Design and rationale of FOCUS (PX-171-011): a randomized, open-label, phase 3 study of carfilzomib versus best supportive care regimen in patients with relapsed and refractory multiple myeloma (R/R MM).

Background

Multiple myeloma (MM) is the second most common hematologic malignancy worldwide [ 1 ]. Approximately 86,000 cases occur annually worldwide, with the frequency very unevenly distributed and the highest incidence in industrialized areas of Australia/New Zealand, Europe, and North America [ 2 ]. In Europe, MM has an incidence of 6/100,000 people and is responsible for at least 19,000 deaths a year [ 1 , 3 , 4 ]. MM is characterized by accumulation of abnormal plasma cells in bone marrow and monoclonal protein in blood and urine and has a heterogeneous clinical presentation [ 1 , 4 ]. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes development of MM [ 1 ].

Although there are MM treatments, the disease remains incurable and survival is limited to 6 to 7 years after autologous stem cell transplantation (ASCT) for patients who undergo the procedure and approximately 3 years in patients who do not [ 1 , 5 , 6 ]. Current treatments for relapsed and/or refractory disease include combination regimens using melphalan or alkylating agents, bortezomib, thalidomide, and lenalidomide with or without corticosteroids [ 6 ]. New therapies in various treatment settings have substantially improved outcomes for patients with relapsed and/or refractory disease, although survival after treatment with all available regimens, including those containing novel agents, is approximately 9 months following becoming refractory to these drugs [ 7 ]. Best supportive care (BSC) for patients with advanced refractory disease for which no approved alternative treatment is available may include low-dose glucocorticoids and/or low-dose alkylating agents, along with other supportive and palliative care options [ 8 ].

Carfilzomib is a next-generation proteasome inhibitor that is structurally and mechanistically distinct from bortezomib. It selectively and irreversibly inhibits the chymotrypsin-like activities of both the constitutive proteasome and the immunoproteasome [ 9 , 10 ]. In preclinical studies, carfilzomib displayed potent cytotoxic and pro-apoptotic activity across a broad panel of tumor-derived cell lines; was a potent proteasome inhibitor in early rodent tissue studies; showed potent inhibition of the proteasome with rapid and irreversible target binding despite high systemic clearance in rats; and was well tolerated in rats and monkeys [ 11 - 13 ].

Early phase 1 studies of carfilzomib showed sustained proteasome inhibition [ 14 , 15 ] and an acceptable safety profile in addition to establishing activity and efficacy in patients with MM [ 15 ]. Observation of fever, chills, shortness of breath, and/or rigors in these studies led to a selection of 20 mg/m 2 as the initial dose, as well as inclusion of hydration and concomitant dexamethasone (4-mg predose during the first cycle). Further investigation subsequently showed higher doses of carfilzomib to be effective, permitting escalated dosing up to 27 mg/m 2 beginning with Cycle 2 [ 15 - 18 ].

Carfilzomib has shown promising activity and tolerability in several phase 2 clinical studies [ 16 ]. In PX-171-003-A1, a large single-arm study of carfilzomib monotherapy in heavily pretreated patients with MM, the overall response rate (ORR) was 23.7% and 37% of patients achieved at least a minimal response (MR) [ 17 ]. The duration of response (DOR) was 7.8 months, and overall survival (OS) was 15.6 months [ 17 ]. In a study of bortezomib-treated and bortezomib-naïve patients with relapsed and/or refractory MM, PX-171-004, overall response rates (ORR) and clinical benefit response (CBR) of 17.1% and 31.4% were reported for bortezomib treated patients [ 19 ] and 47.6% and 61.9% were reported for bortezomib-naïve patients [ 20 ]. Additionally, carfilzomib has been investigated in patients with varying degrees of renal insufficiency (PX-171-005), and an ORR of 21.3% was observed with no difference in carfilzomib pharmacokinetics detected between the cohorts of patients with normal, mild, and severe renal dysfunction and no indication that a change in dose or treatment schedule is necessary for these patients [ 21 ]. Tolerability of extended treatment duration has been shown in long-term follow-up of PX-171-003-A1 [ 22 ].

A cross-trial safety analysis of 768 patients, including 526 patients from the four phase 2 trials 003-A0, 003-A1, 004, and 005 revealed an acceptable safety profile for carfilzomib [ 23 , 24 ]. Importantly, carfilzomib was associated with a low rate of typically mild to moderate, non–dose-limiting peripheral neuropathy (PN) and can be administered to patients with either 1) a history of or 2) pre-existing neuropathy without increased risk of PN. Additionally, treatment-emergent renal events resulting in carfilzomib discontinuations were uncommon and there was no association of worsening renal function due to carfilzomib treatment. Finally, hematologic AEs, although common with carfilzomib treatment, were infrequently dose-limiting.

Based on the results of the phase 2 trial PX-171-003-A1, carfilzomib was recently approved by the US Food and Drug Administration for the treatment of relapsed and refractory MM. Herein we describe the design and rationale of the phase 3 randomized study, FOCUS (Car F ilz O mib for Advan C ed Refractory M U ltiple Myeloma European S tudy, EudraCT No. 2009-016840-38), which is expected to provide important information to facilitate regulatory approvals around the world and expand treatment options to meet the unmet need of patients with advanced MM disease.

Methods/design

FOCUS is a phase 3, randomized, open-label, multicenter study comparing 2 treatment regimens for patients with MM for whom no approved alternative therapies are available.

Objectives

The primary objective of the study is to compare OS in patients with relapsed and refractory MM shown to be refractory to their most recent therapy and who have received all standard approved therapies, randomized to receive carfilzomib or a defined BSC regimen.

Secondary endpoints include PFS, ORR [stringent complete response (sCR) + complete response (CR) + very good partial response (VGPR) + partial response (PR)], CBR (ORR + MR), disease control rate (DCR; CBR + stable disease lasting ≥8 weeks) , DOR (calculated separately for overall response, CBR, and disease control endpoints), and safety.

Patients

Eligible patients must be at least 18 years of age and have measurable MM (defined by serum M protein ≥0.5 g/dL or serum quantitative immunoglobulin A ≥750 mg/dL in patients with IgA secretory MM and/or urine Bence Jones protein ≥200 mg/ 24 h), an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–2, and a life expectancy of at least 1 month. Patients must have received 3 or more prior therapeutic regimens, including treatment with bortezomib (defined as ≥4 cycles at full dose if tolerated); must have been responsive to at least 1 line of therapy (defined as a ≥25% decrease in M protein or total protein) and have relapsed disease, defined as progression while on or after at least 1 treatment regimen; and must have been refractory to their most recent therapy, defined as nonresponsive (eg, stable disease only, or progressive disease while on treatment), or disease progression within 60 days of discontinuation from therapy. Prior treatments must have included an immunomodulatory agent, an alkylating agent, and a corticosteroid. Additionally, patients must have adequate hepatic function and creatinine clearance of ≥15 mL/min.

Exclusion criteria include: Waldenström’s macroglobulinemia or IgM myeloma, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome or plasma cell leukemia; major surgery within 21 days prior to randomization; myocardial infarction in previous 3 months, New York Heart Association Class III/IV congestive heart failure; known human immunodeficiency virus seropositivity or active hepatitis; significant neuropathy (Grade ≥3 or Grade 2 with pain) at randomization; other malignancy in past 3 years; and prior carfilzomib treatment.

Study design and treatment

The study will be conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization E6, and any applicable regulatory requirements. The protocol and amendments have been reviewed by an Independent Ethics Committee. Approval has been provided by the Ethics Committee for each institution or city where the clinical trial is being held. Written informed consent will be obtained before any protocol-specific tests or procedures are conducted. Estimated sample size is 302 patients, and randomization will be stratified based on number of previous therapies and geographic location (Europe vs non-Europe). Eligible patients will be randomized in a 1:1 ratio to carfilzomib or BSC regimen (Table 1 ). BSC will initiate on Cycle 1 Day 1 and will include corticosteroid treatment (prednisolone 30 mg every other day, dexamethasone 6 mg every other day, or equivalent), with optional cyclophosphamide 50 mg PO once daily.

Carfilzomib treatment will be given in 28-day cycles at 20 mg/m 2 IV on Days 1 and 2 of Cycle 1, escalating to 27 mg/m 2 IV for Days 8, 9, 15, and 16 of Cycle 1 and continuing at 27 mg/m 2 for Cycles 2 through 9. For Cycles 10 and higher, carfilzomib will be given at 27 mg/m 2 IV on Days 1, 2, 15, and 16. Oral hydration, IV hydration, and dexamethasone 4 mg PO or IV during Cycle 1 will be included in the treatment regimen. Dosing will be modified as necessary (20 mg/m 2 , 15 mg/m 2 , or 11 mg/m 2 ) to manage toxicity.

For all patients randomized to carfilzomib, required concomitant medications during Cycle 1 include dexamethasone (4 mg PO or IV) and ciprofloxacin (500 mg PO QD). Valacyclovir or an equivalent antiviral is also required for patients treated with carfilzomib who have a history of herpes zoster. Additional medications that are permitted include bisphosphonates and other supportive care therapies at the investigator’s discretion. Uric acid-lowering agents, red blood cell and platelet transfusions, erythropoiesis-stimulating agents, and approved growth factors may be given when clinically indicated. Concurrent treatment with any anticancer therapy or radiation to large marrow reserves with therapeutic or palliative intent are not permitted, nor are corticosteroids at doses higher than those stated in the protocol. Plasmapheresis is not permitted.

Patients will continue randomized study treatment until confirmed disease progression (progressive disease, PD) or unacceptable toxicity. Following confirmation of PD or discontinuation from study treatment, all patients will enter long-term follow-up (LTFU) for survival. Crossover is not allowed upon progression.

Assessment of efficacy

Patients will be evaluated for disease response and progression according to the International Myeloma Working Group (IMWG) response criteria [ 25 ] and for MR according to the European Group for Blood and Marrow Transplantation (EBMT) criteria [ 26 , 27 ]. Evaluations will occur on Day 1 of each cycle, at the post-treatment visit, and during LTFU for those who did not have PD prior to discontinuing treatment. PD must be confirmed by 1) 2 consecutive measurements of rising serum or urine M-protein, 2) development of new lesions or definite increase in size of existing bone lesions or soft tissue plasmacytomas, or 3) hypercalcemia attributed solely to MM. Tumor response for all categories must be confirmed by 1) 2 consecutive M-protein measurements, 2) plasmacytoma evaluation where relevant, 3) no evidence of new or progressive bone lesions and 4) bone marrow biopsy for CR/sCR.

Assessment of safety

All patients who receive at least 1 dose of any study-specific treatment will be included in the safety analysis. Adverse event (AE) data will be collected at each visit from the time the patient signs the consent form and will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and assigned a severity grade using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4.0 grading scale. The investigator may discontinue study treatments for the following reasons: patient withdrawal of consent, confirmed PD, unacceptable toxicity, noncompliance with study procedures, requirement for alternative therapy, and intercurrent illness or worsening of a chronic condition; however, patients will be encouraged to remain on study for survival assessment. Patients with a dose reduction due to toxicity will remain on study; if the reduced dose is well tolerated, the patient may be rechallenged with the original dose at the start of the next cycle.

Statistical analysis

The primary endpoint of the study is OS, defined as the time from randomization to death due to any cause. The study will provide 80% power to detect a 30% reduction in the risk of death. The primary inferential comparison for OS between treatment groups will use the log-rank test assessed against an overall 1-sided significance level of 0.025 stratified by the randomization stratification factors (number of prior therapies and geographical location). The hazard ratio for treatment group will be estimated using a stratified Cox proportional hazards model. The distribution of OS times will be summarized using the Kaplan-Meier method.

An independent data monitoring committee (DMC) has been convened for this study and will act in an advisory capacity in safeguarding the interests of study patients, assessing interim safety and efficacy and for monitoring the overall conduct of the trial.

The inferential tests associated with secondary endpoints PFS, ORR, CBR, DCR, and DOR (including duration of clinical benefit and duration of disease control) will be performed in accordance with a closed testing procedure (CTP) to adjust for the multiplicity. Under the CTP, if the null hypothesis for the primary endpoint (OS) is rejected at the 1-sided significance level of 0.025, then testing of the secondary endpoints will proceed in a sequential step-down manner and a 1-sided significance level of 0.025 will be used at each testing step. Testing of secondary endpoints will continue provided the null hypothesis for each of the previously tested secondary endpoints is rejected.

The distribution of PFS times will be summarized descriptively using the Kaplan-Meier method. The inferential comparison between treatment groups will use the log-rank test stratified by the randomization stratification factor. The hazard ratio for treatment group will be estimated using a stratified Cox proportional hazards model. The inferential comparison between treatment groups for the ORR, CBR, and DCR endpoints will be made using the Cochran-Mantel-Haenszel chi-square test, stratified by the randomization stratification factor. The odds ratio to measure the relative treatment effect and the 95% CI will be estimated using the Mantel-Haenszel method. The DOR will be calculated for patients who achieve sCR, CR, VGPR, and PR. The inferential comparison between treatment groups will use the log-rank test stratified by the randomization stratification factors (region: Europe vs non-Europe, and number of prior lines of therapy: 3 vs 4 vs ≥5). The duration of overall response will be summarized descriptively using the Kaplan-Meier method.

The comparisons for the primary and secondary efficacy endpoints will be between the 2 randomized treatments groups (Regimen C vs Regimen BSC) based on the intent-to-treat population (ITT), consisting of all randomized patients.

Status

FOCUS began enrolling patients in September 2010 with a target enrolment of 302 patients. Approximately 100 institutions are being recruited to participate. The study is currently accruing patients in 7 countries and over 40 sites throughout Europe and is expanding to other parts of the world, with 211 patients enrolled as of the end of June 2012.

Discussion

Based on results of previous trials with similar carfilzomib treatment, carfilzomib is anticipated to provide prolonged disease control compared with BSC [ 16 - 18 , 28 ]. This phase 3 trial will provide more rigorous data compared with those already available for carfilzomib, as it will not be confounded by crossover and is the first carfilzomib study with OS as the primary endpoint. Additionally, the larger study group will provide more robust secondary response data, including PFS and ORR. It has been demonstrated that maximal response is associated with better outcome in a variety of different treatment settings [ 6 ]. In light of this current view of the importance of attaining CR in MM, more robust data will be beneficial.

Previous studies have reported good tolerability for carfilzomib [ 22 - 24 ]. Carfilzomib has shown specific long-term tolerability in follow-up of the pivotal 171-003-A1 trial, as well as an extension trial in which patients who completed other carfilzomib studies are eligible to enroll (PX-171-010, NCT00884312 ) [ 17 , 29 ]. Additionally, an ongoing phase 1/2 study has shown carfilzomib to be tolerable at doses up to 56 mg/m 2 [ 18 ]. The present study will expand upon the existing carfilzomib single-agent tolerability data set.

This is a study of heavily pretreated patients and, similar to studies with other newer drugs in relapsed and refractory MM, challenges may arise in the interpretation of the results. A recent study by the IMWG confirmed that patients generally have a poor outcome after becoming refractory to currently available therapies [ 7 ]. The IMWG data establish a relevant context for interpreting the results of studies involving novel drugs and provide information regarding the natural history of relapsed MM. This information will be useful in interpreting the results of the present study.

With respect to the study design, the European Medicines Agency (EMEA) strongly recommended evaluating whether carfilzomib increased survival in heavily-pretreated patients with MM, necessitating the inclusion of a BSC comparator arm. This ultimately proved to be both scientifically and ethically challenging. In particular, the identification of a universally acceptable salvage regimen for treatment of patients with advanced MM is quite difficult as treatment options for patients with relapsed and refractory MM are frequently limited due to concurrent disease or patients’ inability to tolerate conventional therapies. Several meetings with European experts in MM were held with the expressed aim of defining an acceptable control arm for this trial. While a number of individuals suggested testing carfilzomib against an active control arm, the majority of experts favored a control arm permitting the use of optional cyclophosphamide as it has been shown that continuous low-dose oral cyclophosphamide in combination with prednisone has resulted in response rates of 41–69% with OS up to 28.6 months [ 30 - 32 ]. Following careful thought and consideration of the consensus view, the lead investigators concluded that the best approach to address the needs of both patients and the recommendation of the regulatory agency was for the control arm to include a standard regimen of dexamethasone (or equivalent dosing of a comparable glucocorticoid) with the option of adding continuous low-dose oral cyclophosphamide.

To address the potential ethical concerns raised by the trial design, an extension study is planned that will offer treatment with carfilzomib to control-arm patients who complete the study, provided that an interim analysis of the study data demonstrates a statistically significant survival benefit for carfilzomib relative to BSC. This option would also permit patients progressing on BSC to cross over to the carfilzomib treatment arm. Furthermore, patients are not restricted from receiving further anti-myeloma therapy following study drug discontinuation.

In conclusion, the results of FOCUS in patients with relapsed and refractory MM will provide important information to facilitate regulatory approvals around the world and expand treatment options to meet the unmet need of these patients with advanced disease.

Competing interests

RH has no competing interests to declare. RB declares that he is a current employee of Onyx Pharmaceuticals Inc., South San Francisco, CA and has stock ownership in Onyx. SR declares that she is a current employee of Onyx Pharmaceuticals Inc., South San Francisco, CA and has stock ownership in Onyx. BK declares that she is a current employee of Onyx Pharmaceuticals Inc., South San Francisco, CA, has stock ownership in Onyx and has received a salary from Onyx for a patent related to the manuscript. HL has no competing interests to declare.

Authors' contributions

RH has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data and was involved in drafting/revising the manuscript. RB has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data and was involved in drafting/revising the manuscript. SR has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data. BK has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data and was involved in drafting/revising the manuscript. HL has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data and was involved in drafting/revising the manuscript. All authors read and approved the final manuscript.

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1471-2407/12/415/prepub

Acknowledgments

We gratefully acknowledge the support of Kanya Rajangam, MD (Clinical, Onyx Pharmaceuticals), Ashley Powne (Clinical Operations, Onyx Pharmaceuticals), and Rajneesh Nath, MD (Clinical, Onyx Pharmaceuticals). We would also like to acknowledge the writing assistance of Melissa Kirk, PhD of Fishawack Communications, which was sponsored by Onyx Pharmaceuticals. FOCUS is sponsored by Onyx Pharmaceuticals.

Dimopoulos MA Terpos E Multiple myeloma Annals of oncology: official journal of the European Society for Medical Oncology / ESMO 2010 21 suppl 7 vii143 vii150 20943607 10.1093/annonc/mdq370

Becker N Epidemiology of multiple myeloma Recent results in cancer research Fortschritte der Krebsforschung Progres dans les recherches sur le cancer 2011 183 25 35 21509679 10.1007/978-3-540-85772-3_2

Boyle P Ferlay J Cancer incidence and mortality in Europe, 2004 Annals of oncology: official journal of the European Society for Medical Oncology / ESMO 2005 16 3 481 488 10.1093/annonc/mdi098 15718248

Palumbo A Anderson K Multiple myeloma New Engl J Med 2011 364 1046 1060 10.1056/NEJMra1011442 21410373

Ludwig H Beksac M Blade J Boccadoro M Cavenagh J Cavo M Dimopoulos M Drach J Einsele H Facon T Goldschmidt H Harousseau JL Hess U Ketterer N Kropff M Mendeleeva L Morgan G Palumbo A Plesner T San Miguel J Shpilberg O Sondergeld P Sonneveld P Zweegman S Current multiple myeloma treatment strategies with novel agents: a European perspective Oncologist 2010 15 1 6 25 10.1634/theoncologist.2009-0203 20086168 PMC3227886

Ludwig H Beksac M Blade J Cavenagh J Cavo M Delforge M Dimopoulos M Drach J Einsele H Facon T Goldschmidt H Harousseau JL Hess U Kropff M Leal Costa F da Louw V Magen-Nativ H Mendeleeva L Nahi H Plesner T San-Miguel J Sonneveld P Udvardy M Sondergeld P Palumbo A Multiple myeloma treatment strategies with novel agents in 2011: a European perspective The Oncologist 2011 16 4 388 403 10.1634/theoncologist.2010-0386 21441574 PMC3228121

Kumar SK Lee JH Lahuerta JJ Morgan G Richardson PG Crowley J Haessler J Feather J Hoering A Moreau P LeLeu X Hulin C Klein SK Sonneveld P Siegel D Blade J Goldschmidt H Jagannath S Miguel JS Orlowski R Palumbo A Sezer O Rajkumar SV Durie BG Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2012 26 1 149 157 10.1038/leu.2011.196 PMC4109061 21799510

Mehta J Cavo M Singhal S How I treat elderly patients with myeloma Blood 2010 116 13 2215 2223 10.1182/blood-2009-10-163329 20644120

Arastu-Kapur S Shenk KD Kirk CJ Swinarski D Muchamuel T Bennett MK Parlati F Non-proteasome targets of proteasome inhibitors bortezomib and carfilzomib Haematologica 2009 94 s2 A0939

Arastu-Kapur S Anderl JL Kraus M Parlati F Shenk KD Lee SJ Muchamuel T Bennett MK Driessen C Ball AJ Kirk CJ Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events Clinical cancer research: an official journal of the American Association for Cancer Research 2011 17 9 2734 2743 10.1158/1078-0432.CCR-10-1950 21364033

Yang J Wang Z Fang Y Jiang J Zhao F Wong H Bennett MK Molineaux CJ Kirk CJ Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats Drug metabolism and disposition: the biological fate of chemicals 2011 39 10 1873 1882 10.1124/dmd.111.039164 21752943

Demo SD Kirk CJ Aujay MA Buchholz TJ Dajee M Ho MN Jiang J Laidig GJ Lewis ER Parlati F Shenk KD Smyth MS Sun CM Vallone MK Woo TM Molineaux CJ Bennett MK Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome Cancer Res 2007 67 13 6383 6391 10.1158/0008-5472.CAN-06-4086 17616698

Kuhn DJ Chen Q Voorhees PM Strader JS Shenk KD Sun CM Demo SD Bennett MK van Leeuwen FW Chanan-Khan AA Orlowski RZ Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma Blood 2007 110 9 3281 3290 10.1182/blood-2007-01-065888 17591945 PMC2200918

O'Connor OA Stewart AK Vallone M Molineaux CJ Kunkel LA Gerecitano JF Orlowski RZ A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies Clinical cancer research: an official journal of the American Association for Cancer Research 2009 15 22 7085 7091 10.1158/1078-0432.CCR-09-0822 19903785 PMC4019989

Alsina M Trudel S Furman RR Rosen PJ O'Connor OA Comenzo RL Wong AF Kunkel LA Molineaux CJ Goy A A phase 1 single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma Clinical cancer research: an official journal of the American Association for Cancer Research 2012 Epub August 21, 2012 10.1158/1078-0432.CCR-11-3007 22761464

Jain S Diefenbach C Zain J O'Connor OA Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma Core evidence 2011 6 43 57 21654882 10.2147/CE.S13838 PMC3102580

Siegel DS Martin T Wang M Vij R Jakubowiak AJ Lonial S Trudel S Kukreti V Bahlis N Alsina M Chanan-Khan A Buadi F Reu FJ Somlo G Zonder J Song K Stewart AK Stadtmauer E Kunkel L Wear S Wong AF Orlowski RZ Jagannath S A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma Blood 2012 Epub July 25 10.1182/blood-2012-05-425934 PMC4123387 22833546

Papadopoulos KP Lee P Singhal S Holahan JR Tolcher AW Patnaik A Vesole DH Rosen S Rosen J Bilotti EA Woo T Lee S Hannah AL Siegel DS PX-171-007: A phase 1B study evaluating the safety and efficacy of a 30-minute IV infusion of carfilzomib in patients with relapsed and/or refractory (R/R) multiple myeloma (MM) Haematologica 2011 96 Supplement 2 0898

Vij R Siegel D Jagannath S Jakubowiak A Stewart A McDonagh K Bahlis N Belch A Kunkel L Wear S Wong A Wang M An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib Br J Haematol 2012 158(6):739-748 10.1111/j.1365-2141.2012.09232.x PMC5818209 22845873

Vij R Wang M Kaufman JL Lonial S Jakubowiak AJ Stewart AK Kukreti V Jagannath S McDonagh KT Alsina M Bahlis NJ Reu FJ Gabrail NY Belch A Matous JV Lee P Rosen P Sebag M Vesole DH Kunkel LA Wear SM Wong AF Orlowski RZ Siegel DS An open-label, single-arm, phase 2 (PX-171-004) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma Blood 2012 119 24 5661 5670 10.1182/blood-2012-03-414359 22555973 PMC4123327

Niesvizky R Vij R Martin T Zonder J Wang Z Woo T Wong A Badros A Carfilzomib pharmacokinetics, safety, and activity in patients with relapsed or refractory multiple myeloma and renal dysfunction: final results Haematologica 2011 96 Supplement 2 370 Abstract 0890

Jagannath S Singhal S Siegel DS Martin T Wang M Vij R Jakubowiak AJ Lonial S Kukreti V Bahlis N Chanan-Khan A Alsina M Somlo G Buadi F Reu F Song K Kunkel L Wong A Vallone M Orlowski R Stewart AK The Multiple Myeloma Research Consortium Long-term follow-up in PX-171-003-A1, an open-label, single-arm phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma (R/R MM): analysis by subgroups of interest Haematologica 2011 96 Supplement 2 0308

Singhal SB diCapua Siegel DS Martin T Vij R Wang M Jakubowiak AJ Lonial S Kukreti V Zonder JA Wong AF McCulloch L Kauffman M Badros AZ Niesvizky R Orlowski RZ Stewart AK Jagannath S Pooled safety analysis from phase (ph) 1 and 2 studies of carfilzomib (CFZ) In patients with relapsed and/or refractory multiple myeloma (MM) Blood 2010 116 21 1954

Singhal S Siegel D Martin T Vij R Wang M Jakubowiak A Lonial S Kukreti V Zonder J Wong A McCulloch L Badros A Niesvizky R Orlowski R Stewart A Kotlovker D Jagannath S Integrated safety data from phase 2 studies of monotherapy carfilzomib in patients with relapsed and refractory multiple myeloma (MM): an updated analysis Blood 2011 118 1876

Durie BG Harousseau JL Miguel JS Blade J Barlogie B Anderson K Gertz M Dimopoulos M Westin J Sonneveld P Ludwig H Gahrton G Beksac M Crowley J Belch A Boccadaro M Cavo M Turesson I Joshua D Vesole D Kyle R Alexanian R Tricot G Attal M Merlini G Powles R Richardson P Shimizu K Tosi P Morgan G Rajkumar SV International uniform response criteria for multiple myeloma Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2006 20 9 1467 1473 10.1038/sj.leu.2404284 16855634

Kyle RA Rajkumar SV Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, UK 2009 23 1 3 9 10.1038/leu.2008.291 PMC2627786 18971951

Bladé J Samson D Reece D Apperley J Björkstrand B Gahrton G Gertz M Giralt S Jagannath S Vesole D Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high dose therapy and haempotietic stem cell transplantation Br J Haematol 1998 102 2 1115 1123 9753033 10.1046/j.1365-2141.1998.00930.x

Siegel D Lee P Singhal S Holahan J Tolcher A Patnaik A Vesole D Rosen S Rosen P Bilotti E Lee S Woo T Hannah A Papadopoulos K Phase (ph) 1b evaluation of the safety and efficacy of a 30-minute IV infusion of carfilzomib (CFZ) in patients (pts) with relapsed and/or refractory (R/R) multiple myeloma (MM) Haematology 2011 96 Supplement 1 309

Siegel D Kaufman JL Wang M Martin T Jagannath S Niesvizky R Reu F Alsina M Badros A Gabrail N Kukreti V Singhal S Le M Kotlovker D Bomba D Hannah A Vij R Carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (R/R MM): summary of safety and efficacy data upon long-term treatment Haematologica 2011 96 Supplement 1 1535

Brandes LJ Israels LG Weekly low-dose cyclophosphamide and alternate-day prednisone: an effective low toxicity regimen for advanced myeloma Eur J Haematol 1987 39 4 362 368 3691759 10.1111/j.1600-0609.1987.tb00784.x

de Weerdt O van de Donkb NWCJ Veth G Bloem AC Hagenbeek A Lokhorst HM Continuous low-dose cyclophosphamide-prednisone is effective and well tolerated in patients with advanced multiple myeloma The Netherlands Journal of Medicine 2001 59 50 56 10.1016/S0300-2977(01)00140-1 11476912

Zhou F Guo L Shi H Lin C Hou J Continuous administration of low-dose cyclophosphamide and prednisone as a salvage treatment for multiple myeloma Clinical lymphoma, myeloma & leukemia 2010 10 1 51 55 10.3816/CLML.2010.n.005 20223729