Summary
Sixty-four transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1–28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28-day cycles (CYKLONE regimen). Carfilzomib was dose-escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide-related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression-free survival and overall survival at 24 months was 76% and 96%, respectively (median follow-up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.
Keywords: myeloma therapy, multiple myeloma, clinical trials, clinical studies, experimental therapies
Induction regimens in multiple myeloma (MM) utilizing bortezomib in combination with dexamethasone and cyclophosphamide or lenalidomide have proven effective in transplant-eligible patients, resulting in partial response (PR) rates of more than 90% and approximately one third of patients entering complete response (CR) prior to transplantation (Khan et al, 2012). However, these regimens have been associated with significant neuropathy related to bortezomib use, and venous thrombosis and challenges in stem cell collection related to lenalidomide use (Roussel et al, 2011; Khan et al, 2012; Kumar et al, 2012). Similarly, the addition of bortezomib to thalidomide and dexamethasone (VTD) has been shown to improve response rates in patients with newly diagnosed MM when compared with thalidomide and dexamethasone, but the three-drug combination resulted in a significantly higher incidence of Grade 3/4 peripheral neuropathy (Cavo et al, 2010). The addition of the alkylating agent melphalan and the corticosteroid prednisone to bortezomib and thalidomide created a four-drug combination with impressive results in elderly patients, but has been associated with significantly greater rates of Grade 3/4 neutropenia, thrombocytopenia and peripheral neuropathy, as well as cardiological events compared with melphalan, prednisone and bortezomib (Palumbo et al, 2014). Finally, a four-drug combination of bortezomib, dexamethasone, cyclophosphamide and lenalidomide (VDCR) failed to provide substantial clinical benefits over the three-drug regimens of bortezomib, cyclophosphamide and dexamethasone (VCD) or bortezomib, lenalidomide and dexamethasone (VRD), primarily due to excess myelosuppression from combining cyclophosphamide with lenalidomide (Kumar et al, 2012). Thus, there is an unmet clinical need in patients with newly diagnosed MM for regimens that are efficacious and have improved tolerability.
Carfilzomib is a proteasome inhibitor that has been recently approved in the United States as a single agent for the treatment of patients with relapsed and refractory MM. Carfilzomib binds selectively and irreversibly to its target and exhibits a lower incidence of neuropathy compared to bortezomib (Demo et al, 2007; Kuhn et al, 2007; http://www.velcade.com/Files/PDFs/VELCADE_PRESCRIBING_INFORMATION.pdf; http://www.kyprolis.com/prescribing-information).
Phase I and II studies investigating the combination of carfilzomib with lenalidomide and dexamethasone have found that the regimen is effective and well tolerated in patients with newly diagnosed MM who are transplant-eligible and transplant-ineligible (Jakubowiak et al, 2012; Korde et al, 2013). Indeed, this regimen is, to date, one of the most potent described for inducing deep responses. While results are encouraging with this combination, neither lenalidomide nor carfilzomib are approved for use in the first-line setting. In addition, the regimen fails to capitalize on the use of an alkylating agent (such as cyclophosphamide), a therapeutic class that has been shown to synergize with proteasome inhibitors for increased efficacy in MM cell lines (Yarde et al, 2009).
Consequently, we designed the CYKLONE study to examine a potentially non-myelosuppressive and non-neurotoxic four-drug regimen in which carfilzomib was added to the widely accessible backbone of cyclophosphamide, thalidomide and dexamethasone (CYKLONE regimen) for the treatment of patients with newly diagnosed MM who were transplant-eligible. Our goal was to optimize response prior to transplantation, while minimizing any overlap in toxicities. This regimen takes advantage of all four major classes of drugs used in MM therapy, while recognizing issues in drug access worldwide and the importance of limiting early myelosuppression and neuropathy.
Methods
Patients
Adult transplant-eligible patients with previously untreated symptomatic MM were eligible for enrolment. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2. An ECOG PS of 3 was allowed if considered secondary to pain. Minimum laboratory requirements included absolute neutrophil count ≥1 × 109/l, platelet count of ≥75 × 109/l, haemoglobin ≥80 g/l and creatinine clearance ≥30 ml/min. Patients with peripheral sensory neuropathy Grade ≥2 or severe cardiac comorbidity (including New York Heart Association Class III or IV heart failure, uncontrolled angina, or severe ventricular arrhythmia, cardiac amyloidosis with hypotension or recent history of myocardial infarction) were excluded.
Study design and treatment
CYKLONE was a multicentre, single-arm, open-label, phase Ib/II study. The study utilized a standard 3 + 3 dose-escalation scheme in the phase I portion to determine the maximum tolerated dose (MTD) of carfilzomib for dose-expansion in the phase II portion. The phase II portion was a one-stage binomial design which required eight or more responses out of 24 evaluable patients to reject the null hypothesis that the confirmed response [very good partial response (VGPR) or better] rate is <20% with a type I error of <0·10 and 90% power if the true confirmed response rate is 45%.
Patients received carfilzomib by intravenous infusion over 30 min on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle (Table I). All patients received cyclophosphamide 300 mg/m2 orally (PO) on days 1, 8 and 15; thalidomide 100 mg PO on days 1–28; and dexamethasone 40 mg PO on days 1, 8, 15 and 22. Patients received CYKLONE treatment for four cycles or more, followed by stem cell transplant (SCT). Stem cell collection was performed by institutional protocol, employing single-agent granulocyte colony-stimulating factor with plerixafor rescue in cases of insufficient mobilization. Patients who achieved stable disease (SD) or better could continue treatment for up to eight additional cycles.
Table I.
Treatment administered.
| Carfilzomib dosing cohorts | ||||
|---|---|---|---|---|
| Patients, n | Carfilzomib dose (mg/m2) | |||
| Dose level | Phase I | Phase II | Cycle 1 | Cycle 2 and beyond* |
| −1 | 3 | 0 | 15 | 20 |
| 0 (original MPD) | 3 | 22 | 20 | 27 |
| 1 (MTD) | 6 | 23 | 20 | 36 |
| 2 | 7 | 0 | 20 | 45 |
| Agent | Dose | Days administered | ||
| Carfilzomib | See above | Days 1, 2, 8, 9, 15, 16 | ||
| Cyclophosphamide | 300 mg/m2 | Days 1, 8, 15 | ||
| Thalidomide | 100 mg | Days 1–28 | ||
| Dexamethasone | 40 mg | Days 1, 8, 15, 22 | ||
MPD, maximum planned dose; MTD, maximum tolerated dose.
At dose levels 1 and 2, patients could initiate this dose starting on day 8 of Cycle 1.
Patients received prophylactic treatment with 400 mg oral acyclovir (twice daily) and with antibacterials. Patients also received anticoagulation treatment in the form of aspirin or low-molecular weight heparin for patients intolerant to aspirin. All patients received 250–500 ml of intravenous fluid before and after carfilzomib treatment during Cycle 1. Patients considered at risk for tumour lysis syndrome could continue hydration into Cycle 2.
During phase I, the primary objective was to establish the MTD of carfilzomib when given in combination with cyclophosphamide, thalidomide and dexamethasone. Initial carfilzomib doses tested were 15/20 mg/m2 (dose level −1) and 20/27 mg/m2 (dose level 0): patients received a starting dose of 15 or 20 mg/m2 respectively, in Cycle 1, followed by dose-escalation to 20 or 27 mg/m2 respectively, in Cycle 2 and beyond if the initial dose was well tolerated [i.e., no Grade 3 nonhaematological or Grade 4 haematological adverse event (AE), and no tumour lysis syndrome]. If no dose-limiting toxicities (DLTs) were observed in the phase I portion of the trial, additional patients were to be enrolled at the maximum planned dose (MPD; 20/27 mg/m2).
Emerging evidence (Papadopoulos et al, 2014) indicating that single-agent carfilzomib is well tolerated in patients with relapsed and/or refractory MM at doses up to 56 mg/m2 led to a protocol amendment that allowed for a return to dose escalation. Patients received 20/36 mg/m2 (dose level 1) or 20/45 mg/m2 (dose level 2) carfilzomib. In contrast to the previous dose-escalation phase, at dose levels 1 and 2, patients could initiate dose escalation at day 8 of Cycle 1 if the initial dose was well tolerated. Once the MTD of carfilzomib was established, additional patients were enrolled in a phase II expansion cohort.
Dose-limiting toxicities were defined as the occurrence of the following in Cycles 1 or 2 for patients enrolled prior to the protocol amendment or in Cycle 1 only for patients enrolled after the protocol amendment, and at least possibly attributed to treatment: Grade 4 neutropenia lasting >7 d; febrile neutropenia of any grade; Grade 3 or 4 thrombocytopenia associated with bleeding or Grade 4 thrombocytopenia lasting ≥7 d; Grade ≥2 neuropathy with pain; Grade ≥3 nausea, vomiting or diarrhoea uncontrolled by antiemetic/antidiarrheal therapy; Grade 4 fatigue lasting >7 d; or any other Grade ≥3 nonhaematological toxicity. Any toxicity that resulted in a dose delay of >21 d of the intended next dose was also considered a DLT. A standard 3 + 3 dose-escalation scheme was used, in which three patients were treated at each dose level and observed for DLTs before new patients were treated.
The primary objective of the phase II portion of the study was to evaluate the proportion of patients with a response of ≥VGPR after four cycles of the CYKLONE regimen. Secondary objectives of the trial were to evaluate the overall response rate (ORR; PR or better as best response across all cycles of treatment), duration of progression-free survival (PFS) and overall survival (OS), safety and tolerability of the regimen and to assess the success of stem cell collection following treatment.
The study protocol was approved by the institutional review board of participating institutions. All patients provided written informed consent. The study is registered at http://www.clinicaltrials.gov as NCT01057225.
Assessments
Grading of AEs was performed according to Common Terminology Criteria for AEs, version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf).
Disease assessments were conducted at baseline and at the end of each cycle. Response was assessed by investigators according to International Myeloma Working Group criteria (Kumar et al, 2009; Mikhael et al, 2013), with the addition of minimal response (MR) per European Blood and Marrow Transplantation Group criteria (Bladé et al, 1998; Kyle & Rajkumar, 2009).
Statistical analysis
Approximately 60 patients were planned for total enrolment post-protocol amendment, including 24 efficacy-evaluable patients in the phase II portion of the study. All enrolled patients who began treatment were evaluated for safety and response. Survival times (PFS and OS) were estimated using the Kaplan–Meier method. PFS was defined as the time from registration to disease progression or death, whichever was earlier. OS was defined as the time from registration to death due to any cause.
The phase II primary end point was the proportion of patients with confirmed ≥VGPR following four cycles of treatment. Patients who received at least one dose at the MTD post-protocol amendment were considered evaluable for response for the primary end point.
Results
Patients and treatment
The study was initiated in March 2010, and enrolment completed in November 2013. Data cut-off was February 14, 2014. Sixty-four patients were enrolled in four centres in the United States; patient flow and disposition are depicted in Fig 1. The median patient age was 62·5 years (Table II). Forty-five patients were intermediate or high risk according to the Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) criteria (Kumar et al, 2009; Mikhael et al, 2013); eight patients had t(4;14) disease and six patients had del17p disease. Eight patients (13%) had an ECOG PS of 2 or 3, including two patients with an ECOG PS of 3.
Fig 1.
Patient flow. Stem cell transplantation occurred after completion of protocol therapy and was not part of protocol therapy. CYKLONE, carfilzomib, cyclophosphamide, thalidomide and dexamethasone; MPD, maximum planned dose; MTD, maximum tolerated dose; AE, adverse event.
Table II.
Patient demographics and baseline characteristics.
| Patients (N = 64) | |
|---|---|
| Age, years median (range) | 62·5 (27–82) |
| Sex, n (%) | |
| Female | 30 (47) |
| Male | 34 (53) |
| Race/ethnicity, n (%) | |
| White | 54 (84) |
| Hispanic/Latino | 4 (6) |
| Black/African-American | 4 (6) |
| Asian | 1 (2) |
| Missing/unknown | 1 (2) |
| ECOG performance status, n (%) | |
| 0 | 38 (59) |
| 1 | 18 (28) |
| 2 | 6 (9) |
| 3 | 2 (3) |
| International Staging System, n (%) | |
| I | 23 (36) |
| II | 27 (42) |
| III | 14 (22) |
| mSMART criteria | |
| High risk | 6 (9) |
| Intermediate risk | 39 (61) |
| Standard risk | 15 (23) |
| FISH not done | 4 (6) |
ECOG indicates Eastern Cooperative Oncology Group; mSMART, Mayo Stratification of Myeloma and Risk-Adapted Therapy; FISH, fluorescence in situ hybridization (Kumar et al, 2009; Mikhael et al, 2013).
Median follow-up was 17·5 months (range, 1·1–63·8 months). At data cut-off, eight patients remained on treatment. Patients who have ended treatment (n = 56) received a median of four cycles of treatment (range, 1–12). Among patients who have ended treatment, 93% completed at least four cycles of treatment: 59% (33/56) received four cycles of treatment and 34% (19/56) received five or more cycles of treatment.
Maximum tolerated dose
In the original dose-escalation phase, three patients each were enrolled to receive 15/20 mg/m2 (dose level −1) and 20/27 mg/m2 (dose level 0) carfilzomib (Table I). As no DLTs were observed, an additional 21 patients were enrolled at the original MPD (the 20/27-mg/m2 dose level).
Reported tolerability for single-agent carfilzomib at higher doses (Papadopoulos et al, 2014) led to a protocol amendment allowing a return to dose escalation. An additional 13 patients were enrolled to receive 20/36 mg/m2 (dose level 1; n = 6) and 20/45 mg/m2 (dose level 2; n = 7) carfilzomib. One additional patient was enrolled to receive 20/36 mg/m2, but this patient received 20/27 mg/m2 instead, for a total of 25 patients at the 20/27-mg/m2 dose level.
At a dose level of 20/45 mg/m2 carfilzomib, three out of seven patients experienced DLTs in Cycle 1, consisting of one case each of Grade 3 alanine aminotransferase increase and a Grade 3 infusion reaction, and one patient with Grade 4 heart failure with Grade 3 dyspnoea, atrial fibrillation and fatigue. All DLTs were considered to be at least possibly carfilzomib-related.
No DLTs were observed in the six patients treated with the 20/36-mg/m2 dose. Thus, 20/36 mg/m2 was determined to be the MTD for carfilzomib and an additional 23 patients were enrolled at this dose, for a total of 29 patients treated at the 20/36-mg/m2 dose level.
Safety and tolerability
All 64 patients were included in the safety analysis (15/20 mg/m2, n = 3; 20/27 mg/m2, n = 25; 20/36 mg/m2, n = 29; 20/45 mg/m2, n = 7). Forty-three patients (67%) experienced a Grade ≥3 AE possibly related to CYKLONE study treatment (15/20 mg/m2, n = 0/3; 20/27 mg/m2, n = 12/25; 20/36 mg/m2, n = 26/29; 20/45 mg/m2, n = 5/7).
Frequent haematological AEs of any grade, regardless of attribution, included neutropenia (55%), thrombocytopenia (47%), anaemia (44%), lymphopenia (42%) and leucopenia (39%) (Table III). Frequently reported nonhaematological AEs of any grade, regardless of attribution, included fatigue (80%), constipation (53%), hyperglycaemia (39%) and lethargy (25%). Other AEs of interest are reported in Table IV. All incidences of peripheral neuropathy were Grade 1 and considered predominantly related to thalidomide treatment. Dyspnoea (20%) and cough (6%) were the only cardiac or pulmonary events of any-grade toxicity reported in at least 5% of patients. Thromboembolic events were reported in four (6%) patients: one Grade 1, one Grade 3 and two Grade 4. The most common Grade ≥3 AEs were haematological and included lymphopenia (38%), neutropenia (23%), anaemia (20%) and leucopenia (13%). Grade ≥3 nonhaematological AEs included hyperglycaemia, increased alanine aminotransferase, hypophosphataemia and hypertension (each reported in 6% of patients).
Table III.
Adverse events (AEs) with Grade ≥3 regardless of attribution reported in ≥5% of patients (N = 64).
| Regardless of attribution, n(%) | At least possibly related, n(%) | |||||
|---|---|---|---|---|---|---|
| All grades | Grade ≥3 | Grade ≥4 | All grades | Grade ≥3 | Grade ≥4 | |
| Haematological AE | ||||||
| Lymphopenia | 27 (42) | 24 (38) | 3 (5) | 25 (39) | 22 (34) | 3 (5) |
| Neutropenia | 35 (55) | 15 (23) | 5 (8) | 35 (55) | 15 (23) | 5 (8) |
| Anaemia | 28 (44) | 13 (20) | 0 | 20 (31) | 6 (9) | 0 |
| Leucopenia | 25 (39) | 8 (13) | 1 (2) | 25 (39) | 8 (13) | 1 (2) |
| Nonhaematological AE | ||||||
| Hyperglycaemia | 24 (38) | 4 (6) | 0 | 24 (38) | 4 (6) | 0 |
| Alanine aminotransferase increased | 10 (16) | 4 (6) | 0 | 9 (14) | 3 (5) | 0 |
| Hypophosphataemia | 10 (16) | 4 (6) | 0 | 7 (11) | 2 (3) | 0 |
| Hypertension | 6 (9) | 4 (6) | 0 | 6 (9) | 4 (6) | 0 |
Table IV.
Other adverse events (AEs) of interest (N = 64).
| AE, n (%) | All grades | Grade ≥3 |
|---|---|---|
| Elevated creatinine | 25 (39) | 3 (5) |
| Peripheral neuropathy | 20 (31) | 0 |
| Dyspnoea | 13 (20) | 2 (3) |
| Hypertension | 6 (9) | 4 (6) |
| Cardiac events | 10 (16) | 4 (6)* |
| Renal events | 6 (9) | 3 (5)† |
| Nervous system events | 44 (69) | 3 (5)‡ |
| Cough | 4 (6) | 0 |
| Thromboembolic events | 4 (6) | 3 (5) |
Four patients experienced Grade ≥3 cardiac AEs, including heart failure (one Grade 3 and one Grade 4), chest pain (one Grade 3), atrial fibrillation (one Grade 3), conduction disorder (one Grade 3), restrictive cardiomyopathy (one Grade 3) and ventricular tachycardia (one Grade 3).
Three patients experienced Grade ≥3 renal AEs, including acute kidney injury (one Grade 3), other unspecified renal and urinary disorder (one Grade 3) and acute renal insufficiency (one Grade 4).
Three patients experienced Grade ≥3 nervous system AEs, including seizure (two Grade 3), syncope (one Grade 3) and reversible cerebral vasoconstriction syndrome (one Grade 3).
One death occurred during treatment or within 30 d of treatment discontinuation: the patient was hospitalized on day 2 of Cycle 3 and was treated aggressively for pneumonia but died on study the following day. Seven patients (11%) discontinued treatment before completing the study protocol (Fig 1). Two patients discontinued due to AEs. The first had Grade 4 renal failure during Cycle 7, which led to discontinuation prior to completion of Cycle 7 therapy (renal insufficiency began as Grade 3 during Cycle 5, persisted in Cycle 6 and was upgraded to Grade 4 in Cycle 7; the AE was determined to be possibly related to study treatment). This patient also had other Grade ≥3 AEs during Cycles 5–7 that were at least possibly related to treatment, including hypertension (Grade 3, Cycles 5–7) and seizure (Grade 3, Cycle 5). The second patient who discontinued due to AEs had renal insufficiency (creatinine increased from 88·4 to 344·8 µmol/l) after receiving just carfilzomib on day 1 of Cycle 2. This patient also had other Grade ≥3 AEs during Cycle 1 that were at least possibly related to study treatment, including atrial fibrillation, fatigue, dyspnoea, creatinine increase and leucocytosis (all Grade 3), and neutropenia and heart failure (both Grade 4).
For 64 patients across 281 total cycles of treatment, 28 (44%) patients required a dose reduction for at least one drug, including 18 (28%) for carfilzomib, seven (11%) for thalidomide, eight (13%) for cyclophosphamide and 12 (19%) for dexamethasone. At least one dose was omitted for at least one drug for 40 (63%) patients, including 21 (33%) for carfilzomib, 31 (48%) for thalidomide, 13 (20%) for cyclophosphamide and 19 (30%) for dexamethasone. An entire cycle was omitted for at least one drug for eight (13%) patients, including six (9%) for thalidomide, two (3%) for cyclophosphamide and two (3% for dexamethasone. Carfilzomib was not omitted for an entire cycle for any patient.
Efficacy
Sixty-four patients were evaluated for response. In the overall population, the ORR was 91% across all cycles of treatment, including 44 patients (69%) who achieved ≥VGPR as their best response (Table V; Fig 2A,B), including five patients (8%) with stringent CR (sCR) or CR, all confirmed by bone marrow biopsy. Among the six (9%) patients who did not achieve ≥PR, three had MR, two had SD for at least one cycle and one refused treatment after one cycle with no disease assessment before going off study. Among patients treated at the MTD, 59% (17/29) achieved ≥VGPR after four cycles, the primary end point, including three sCR/CR (all confirmed by bone marrow biopsy).
Table V.
Best response to treatment, all cycles.
| Dose level −1 15/20 mg/m2 (n = 3) |
Dose level 0 20/27 mg/m2 (n = 25) |
Dose level 1 20/36 mg/m2 (n = 29) |
Dose level 2 20/45 mg/m2 (n = 7) |
All patients (n = 64) |
|
|---|---|---|---|---|---|
| Best response, n (%) | |||||
| sCR | 0 | 0 | 2 (7) | 0 | 2 (3) |
| CR | 0 | 2 (8) | 1 (3) | 0 | 3 (5) |
| VGPR | 1 (33) | 17 (68) | 15 (52) | 5 (71) | 39 (51) |
| PR | 2 (67) | 5 (20) | 8 (28) | 0 | 14 (22) |
| MR | 0 | 0 | 2 (7) | 1 (14) | 3 (5) |
| SD | 0 | 1 (4) | 0 | 1 (14) | 2 (3) |
| Other | 0 | 0 | 1* | 0 | 1* (2) |
| Overall response rate, n (%) | 3/3 (100) | 24/25 (96) | 26/29 (90) | 5/7 (71) | 58/64 (91) |
sCR, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response; MR, minimal response; SD, stable disease.
Refused further treatment after one cycle with no disease assessment prior to going off study.
Fig 2.
Best response, by cycle. (A) Cumulative best response to treatment, by cycle. *Day 100 post-SCT response data are reported for 34 patients (six sCR, 19 CR, †six VGPR, and three PR). For all other patients, best response to the end of all cycles is included. †Among the 19 patients with CR post-SCT, four had CR confirmed with negative immunofixation, 11 had CR with no measurable M-protein without immunofixation having been performed and four had CR with no measurable M-protein but positive immunofixation. (B) Cumulative percentage of patients experiencing a VGPR or better as best response, by cycle. CR, complete response; sCR, stringent complete response; VGPR, very good partial response; PR, partial response; MR, minimal response; SCT, stem cell transplantation.
In general, responses were rapid and improved with continued treatment (Fig 2). At the end of Cycle 1, 81% of patients achieved ≥PR (including 23% with VGPR), and at the end of four cycles, this number had increased to 91%, with 58% VGPR and 8% sCR/CR (all confirmed by bone marrow biopsy).
Stem cell mobilization was successful in all patients in whom it was attempted (n = 42). The primary reason patients did not proceed to autologous SCT (ASCT) was patient preference (either delayed or deferred ASCT). Other reasons included poor performance status, delay due to profound response and toxicity. Our institution has a very inclusive approach to ASCT eligibility, and some patients initially deemed eligible prior to the start of CYKLONE were then deemed ineligible after induction. As of data cut-off, 34 patients (53%) had proceeded to SCT. In patients who proceeded to SCT, best responses up to day-100 post-SCT included six (18%) sCR, 19 (56%) CR, six (18%) VGPR and three (9%) PR (Fig 2), demonstrating improvements in response compared with those observed at the end of treatment [one (5%) sCR, two (6%) CR, 21 (62%) VGPR, nine (26%) PR and one (3%) SD].
The PFS rate was 85% at 12 months and 76% at 24 months (Fig 3). At 12 and 24 months, the OS rate was 96%. Among 11 patients who had disease progression, 10 were intermediate risk by mSMART criteria at baseline and two had t(4;14) disease.
Fig 3.
Progression-free survival (PFS) and overall survival (OS) for all patients (N = 64). (A) Estimated 12- and 24-month PFS rates were 85% [95% confidence interval (CI) 71–93%] and 76% (95% CI 59–87%), respectively. (B) Estimated 12- and 24-month OS rates were 96% (95% CI 86–99%) and 96% (95% CI 86–99%), respectively.
Discussion
Results from this phase Ib/II study demonstrated that the CYKLONE regimen is highly effective in patients with newly diagnosed MM, with an ORR of 91% after four cycles of treatment. In patients treated at the MTD (20/36 mg/m2 carfilzomib) in the phase II portion of the trial, 59% (17 out of 29 patients) achieved a VGPR or better by the end of Cycle 4. Response rates compare favourably to other combinations that have included carfilzomib, including regimens using drugs which are more expensive and not as readily available as thalidomide and cyclophosphamide (e.g., lenalidomide) (Tables SI and SII). Efficacy data from the overall patient population showed that treatment with CYKLONE induced rapid and deep responses in patients, with 81% of patients achieving a PR or better by the end of Cycle 1. Responses improved with continued treatment, and by the end of Cycle 4, the number of patients achieving a PR or better had increased to 91%, with the remaining 9% achieving MR or SD for at least one cycle with the exception of one patient who refused treatment after one cycle and did not have a disease evaluation. Two-year PFS and OS rates were 76% and 96%, respectively. Importantly, the CYKLONE regimen did not appear to adversely impact stem cell collection, as stem cells were successfully mobilized from all patients in whom it was attempted.
Toxicities were manageable with this four-drug regimen, and were consistent with the known safety profiles of the therapeutic agents administered. Beyond dyspnoea and cough, limited cardiac or pulmonary toxicity was observed. Only Grade 1 neuropathy was reported, which was primarily attributed to thalidomide treatment.
The recent phase II EVOLUTION study similarly studied the combination of a proteasome inhibitor (bortezomib) with cyclophosphamide, dexamethasone and an immunomodulatory agent (lenalidomide) in patients with newly diagnosed MM. Patients were randomized to receive induction therapy with a three-drug regimen (either VDC or VRD) or a four-drug regimen (VDCR), followed by bortezomib maintenance therapy (Kumar et al, 2012). An ORR of 80% following four cycles of VDCR treatment was reported, with 33% of patients achieving ≥VGPR. Although the trials are not directly comparable, it is interesting to note the lower rates of Grade ≥3 neuropathy, neutropenia and thrombocytopenia in the carfilzomib- and thalidomide-based CYKLONE regimen reported above (0%, 23% and 4·7% respectively) relative to those reported with the four-drug bortezomib- and lenalidomide-based regimen VDCR in the EVOLUTION study (13%, 44% and 14%, respectively).
It is worth noting that the EVOLUTION study examined cyclophosphamide administered on days 1 and 8 in the VDC and VDCR regimens, along with a modified VDC regimen in which cyclophosphamide was also given on days 15 and 22 (VDC-mod) (Kumar et al, 2012). The investigators found that the VDC-mod regimen resulted in higher response rates than the other regimens examined, supporting the use of a more frequent cyclophosphamide dosing schedule. In our study, cyclophosphamide was administered on days 1, 8 and 15, but there may be additional benefit in the use of a continuous weekly cyclophosphamide dosing schedule (i.e., without a week-4 break), and such a schedule should perhaps be considered for examination in future CYKLONE regimens.
The proven efficacy of thalidomide in patients with newly diagnosed MM (Palumbo et al, 2008; Cavo et al, 2010), along with its worldwide availability and low cost, make it a logical combination partner for newer targeted agents, including carfilzomib. An ongoing phase II trial is examining carfilzomib with thalidomide and dexamethasone (KTd) as induction and consolidation therapy in patients receiving stem cell transplantation, where the triplet regimen has been found to be active and well tolerated (Sonneveld et al, 2013). Sonneveld et al (2013) reported Grade 2 and 3 peripheral neuropathy in 15% and 3% of patients respectively, which are higher than the rates reported in our study (0% and 0%) but consistent with rates of Grade ≥3 peripheral neuropathy (2–4%) reported in patients with newly diagnosed MM treated with just thalidomide (200 mg/d) and dexamethasone (40 mg/d) (Rajkumar et al, 2002, 2006, 2008; Cavo et al, 2005). It should be noted that the KTd regimen utilized similar doses of carfilzomib (20/27, 20/36 and 20/45 mg/m2) but a higher dose of thalidomide (200 mg/d) during induction therapy relative to the CYKLONE regimen.
A number of studies are examining other regimens combining carfilzomib with an immunomodulatory agent and dexamethasone in the front-line setting, mostly as triplet combinations. As discussed in the introduction, carfilzomib, lenalidomide and dexamethasone are being examined in transplant-eligible and transplant-ineligible patients, where similar rates of VGPR and higher rates of CR have been observed relative to rates reported with CYKLONE (Jakubowiak et al, 2012; Korde et al, 2013). In addition, carfilzomib, pomalidomide and dexamethasone are being investigated in patients with relapsed and/or refractory MM (Shah et al, 2013). While results from these studies will be informative for understanding the best use of proteasome inhibitor- and immunomodulatory agent-based combinations in the front-line setting, it is important to note that the CYKLONE regimen utilized in this study takes advantage of the low cost and ready availability of thalidomide and cyclophosphamide, while providing good efficacy. Additionally, as survival rates continue to improve for patients with MM, it is critical to consider subsequent therapeutic options while treating the newly diagnosed patient. Importantly, as the CYKLONE regimen does not use bortezomib or lenalidomide, patients initially treated with CYKLONE may still receive treatment with these other agents if needed during consolidation or maintenance therapy, or at relapse.
In conclusion, at the MTD of 20/36 mg/m2 carfilzomib, 300 mg/m2 cyclophosphamide, 100 mg thalidomide and 40 mg dexamethasone, the CYKLONE combination was well tolerated and highly efficacious in newly diagnosed MM patients. The regimen induces rapid and deep responses with limited neuropathy, cardiac, or pulmonary toxicity. CYKLONE may be an attractive treatment option in many settings due to the worldwide availability of thalidomide combined with the lower cost of thalidomide relative to lenalidomide, and our results support additional research into this combination. Further randomized, prospective studies are needed to expand upon these findings, and comparative studies of the CYKLONE regimen with longer treatment duration at the defined MTD should be considered.
Supplementary Material
Acknowledgements
This study was supported by research funding from Onyx Pharmaceuticals, Inc., an Amgen subsidiary. Medical writing and editing services were provided by Cheryl Chun, PhD, (BlueMomentum, a division of KnowledgePoint360 Group, San Bruno, CA), and supported by funding from Onyx Pharmaceuticals, Inc. JM has received research funding from Celgene, Onyx Pharmaceuticals, Sanofi-Aventis, Abbvie and Novartis. CRB has received research funding from Millennium Pharmaceuticals, Celgene and Novartis. LJC has received honoraria from Sanofi-Aventis and research support from Onyx Pharmaceuticals, Celgene, Pfizer, Novartis, BSK and Sanofi-Aventis. PLB has served as consultant for Threshold Pharmaceuticals, Janssen Biotech, Janssen Pharmaceuticals, Mundipharma, Bristol-Myers Squibb and Onyx Pharmaceuticals. AKS has served as a consultant for Celgene, Bristol-Myers Squibb, Array BioPharma and Sanofi-Aventis, and his institution has received funding from Onyx Pharmaceuticals, Millennium Pharmaceuticals and Genentech. ENL, FB, AM, SKNR, KG, and ACD have no disclosures to report.
Footnotes
Author contributions
JM, AKS, and ACD designed the research. JM, CBR, ENL, LJC, PLB, FB, AM, and AKS performed the research. ACD and SKN performed the statistical analysis. JM, KG, ACD, and AKS analysed and interpreted the data. JM wrote the initial draft of the manuscript. All authors reviewed the draft manuscript and approved the final version for submission.
Additional Supporting Information may be found in the online version of this article:
Table SI. Company-supported carfilzomib studies.
Table SII. Company-sponsored carfilzomib studies.
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