. US Food and Drug Administration. Carfilzomib. www.fda.gov/Drugs/Information OnDrugs/ApprovedDrugs/ucm312945.htm. Accessed July 21, 2012.
3. Kistler K, Rajangam K, Faich G, et al. Cardiac event rates in patients with newly diagnosed and relapsed multiple myeloma in US clinical practice. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 2916.
4. Lonial S, Niesvizky R, McCulloch L, et al. Cardiac and pulmonary safety profile of single-agent carfilzomib from four phase 2 studies in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4037.
5. Siegel DS, Wang M, Martin T, et al. A phase 2 study of prolonged carfilzomib therapy in patients with multiple myeloma previously enrolled in carfilzomib phase 1 and 2 clinical trials. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 2962.
6. Badros A, Papadopoulos KP, Zojwalla N, et al. A phase 1b study of 30-minute infusion carfilzomib 20/45 and 20/56 mg/m2 plus 40 mg weekly dexamethasone in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4036.
7. Berdeja JG, Hart L, Lamar R, et al. A single-arm open-label, multi-center phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4048.
8. Shah JJ, Thomas S, Weber D, et al. Phase 1/1b study of the efficacy and safety of the combination of panobinostat + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4081.
9. Shah JJ, Stadtmauer EA, Abonour R, et al. Multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 74.
10. Shah JJ, Thomas S, Weber D, et al. Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 + carfilzomib in patients with relapsed and/or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4082.
11. Korde H, Landgren O. Phase II: carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012; 120:Abstract 732.
12. Palumbo A, Bringhen S, Villani O, et al. Carfilzomib, cyclophosphamide and dexamethasone (CCd) for newly diagnosed multiple myeloma (MM) patients. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 730.
13. Mikhael JR, Reeder CB, Libby EN III, et al. Results from the phase II dose expansion of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 445.
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