Bone Marrow Transplantation (2015), 1–5 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt
ORIGINAL ARTICLE
CyBorD induction therapy in clinical practice N Areethamsirikul, E Masih-Khan, C-M Chu, V Jimenez-Zepeda, DE Reece, S Trudel, V Kukreti, R Tiedemann and C Chen Cyclophosphamide, bortezomib and dexamethasone (CyBorD) is a highly active three-drug induction regimen for untreated transplant-eligible multiple myeloma patients. Although CyBorD has been evaluated only in the phase 2 setting in a limited number of patients, its high efficacy and ease of administration have led to its widespread use. Given that clinical trial efficacy can overestimate real-life effectiveness, we reviewed our institutional experience with 109 newly diagnosed patients who were treated with CyBorD in a non-clinical trial setting. After a median of four cycles, overall response rate (ORR) and very good partial response rate or better (⩾ VGPR) were 95 and 66%, respectively, comparable to phase 2 studies of CyBorD and other three/four-drug induction regimens. All patients subsequently underwent successful stem cell collection and upgraded responses to ORR 98% and ⩾ VGPR 79% post transplant. At a median follow-up of 19.8 months after diagnosis, the 2-year OS probability was 95.3% (95%CI: 89– 98). The presence of concurrent plasmacytoma at diagnosis was the only prognostic factor predicting poorer survival (HR = 5.56; 95%CI: 0.92–33.74; P = 0.03). CyBorD was well-tolerated, with no severe peripheral neuropathy and minimal hematologic toxicity. Therefore, CyBorD is a convenient, well-tolerated, highly effective induction regimen in preparation for autologous SCT in real-life clinical practice. Bone Marrow Transplantation advance online publication, 19 January 2015; doi:10.1038/bmt.2014.288
INTRODUCTION Currently, the standard of care for induction therapy in preparation for autologous SCT (ASCT) involves incorporation of novel agents such as bortezomib and/or immunomodulatory agents (thalidomide or lenalidomide).1–11 Two- and three-drug combinations can lead to high overall response rates (ORR) of 61–100% and very good partial responses (VGPR) of 34–67%.1–5,7–13 No combination, however, has shown clear superiority in terms of progression-free survival (PFS) or overall survival (OS). Hence, in clinical practice, a balance between efficacy, toxicity, ease of administration and cost should be considered when identifying an optimal induction regimen. CyBorD is a highly active three-drug induction regimen that has been widely adopted for use in preparation for transplant. In the original phase 2 study evaluating CyBorD using biweekly bortezomib 1.3 mg/m2 (days 1, 4, 8 and 11), weekly cyclophosphamide (Cy) 300 mg/m2 orally (days 1, 8, 15 and 22) and dexamethasone 40 mg orally (days 1–4, 9–12 and 17–20) on a 28-day cycle, ORR of 88% and ⩾ VGPR rates of 61% were achieved after four cycles (n = 33).7 In an expanded cohort of the same trial (n = 30), a modified dosing schedule using a higher bortezomib dose—1.5 mg/m2 given once weekly (days 1, 8, 15, 22) and in combination with a lower dose of dexamethasone (40 mg once weekly for cycles 3 and 4)—attained responses equivalent to the twice-weekly cohort (ORR 93% and ⩾ VGPR 60%) with less toxicity. The incidence of peripheral neuropathy was lower (57 vs 64%), with no grade 3–4 peripheral neuropathy documented, despite the higher total dose of bortezomib used in each cycle (6 vs 5.2 mg/m2).8 The excellent long-term survival outcome has been recently reported (median PFS was 40 months, 5-year PFS 42%, 5-year OS 70%).14 Although CyBorD has been evaluated only in phase 2 studies, it has gained widespread popularity as an induction regimen due to its remarkable efficacy, excellent safety profile and ease of administration, and has been
adopted for routine use at many institutions, including our own. Given that clinical trial efficacy can overestimate real-life effectiveness due to exclusion of patients with high-risk features, renal impairment and poor performance status, we aimed to evaluate our institutional experience of CyBorD to assess efficacy, tolerability and safety of CyBorD in real-life clinical practice. MATERIALS AND METHODS Patients Between April 2007 and April 2012, 109 multiple myeloma patients who received CyBorD induction therapy outside of a clinical trial in preparation for ASCT were reviewed. Patient demographics, disease characteristics, details of induction therapy and ASCT, and survival outcomes were obtained from retrospective review of patient charts and a prospectively maintained transplant database. Approval for this review was obtained from the Princess Margaret Cancer Centre Institutional Review Board in accordance with the Declaration of Helsinki.
Details of CyBorD regimen, stem cell mobilization and ASCT The CyBorD regimen consisted of bortezomib 1.5 mg/m2 i.v. on days 1, 8, 15 and 22, Cy 300 mg/m2 orally on days 1, 8, 15 and 22 and dexamethasone 40 mg orally on days 1–4, 9–12, 17–20 for the first two cycles, then 40 mg weekly for subsequent cycles. CyBorD was given on a 28-day cycle for a target of 4–6 cycles before proceeding to stem cell collection and transplantation. Additional cycles could be given after stem cell collection while awaiting transplant in the event of a delay. All patients received acyclovir for herpes zoster prophylaxis. Stem cell mobilization was conducted as per the institutional protocol using high-dose Cy 2.5 gm/m2 followed by G-CSF 10 µg/kg/day. High-dose melphalan 200 mg/m2 was used as the standard conditioning regimen.
Response assessment Clinical responses were assessed after each cycle during the CyBorD induction period, before stem cell mobilization and at 100 days post
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Correspondence: Dr C Chen, Princess Margaret Cancer Centre, Department of Medical Oncology and Hematology, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. E-mail: [email protected] Received 19 August 2014; revised 9 October 2014; accepted 15 October 2014
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
2 transplant. The International Myeloma Working Group Uniform Response Criteria were used to assess treatment response.15 Complete response (CR) was defined as negative immunofixation on serum and urine with disappearance of any soft tissue plasmacytomas and o5% BM plasma cells. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ⩾90% reduction in M-protein with urine M-proteino100 mg/24 h. Partial response (PR) was defined as a 50% reduction in serum M-protein. Progressive disease (PD) was defined as a 25% increase in serum or urine M-protein with a minimum absolute increase of ⩾ 5.0 g/L in serum or ⩾ 200 mg/24 h in urine. Stable disease (SD) was defined as not meeting criteria for VGPR, PR or PD. In this clinical experience, BM biopsies were not routinely performed after induction or post-ASCT, therefore confirmation of CR was not available in the usual circumstance and patients with the absence of monoclonal protein on immunologic studies were classified as having a VGPR or better (⩾ VGPR).
Table 1.
All adverse events during CyBorD treatment were reviewed. Toxicities were graded according to the National Cancer Institute Common Toxicity criteria (NCI-CTC), version 4.0.
OS information was available in all patients, and was calculated from time of myeloma diagnosis to date of death or last follow-up. Survival analyses were performed using the Kaplan–Meier method. Univariate analyses of baseline characteristics and response assessments were performed using the Cox proportional hazard model and log rank methods. As most patients were referred after recovery from ASCT back to their initial center of care, data on progression were not collected for this analysis.
Bone Marrow Transplantation (2015), 1 – 5
Gender Male Female
65 (60) 44 (40)
International staging systema I II III
31 (33) 24 (26) 39 (21)
Myeloma subtypes IgG IgA IgD Light chain only Non-secretory
58 21 2 25 3
Laboratory values at diagnosis, median (range) Hemoglobin, g/L White blood cell, × 109/L Platelet, × 109/L Creatinine, μmol/L Serum creatinine ⩾ 177 μmol/L Beta2 microglobulin, mg/L
Statistical analysis
Efficacy We were able to assess treatment response after CyBorD induction in 108 patients. One non-secretory myeloma patient could not be evaluated due to missing BM information. After a median of four cycles (range 1–6) of chemotherapy, high-response rates were achieved: ORR 95% and ⩾ VGPR 66%. One hundred and two patients (94%) who completed four cycles of CyBorD achieved an ORR of 95% and ⩾ VGPR of 68% as summarized in Table 2. Best treatment responses were achieved after a median of four cycles (range 1–6). High efficacy was also demonstrated in myeloma patients with high-risk features as summarized in Table 3. All patients with high risk FISH cytogenetics responded after CyBorD induction. However, patients who presented with concurrent plasmacytomas had the lowest response rates (ORR 90% and ⩾ VGPR 55%) amongst patients with high-risk features. Fourteen patients (74%) with renal impairment at baseline improved their serum creatinine levels to o 177 umol/L after CyBorD induction. Six patients did not complete the four planned cycles of CyBorD:
Number of patients (%) 58 (37–71)
Age, median (range)
Toxicity
RESULTS Patients Baseline characteristics of all 109 MM patients who received weekly CyBorD induction in preparation for ASCT are summarized in Table 1. Fifteen patients had high-risk FISH cytogenetics with del 17p, t(4;14) or t(14;16), including one patient with concurrent del 17p and t(14;16). Nineteen patients (17%) presented with renal impairment (defined as serum creatinine 4177 μmol/L) with a mean serum creatinine of 363 μmol/L (range 177–832). Two patients were receiving regular hemodialysis at the time of first cycle of CyBorD. Five patients had plasma cell leukemia (PCL) at presentation (circulating plasma cells greater than 20%). Not surprisingly, three of the five PCL patients had high risk FISH cytogenetics: one patient with t(14;16) and two patients with del (17p). Plasmacytomas were present in 21 patients (19%). One patient had concurrent light chain amyloidosis involving the liver, spleen, pancreas and lymph nodes.
Baseline characteristics (n = 109)
(53) (19) (2) (23) (3)
108 (27–155) 6.0 (2.1–32) 241 (22–651) 88 (44–832) 19 (17%)b 3.8 (0.9–25)
FISH cytogeneticsc del 13q del 17p t(4;14) t(14;16)
28 10 2 4
Plasmacytoma at diagnosis Paraspinal Bone Lymph node Nasopharynx Plasma cell leukemia
21 (19) 10 (48) 7 (33) 3 (14) 1 (5) 5 (5)
(32) (11) (2) (7)
n = 94 patients. bIncluding two patients on regular hemodialysis. cdel 13q, del 17p and t(4;14) were tested in 88 patients; t(14;16) was tested in 54 patients.
a
Table 2.
Efficacy and toxicity compared to historical phase 2 data
Response ORR ⩾ VGPR After four cycles ORR ⩾ VGPR After auto-SCT ORR ⩾ VGPR
Reeder et al.7 (n = 33)
Reeder et al.8 (n = 30)
Our data (n = 108)
88% 61% (n = 28) 96% 71% (n = 23) 100% 74%
93% 60% (n = 27) 93% 63% — — —
95% 66% (n = 102) 95% 68% (n = 102) 98% 79%
Abbreviations: n = number of patients; ORR = overall response; VGPR = very good partial response.
three patients underwent ASCT following response after three cycles of CyBorD, two patients had disease progression after one and three cycles of CyBorD and were switched to second-line treatment, one patient had severe Crohn’s disease with bowel obstruction required surgery and discontinued treatment after one cycle. As summarized in Table 4, eight patients progressed before ASCT, after a median of four cycles (range 1–4 cycles), with © 2015 Macmillan Publishers Limited
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
3 Table 3.
Treatment responses for high risk patients compared to historical phase 2 data
Risk category
Frequency (%)
del 17p t(4;14) t(14;16) ISS stage III PCL EMP RI
10/88 (11) 2/88 (2) 4/54 (7) 39/94 (41) 5/109 (5) 21/109 (19) 19/109 (17)
⩾ VGPR (%)
ORR (%)
10/10 (100) 2/2 (100) 4/4 (100) 39/39 (100) 5/5 (100) 18/20 (90) 19/19 (100)
Reeder et al.7 Frequency (%)
ORR (%)
⩾ VGPR (%)
4/31 (13) 6/33 (18) — 10/33 (30) — — —
3/4 (75) 5/6 (83) — 8/10 (80) — — —
2/4 (50) 3/6 (50) — 6/10 (60) — — —
7/10 (70) 2/2 (100) 3/4 (75) 28/39 (72) 3/5 (60) 11/20 (55) 13/19 (68)
Abbreviations: del = deletion; EMP = extramedullary plasmacytoma; ISS = international staging system; ORR = overall response rate; PCL = plasma cell leukemia; RI = renal impairment; VPGR = very good partial response.
Table 4.
Relapsed myeloma patients after CyBorD induction (n = 8)
Pt
Gender
Age
Subtype
FISH
High-risk features
Best response with CyBorD
1 2 3 4 5 6 7 8
M M F F M F F F
44 58 53 46 55 64 58 45
FLC, K IgG, K IgG, L IgA, K IgG, K IgG, L IgA, L IgA, L
— Trisomy14, t(11,14) — Del 13q — — — Del 17p
EMP — RI PCL — — EMP RI
⩾ VGPR SD PR PR PR PR PD ⩾ VGPR
No. of CyBorD cycles before PD 4 4 4 4 4 4 1 3
Second-line treatment
ASCT
Response at D+100 post ASCT
Last follow-up
Rd RVD Rd Rd Rd — DT-PACE, CNS RT, D-PACE, Rd
Yes Yes Yes Yes Yes Yes Yes No
⩾ VGPR ⩾ VGPR ⩾ VGPR PR ⩾ VGPR PR PD —
Alive Alive Alive Alive Alive Alive Dead Dead
Abbreviations: CNS RT = central nervous system radiotherapy; Cy = etoposide; D-PACE = dexamethasone, cisplatin, doxorubicin; DT-PACE = dexamethasone, thalidomide, cisplatin, doxorubicin; EMP = extramedullary plasmacytoma; F = female; FLC = free light chain; K = kappa; L = lambda; M = male; PCL = plasma cell leukemia; PD = progressive disease; PR = partial response; Pt = patient; Rd = lenalidomide and dexamethasone; RI = renal impairment; RVD = lenalidomide, bortezomib, dexamethasone; SD = stable disease; VGPR = very good partial response.
the majority receiving lenalidomide-based therapy as their second-line induction regimen. Stem cell mobilization and ASCT All patients underwent stem cell mobilization using Cy and G-CSF, except for one patient with concurrent MM and light chain amyloidosis who received G-CSF alone for mobilization. All patients had successful stem cell collections, requiring a median of one leukapheresis (range 1–4). The median number of CD34+ cells collected was 8 ×106/kg body weight (range 2.3–24.5 × 106/ kg). All patients proceeded to auto-SCT, except for three patients (one patient with del 17p progressed and died before ASCT, one patient was deemed ineligible due to severe mitral stenosis and one patient declined). Melphalan 200 mg/m2 was used for conditioning in 100 patients (94%). Six patients received reduced dose melphalan (140 mg/m2) due to renal impairment. A median of 4.04 × 106/kg CD34+ cells were infused (range 1.48–12.4). Higher-response rates were obtained at 100 days post transplant (ORR 98%; ⩾ VGPR 79%). Toxicity All patients were assessed for toxicity. Grade 3–4 adverse events related to therapy are summarized in Table 5. The most common grade 3–4 adverse events were infection (10%) and neutropenia (4%). Pneumonia was the most common site of infection (5%). Using routine antiviral prophylaxis, grade 3–4 herpes infections were not common (2.8%). Grade 1–2 peripheral neuropathy occurred in 33 patients (31%), with no severe (grade 3–4) © 2015 Macmillan Publishers Limited
neuropathy noted. Grade 3–4 hematologic adverse events were uncommon with only 4 patients (4%) with grade 3–4 neutropenia and no grade 3–4 thrombocytopenia or anemia. CyBorD was welltolerated even in patients with renal failure (n = 19) with no grade 3–4 hematologic toxicity among these patients. Grade 3–4 nonhematologic adverse events occurred in 4 patients with renal impairment (21%) (Table 5). Dose modifications Dose reductions and/or delays of any agents in the regimen were required in 29 patients (27%). The most frequently dose-reduced agent was dexamethasone in 15 patients (14%), mainly due to edema (7%). Eight patients (7%) required dose reduction of bortezomib, mainly due to grade 1–2 neuropathy. Only 4 patients (4%) required Cy dose modification, due to grade 4 neutropenia, severe nausea/fatigue, renal impairment and non-treatment related grade 4 transaminitis, respectively. Grade 4 transaminitis in one patient was attributed to isoniazid administered for latent tuberculosis but Cy was dose-reduced as a precaution; with isoniazid discontinuation, the transaminitis resolved completely. Among 19 patients with renal impairment, 5 patients (26%) required dose reduction of the agents in CyBorD; dexamethasone in 4 patients (21%) due to grade 1–2 peripheral edema (three patients) and grade 2 myopathy (one patient); Cy in two patients due to severe fatigue and nausea (one patient), empiric reduction for renal impairment due to physician preference (one patient) and bortezomib in one patient due to grade 1 peripheral neuropathy. Bone Marrow Transplantation (2015), 1 – 5
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
4
Reeder et al.7 Reeder et al.8 Our data Our RI (n = 33) (%) (n = 30) (%) (n = 109) subgroup (n = 19) Grade 3–4 toxicities Overall Anemia Thrombocytopenia Neutropenia Peripheral neuropathy Hyperglycemia Infection Diarrhea Fatigue Nausea Fluid retention Hypokalemia Elevated creatinine Fever Thrombosis Dose reduction Bortezomib Dexamethasone Cy
48 9 21 12 6
37 0 0 7 0
29 (27%) 0% 0% 4 (4%) 0%
4 (21%) 0% 0% 0% 0%
13 0 6 0 0 0 9 0 0 7
— — — — — — — — — —
3 11 1 3 1 2
(3%) (10%) (1%) (3%) (1%) (2%) 0% 1 (1%) 3 (3%) 0%
2 (11%) 0% 0% 0% 1 (5%) 0% 0% 1 (5%) 0% 0%
21 30 21
13 20 —
8 (7%) 15 (14%) 4 (4%)
1 (5%) 4 (21%) 2 (11%)
80 60 40
80 60 40 20
Year
Survival probabilities (95% Cl)
1-year
95.3% (0.891-0.980)
2-year
95.3% (0.891-0.980)
5-year
91.5% (0.782-0.968)
No (n=85) Yes (n=21) P-value=0.0365 (Log rank test)
20 0 0
1
3
2
4
Time (years) Median and range of follow up time for OS2 (EMP=Yes) is 12.5 (1.2-30.4) months. Median and range of follow up time for OS2 (EMP=No) is 12.6 (1.5-56.8) months.
Figure 2. The presence of concurrent plasmacytoma at diagnosis impacting OS. Table 6. Comparison amongst commonly used three- and four-drug induction regimens Regimen
PAD[11] VTD[3] VRD[9] CRD[13] VDR[12] VDCR[12] VTDC[16] CyBorD
100 Probability of survival (%)
100 Probability of survival (%)
Table 5. Grade 3–4 treatment-related adverse events and dose reduction with renal impairment (RI) in comparison to historical cohorts
N
413 236 66 53 42 48 49 109
After induction
After ASCT
ORR (%)
⩾ VGPR (%)
ORR (%)
⩾ VGPR (%)
78 93 100 85 85 80 96 95
42 62 67 47 51 33 69 66
88 93 — — — — 100 98
62 79 — — — — 82 78
Abbreviations: CyBorD = Cy-bortezomib-dexamethasone; CRD = Cylenalidomide-dexamethasone; n = number of patients; PAD = bortezomib-doxorubicin-dexamethasone; VDR = bortezomib-lenalidomide-dexamethasone; VDCR = bortezomib-dexamethasone-Cy-lenalidomide; VTDC = bortezomibthalidomide-dexamethasone-Cy.
0 0
1
2
3 Time (years)
4
5
Figure 1. Kaplan–Meier OS curve for all 109 patients with probability of OS at 1, 2 and 5 years.
Survival outcomes At a median follow-up of 19.8 months after diagnosis (range 7–67.7), 6 of 109 patients (6%) have died. Causes of death include the following: disease progression (four patients) and pneumonia within 100 days of ASCT (two patients). Survival probabilities at 1, 2 and 5 years were 95.3% (95%CI: 89–98), 95.3% (95%CI: 89–98) and 91.5% (95%CI: 78–96), respectively, as shown in Figure 1. On univariate analysis, the presence of concurrent plasmacytomas at diagnosis was the poor prognostic factor impacting survival (HR = 5.56; 95%CI: 0.92–33.74; P = 0.03) as demonstrated in Figure 2. DISCUSSION Novel three and even four-drug combinations have become standard as induction treatment for MM patients preparing for Bone Marrow Transplantation (2015), 1 – 5
high-dose therapy and stem cell rescue.3,5,7–13 Ideally, an induction regimen should be highly effective, convenient, welltolerated and economical. Given these lofty aspirations, the optimal induction regimen has not yet been identified. CyBorD has gained popularity as an induction regimen given its ease of administration and excellent safety profile; however, efficacy has been extrapolated into real-life practice only from data generated by phase 2 trials. In our evaluation of CyBorD use in a non-trial setting, we were able to confirm the high efficacy of once weekly CyBorD with an ORR 95% and ⩾ VGPR rate of 66%, comparable to results from the original CyBorD phase 2 data published by Reeder et al. (Table 4), as well as to other three- and four-drug combinations in the literature.9–13,16 Of note, CyBorD outcomes appear comparable to that of VRD (bortezomib, lenalidomide and dexamethasone) and VTD (bortezomib, thalidomide and dexamethasone), two of the most effective induction regimens reported with ORR of 100 and 93–95%; ⩾ VGPR of 67% and 60– 62%, respectively.3,9,10 Comparison of induction response among three- and four-drug regimens is summarized in Table 6. In the EVOLUTION trial, the four-drug regimen, bortezomib, lenalidomide, Cy and dexamethasone (VDCR), failed to show benefit over other three-drug regimens including a regimen with similar components to CyBorD.12 Fewer toxicities and drug © 2015 Macmillan Publishers Limited
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
5 discontinuations with the three-drug versus four-drug combinations suggest that ‘more’ is not necessarily better. In our study, CyBorD toxicities were manageable, with few grade 3–4 hematologic adverse events and no compromise in ability to mobilize stem cells. The absence of grade 3–4 peripheral neuropathy is remarkable and compares favorably with rates of this complication associated with other novel agent combinations, specifically 10% with VTD (bortezomib, thalidomide and dexamethasone), 13% with VRCD, and 8% with VTCD (bortezomib, thalidomide, Cy and dexamethasone).3,12,16 CyBorD is convenient and easy to administer with the bortezomib in a once-weekly schedule. Moreover, the current standard of care has moved from an i.v. to a s.c. mode of administration for bortezomib, associated with further reduction of the incidence of peripheral neuropathy with similar efficacy to the i.v. route.17 In addition, the use of a higher single dose of s.c. bortezomib (with volumes up to 3 ml) is feasible, with limited skin reactions, and eliminates the need to administer at two injection sites in 81% of patients.18 The s.c. route further enhances the convenience of this regimen. Without the constraints of clinical trial eligibility, our real-life experience with CyBorD included the treatment of patients with high-risk features, including PCL and severe renal impairment (including dialysis-dependency). All PCL patients in our series responded to CyBorD and those with renal impairment appeared to tolerate the regimen well, with a high rate of renal improvement. No renal dose adjustment is required with bortezomib even in dialysis-dependent patients19,20 and Cy requires dose reduction only with severely impaired creatinine clearance of 10 ml/min or less. Therefore, this induction regimen is well-suited for use in newly diagnosed myeloma patients in whom renal impairment is common. Finally, it is worth commenting that CyBorD is a relatively costeffective regimen. When compared with VRD induction, VCD (a similar regimen of bortezomib, Cy and dexamethasone) led to similar survival outcomes and manageable toxicities, but at a significant cost differential ($29 468 USD less per treatment course for VCD compared with VRD).21 CONCLUSION CyBorD using weekly bortezomib as a three-drug induction regimen before ASCT is highly effective in real-life clinical practice. We demonstrated efficacy similar to the data from phase 2 studies of CyBorD and other novel three/four-drug regimens. CyBorD is well-tolerated with routine administration of a single higher dose given weekly s.c. and represents a convenient and relatively costeffective induction regimen. CONFLICT OF INTEREST CC received honoraria from Janssen and Celgene. ST received honoraria from Celgene. VK received honoraria form Celgene and Lundbeck. RT received honoraria from Janssen and Celgene. DR received research funds from Millinneum, Janssen and Celgene, honoraria from Janssen, Celgene and Amgen, Consulting fees from Janssen and Celgene. The remaining authors declare no conflict of interest.
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3 Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 2010; 376: 2075–2085. 4 Gay F, Hayman SR, Lacy MQ, Buadi F, Gertz MA, Kumar S et al. Lenalidomide plus dexamethasone versus thalidomide plus dexamethasone in newly diagnosed multiple myeloma: a comparative analysis of 411 patients. Blood 2010; 115: 1343–1350. 5 Kaufman JL, Nooka A, Vrana M, Gleason C, Heffner LT, Lonial S. Bortezomib, thalidomide, and dexamethasone as induction therapy for patients with symptomatic multiple myeloma: a retrospective study. Cancer 2010; 116: 3143–3151. 6 Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, Kabat B et al. Long-term results of response to therapy, time to progression, and survival with lenalidomide plus dexamethasone in newly diagnosed myeloma. Mayo Clin Proc 2007; 82: 1179–1184. 7 Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia 2009; 23: 1337–1341. 8 Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood 2010; 115: 3416–3417. 9 Richardson PG, Weller E, Lonial S, Jakubowiak AJ, Jagannath S, Raje NS et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 2010; 116: 679–686. 10 Rosinol L, Oriol A, Teruel AI, Hernandez D, Lopez-Jimenez J, de la Rubia J et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 2012; 120: 1589–1596. 11 Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 2012; 30: 2946–2955. 12 Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012; 119: 4375–4382. 13 Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J et al. Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol 2011; 86: 640–645. 14 Reeder CB, Reece DE, Kukreti V, Mikhael JR, Chen C, Trudel S et al. Long-term survival with cyclophosphamide, bortezomib and dexamethasone induction therapy in patients with newly diagnosed multiple myeloma. Br J Haematol 2014; 167: 563–565. 15 Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K et al. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473. 16 Ludwig H, Viterbo L, Greil R, Masszi T, Spicka I, Shpilberg O et al. Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. J Clin Oncol 2013; 31: 247–255. 17 Mateos MV, San Miguel JF. Safety and efficacy of subcutaneous formulation of bortezomib versus the conventional intravenous formulation in multiple myeloma. Ther Adv Hematol 2012; 3: 117–124. 18 Ng P, Incekol D, Lee R, Paisley E, Dara C, Brandle I et al. Tolerability of Velcade (Bortezomib) subcutaneous administration using a maximum volume of 3 mL per injection site. J Oncol Pharm Pract 2014; 29: 29. 19 Chanan-Khan AA, San Miguel JF, Jagannath S, Ludwig H, Dimopoulos MA. Novel therapeutic agents for the management of patients with multiple myeloma and renal impairment. Clin Cancer Res 2012; 18: 2145–2163. 20 Dimopoulos MA, Roussou M, Gkotzamanidou M, Nikitas N, Psimenou E, Mparmparoussi D et al. The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma. Leukemia 2013; 27: 423–429. 21 Kumar SK, Engebretson AE, Buadi FK, Lacy MQ, Dispenzieri A, Duh MS et al. Comparable Outcomes With Bortezomib-Cyclophosphamide-Dexamethasone (VCD) and Bortezomib-Lenalidomide-Dexamethasone (VRD) For Initial Treatment Of Newly Diagnosed Multiple Myeloma (MM). Blood 2013; 122: 3178.
Bone Marrow Transplantation (2015), 1 – 5
ORIGINAL ARTICLE
CyBorD induction therapy in clinical practice N Areethamsirikul, E Masih-Khan, C-M Chu, V Jimenez-Zepeda, DE Reece, S Trudel, V Kukreti, R Tiedemann and C Chen Cyclophosphamide, bortezomib and dexamethasone (CyBorD) is a highly active three-drug induction regimen for untreated transplant-eligible multiple myeloma patients. Although CyBorD has been evaluated only in the phase 2 setting in a limited number of patients, its high efficacy and ease of administration have led to its widespread use. Given that clinical trial efficacy can overestimate real-life effectiveness, we reviewed our institutional experience with 109 newly diagnosed patients who were treated with CyBorD in a non-clinical trial setting. After a median of four cycles, overall response rate (ORR) and very good partial response rate or better (⩾ VGPR) were 95 and 66%, respectively, comparable to phase 2 studies of CyBorD and other three/four-drug induction regimens. All patients subsequently underwent successful stem cell collection and upgraded responses to ORR 98% and ⩾ VGPR 79% post transplant. At a median follow-up of 19.8 months after diagnosis, the 2-year OS probability was 95.3% (95%CI: 89– 98). The presence of concurrent plasmacytoma at diagnosis was the only prognostic factor predicting poorer survival (HR = 5.56; 95%CI: 0.92–33.74; P = 0.03). CyBorD was well-tolerated, with no severe peripheral neuropathy and minimal hematologic toxicity. Therefore, CyBorD is a convenient, well-tolerated, highly effective induction regimen in preparation for autologous SCT in real-life clinical practice. Bone Marrow Transplantation advance online publication, 19 January 2015; doi:10.1038/bmt.2014.288
INTRODUCTION Currently, the standard of care for induction therapy in preparation for autologous SCT (ASCT) involves incorporation of novel agents such as bortezomib and/or immunomodulatory agents (thalidomide or lenalidomide).1–11 Two- and three-drug combinations can lead to high overall response rates (ORR) of 61–100% and very good partial responses (VGPR) of 34–67%.1–5,7–13 No combination, however, has shown clear superiority in terms of progression-free survival (PFS) or overall survival (OS). Hence, in clinical practice, a balance between efficacy, toxicity, ease of administration and cost should be considered when identifying an optimal induction regimen. CyBorD is a highly active three-drug induction regimen that has been widely adopted for use in preparation for transplant. In the original phase 2 study evaluating CyBorD using biweekly bortezomib 1.3 mg/m2 (days 1, 4, 8 and 11), weekly cyclophosphamide (Cy) 300 mg/m2 orally (days 1, 8, 15 and 22) and dexamethasone 40 mg orally (days 1–4, 9–12 and 17–20) on a 28-day cycle, ORR of 88% and ⩾ VGPR rates of 61% were achieved after four cycles (n = 33).7 In an expanded cohort of the same trial (n = 30), a modified dosing schedule using a higher bortezomib dose—1.5 mg/m2 given once weekly (days 1, 8, 15, 22) and in combination with a lower dose of dexamethasone (40 mg once weekly for cycles 3 and 4)—attained responses equivalent to the twice-weekly cohort (ORR 93% and ⩾ VGPR 60%) with less toxicity. The incidence of peripheral neuropathy was lower (57 vs 64%), with no grade 3–4 peripheral neuropathy documented, despite the higher total dose of bortezomib used in each cycle (6 vs 5.2 mg/m2).8 The excellent long-term survival outcome has been recently reported (median PFS was 40 months, 5-year PFS 42%, 5-year OS 70%).14 Although CyBorD has been evaluated only in phase 2 studies, it has gained widespread popularity as an induction regimen due to its remarkable efficacy, excellent safety profile and ease of administration, and has been
adopted for routine use at many institutions, including our own. Given that clinical trial efficacy can overestimate real-life effectiveness due to exclusion of patients with high-risk features, renal impairment and poor performance status, we aimed to evaluate our institutional experience of CyBorD to assess efficacy, tolerability and safety of CyBorD in real-life clinical practice. MATERIALS AND METHODS Patients Between April 2007 and April 2012, 109 multiple myeloma patients who received CyBorD induction therapy outside of a clinical trial in preparation for ASCT were reviewed. Patient demographics, disease characteristics, details of induction therapy and ASCT, and survival outcomes were obtained from retrospective review of patient charts and a prospectively maintained transplant database. Approval for this review was obtained from the Princess Margaret Cancer Centre Institutional Review Board in accordance with the Declaration of Helsinki.
Details of CyBorD regimen, stem cell mobilization and ASCT The CyBorD regimen consisted of bortezomib 1.5 mg/m2 i.v. on days 1, 8, 15 and 22, Cy 300 mg/m2 orally on days 1, 8, 15 and 22 and dexamethasone 40 mg orally on days 1–4, 9–12, 17–20 for the first two cycles, then 40 mg weekly for subsequent cycles. CyBorD was given on a 28-day cycle for a target of 4–6 cycles before proceeding to stem cell collection and transplantation. Additional cycles could be given after stem cell collection while awaiting transplant in the event of a delay. All patients received acyclovir for herpes zoster prophylaxis. Stem cell mobilization was conducted as per the institutional protocol using high-dose Cy 2.5 gm/m2 followed by G-CSF 10 µg/kg/day. High-dose melphalan 200 mg/m2 was used as the standard conditioning regimen.
Response assessment Clinical responses were assessed after each cycle during the CyBorD induction period, before stem cell mobilization and at 100 days post
Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. Correspondence: Dr C Chen, Princess Margaret Cancer Centre, Department of Medical Oncology and Hematology, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. E-mail: [email protected] Received 19 August 2014; revised 9 October 2014; accepted 15 October 2014
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
2 transplant. The International Myeloma Working Group Uniform Response Criteria were used to assess treatment response.15 Complete response (CR) was defined as negative immunofixation on serum and urine with disappearance of any soft tissue plasmacytomas and o5% BM plasma cells. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or ⩾90% reduction in M-protein with urine M-proteino100 mg/24 h. Partial response (PR) was defined as a 50% reduction in serum M-protein. Progressive disease (PD) was defined as a 25% increase in serum or urine M-protein with a minimum absolute increase of ⩾ 5.0 g/L in serum or ⩾ 200 mg/24 h in urine. Stable disease (SD) was defined as not meeting criteria for VGPR, PR or PD. In this clinical experience, BM biopsies were not routinely performed after induction or post-ASCT, therefore confirmation of CR was not available in the usual circumstance and patients with the absence of monoclonal protein on immunologic studies were classified as having a VGPR or better (⩾ VGPR).
Table 1.
All adverse events during CyBorD treatment were reviewed. Toxicities were graded according to the National Cancer Institute Common Toxicity criteria (NCI-CTC), version 4.0.
OS information was available in all patients, and was calculated from time of myeloma diagnosis to date of death or last follow-up. Survival analyses were performed using the Kaplan–Meier method. Univariate analyses of baseline characteristics and response assessments were performed using the Cox proportional hazard model and log rank methods. As most patients were referred after recovery from ASCT back to their initial center of care, data on progression were not collected for this analysis.
Bone Marrow Transplantation (2015), 1 – 5
Gender Male Female
65 (60) 44 (40)
International staging systema I II III
31 (33) 24 (26) 39 (21)
Myeloma subtypes IgG IgA IgD Light chain only Non-secretory
58 21 2 25 3
Laboratory values at diagnosis, median (range) Hemoglobin, g/L White blood cell, × 109/L Platelet, × 109/L Creatinine, μmol/L Serum creatinine ⩾ 177 μmol/L Beta2 microglobulin, mg/L
Statistical analysis
Efficacy We were able to assess treatment response after CyBorD induction in 108 patients. One non-secretory myeloma patient could not be evaluated due to missing BM information. After a median of four cycles (range 1–6) of chemotherapy, high-response rates were achieved: ORR 95% and ⩾ VGPR 66%. One hundred and two patients (94%) who completed four cycles of CyBorD achieved an ORR of 95% and ⩾ VGPR of 68% as summarized in Table 2. Best treatment responses were achieved after a median of four cycles (range 1–6). High efficacy was also demonstrated in myeloma patients with high-risk features as summarized in Table 3. All patients with high risk FISH cytogenetics responded after CyBorD induction. However, patients who presented with concurrent plasmacytomas had the lowest response rates (ORR 90% and ⩾ VGPR 55%) amongst patients with high-risk features. Fourteen patients (74%) with renal impairment at baseline improved their serum creatinine levels to o 177 umol/L after CyBorD induction. Six patients did not complete the four planned cycles of CyBorD:
Number of patients (%) 58 (37–71)
Age, median (range)
Toxicity
RESULTS Patients Baseline characteristics of all 109 MM patients who received weekly CyBorD induction in preparation for ASCT are summarized in Table 1. Fifteen patients had high-risk FISH cytogenetics with del 17p, t(4;14) or t(14;16), including one patient with concurrent del 17p and t(14;16). Nineteen patients (17%) presented with renal impairment (defined as serum creatinine 4177 μmol/L) with a mean serum creatinine of 363 μmol/L (range 177–832). Two patients were receiving regular hemodialysis at the time of first cycle of CyBorD. Five patients had plasma cell leukemia (PCL) at presentation (circulating plasma cells greater than 20%). Not surprisingly, three of the five PCL patients had high risk FISH cytogenetics: one patient with t(14;16) and two patients with del (17p). Plasmacytomas were present in 21 patients (19%). One patient had concurrent light chain amyloidosis involving the liver, spleen, pancreas and lymph nodes.
Baseline characteristics (n = 109)
(53) (19) (2) (23) (3)
108 (27–155) 6.0 (2.1–32) 241 (22–651) 88 (44–832) 19 (17%)b 3.8 (0.9–25)
FISH cytogeneticsc del 13q del 17p t(4;14) t(14;16)
28 10 2 4
Plasmacytoma at diagnosis Paraspinal Bone Lymph node Nasopharynx Plasma cell leukemia
21 (19) 10 (48) 7 (33) 3 (14) 1 (5) 5 (5)
(32) (11) (2) (7)
n = 94 patients. bIncluding two patients on regular hemodialysis. cdel 13q, del 17p and t(4;14) were tested in 88 patients; t(14;16) was tested in 54 patients.
a
Table 2.
Efficacy and toxicity compared to historical phase 2 data
Response ORR ⩾ VGPR After four cycles ORR ⩾ VGPR After auto-SCT ORR ⩾ VGPR
Reeder et al.7 (n = 33)
Reeder et al.8 (n = 30)
Our data (n = 108)
88% 61% (n = 28) 96% 71% (n = 23) 100% 74%
93% 60% (n = 27) 93% 63% — — —
95% 66% (n = 102) 95% 68% (n = 102) 98% 79%
Abbreviations: n = number of patients; ORR = overall response; VGPR = very good partial response.
three patients underwent ASCT following response after three cycles of CyBorD, two patients had disease progression after one and three cycles of CyBorD and were switched to second-line treatment, one patient had severe Crohn’s disease with bowel obstruction required surgery and discontinued treatment after one cycle. As summarized in Table 4, eight patients progressed before ASCT, after a median of four cycles (range 1–4 cycles), with © 2015 Macmillan Publishers Limited
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
3 Table 3.
Treatment responses for high risk patients compared to historical phase 2 data
Risk category
Frequency (%)
del 17p t(4;14) t(14;16) ISS stage III PCL EMP RI
10/88 (11) 2/88 (2) 4/54 (7) 39/94 (41) 5/109 (5) 21/109 (19) 19/109 (17)
⩾ VGPR (%)
ORR (%)
10/10 (100) 2/2 (100) 4/4 (100) 39/39 (100) 5/5 (100) 18/20 (90) 19/19 (100)
Reeder et al.7 Frequency (%)
ORR (%)
⩾ VGPR (%)
4/31 (13) 6/33 (18) — 10/33 (30) — — —
3/4 (75) 5/6 (83) — 8/10 (80) — — —
2/4 (50) 3/6 (50) — 6/10 (60) — — —
7/10 (70) 2/2 (100) 3/4 (75) 28/39 (72) 3/5 (60) 11/20 (55) 13/19 (68)
Abbreviations: del = deletion; EMP = extramedullary plasmacytoma; ISS = international staging system; ORR = overall response rate; PCL = plasma cell leukemia; RI = renal impairment; VPGR = very good partial response.
Table 4.
Relapsed myeloma patients after CyBorD induction (n = 8)
Pt
Gender
Age
Subtype
FISH
High-risk features
Best response with CyBorD
1 2 3 4 5 6 7 8
M M F F M F F F
44 58 53 46 55 64 58 45
FLC, K IgG, K IgG, L IgA, K IgG, K IgG, L IgA, L IgA, L
— Trisomy14, t(11,14) — Del 13q — — — Del 17p
EMP — RI PCL — — EMP RI
⩾ VGPR SD PR PR PR PR PD ⩾ VGPR
No. of CyBorD cycles before PD 4 4 4 4 4 4 1 3
Second-line treatment
ASCT
Response at D+100 post ASCT
Last follow-up
Rd RVD Rd Rd Rd — DT-PACE, CNS RT, D-PACE, Rd
Yes Yes Yes Yes Yes Yes Yes No
⩾ VGPR ⩾ VGPR ⩾ VGPR PR ⩾ VGPR PR PD —
Alive Alive Alive Alive Alive Alive Dead Dead
Abbreviations: CNS RT = central nervous system radiotherapy; Cy = etoposide; D-PACE = dexamethasone, cisplatin, doxorubicin; DT-PACE = dexamethasone, thalidomide, cisplatin, doxorubicin; EMP = extramedullary plasmacytoma; F = female; FLC = free light chain; K = kappa; L = lambda; M = male; PCL = plasma cell leukemia; PD = progressive disease; PR = partial response; Pt = patient; Rd = lenalidomide and dexamethasone; RI = renal impairment; RVD = lenalidomide, bortezomib, dexamethasone; SD = stable disease; VGPR = very good partial response.
the majority receiving lenalidomide-based therapy as their second-line induction regimen. Stem cell mobilization and ASCT All patients underwent stem cell mobilization using Cy and G-CSF, except for one patient with concurrent MM and light chain amyloidosis who received G-CSF alone for mobilization. All patients had successful stem cell collections, requiring a median of one leukapheresis (range 1–4). The median number of CD34+ cells collected was 8 ×106/kg body weight (range 2.3–24.5 × 106/ kg). All patients proceeded to auto-SCT, except for three patients (one patient with del 17p progressed and died before ASCT, one patient was deemed ineligible due to severe mitral stenosis and one patient declined). Melphalan 200 mg/m2 was used for conditioning in 100 patients (94%). Six patients received reduced dose melphalan (140 mg/m2) due to renal impairment. A median of 4.04 × 106/kg CD34+ cells were infused (range 1.48–12.4). Higher-response rates were obtained at 100 days post transplant (ORR 98%; ⩾ VGPR 79%). Toxicity All patients were assessed for toxicity. Grade 3–4 adverse events related to therapy are summarized in Table 5. The most common grade 3–4 adverse events were infection (10%) and neutropenia (4%). Pneumonia was the most common site of infection (5%). Using routine antiviral prophylaxis, grade 3–4 herpes infections were not common (2.8%). Grade 1–2 peripheral neuropathy occurred in 33 patients (31%), with no severe (grade 3–4) © 2015 Macmillan Publishers Limited
neuropathy noted. Grade 3–4 hematologic adverse events were uncommon with only 4 patients (4%) with grade 3–4 neutropenia and no grade 3–4 thrombocytopenia or anemia. CyBorD was welltolerated even in patients with renal failure (n = 19) with no grade 3–4 hematologic toxicity among these patients. Grade 3–4 nonhematologic adverse events occurred in 4 patients with renal impairment (21%) (Table 5). Dose modifications Dose reductions and/or delays of any agents in the regimen were required in 29 patients (27%). The most frequently dose-reduced agent was dexamethasone in 15 patients (14%), mainly due to edema (7%). Eight patients (7%) required dose reduction of bortezomib, mainly due to grade 1–2 neuropathy. Only 4 patients (4%) required Cy dose modification, due to grade 4 neutropenia, severe nausea/fatigue, renal impairment and non-treatment related grade 4 transaminitis, respectively. Grade 4 transaminitis in one patient was attributed to isoniazid administered for latent tuberculosis but Cy was dose-reduced as a precaution; with isoniazid discontinuation, the transaminitis resolved completely. Among 19 patients with renal impairment, 5 patients (26%) required dose reduction of the agents in CyBorD; dexamethasone in 4 patients (21%) due to grade 1–2 peripheral edema (three patients) and grade 2 myopathy (one patient); Cy in two patients due to severe fatigue and nausea (one patient), empiric reduction for renal impairment due to physician preference (one patient) and bortezomib in one patient due to grade 1 peripheral neuropathy. Bone Marrow Transplantation (2015), 1 – 5
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
4
Reeder et al.7 Reeder et al.8 Our data Our RI (n = 33) (%) (n = 30) (%) (n = 109) subgroup (n = 19) Grade 3–4 toxicities Overall Anemia Thrombocytopenia Neutropenia Peripheral neuropathy Hyperglycemia Infection Diarrhea Fatigue Nausea Fluid retention Hypokalemia Elevated creatinine Fever Thrombosis Dose reduction Bortezomib Dexamethasone Cy
48 9 21 12 6
37 0 0 7 0
29 (27%) 0% 0% 4 (4%) 0%
4 (21%) 0% 0% 0% 0%
13 0 6 0 0 0 9 0 0 7
— — — — — — — — — —
3 11 1 3 1 2
(3%) (10%) (1%) (3%) (1%) (2%) 0% 1 (1%) 3 (3%) 0%
2 (11%) 0% 0% 0% 1 (5%) 0% 0% 1 (5%) 0% 0%
21 30 21
13 20 —
8 (7%) 15 (14%) 4 (4%)
1 (5%) 4 (21%) 2 (11%)
80 60 40
80 60 40 20
Year
Survival probabilities (95% Cl)
1-year
95.3% (0.891-0.980)
2-year
95.3% (0.891-0.980)
5-year
91.5% (0.782-0.968)
No (n=85) Yes (n=21) P-value=0.0365 (Log rank test)
20 0 0
1
3
2
4
Time (years) Median and range of follow up time for OS2 (EMP=Yes) is 12.5 (1.2-30.4) months. Median and range of follow up time for OS2 (EMP=No) is 12.6 (1.5-56.8) months.
Figure 2. The presence of concurrent plasmacytoma at diagnosis impacting OS. Table 6. Comparison amongst commonly used three- and four-drug induction regimens Regimen
PAD[11] VTD[3] VRD[9] CRD[13] VDR[12] VDCR[12] VTDC[16] CyBorD
100 Probability of survival (%)
100 Probability of survival (%)
Table 5. Grade 3–4 treatment-related adverse events and dose reduction with renal impairment (RI) in comparison to historical cohorts
N
413 236 66 53 42 48 49 109
After induction
After ASCT
ORR (%)
⩾ VGPR (%)
ORR (%)
⩾ VGPR (%)
78 93 100 85 85 80 96 95
42 62 67 47 51 33 69 66
88 93 — — — — 100 98
62 79 — — — — 82 78
Abbreviations: CyBorD = Cy-bortezomib-dexamethasone; CRD = Cylenalidomide-dexamethasone; n = number of patients; PAD = bortezomib-doxorubicin-dexamethasone; VDR = bortezomib-lenalidomide-dexamethasone; VDCR = bortezomib-dexamethasone-Cy-lenalidomide; VTDC = bortezomibthalidomide-dexamethasone-Cy.
0 0
1
2
3 Time (years)
4
5
Figure 1. Kaplan–Meier OS curve for all 109 patients with probability of OS at 1, 2 and 5 years.
Survival outcomes At a median follow-up of 19.8 months after diagnosis (range 7–67.7), 6 of 109 patients (6%) have died. Causes of death include the following: disease progression (four patients) and pneumonia within 100 days of ASCT (two patients). Survival probabilities at 1, 2 and 5 years were 95.3% (95%CI: 89–98), 95.3% (95%CI: 89–98) and 91.5% (95%CI: 78–96), respectively, as shown in Figure 1. On univariate analysis, the presence of concurrent plasmacytomas at diagnosis was the poor prognostic factor impacting survival (HR = 5.56; 95%CI: 0.92–33.74; P = 0.03) as demonstrated in Figure 2. DISCUSSION Novel three and even four-drug combinations have become standard as induction treatment for MM patients preparing for Bone Marrow Transplantation (2015), 1 – 5
high-dose therapy and stem cell rescue.3,5,7–13 Ideally, an induction regimen should be highly effective, convenient, welltolerated and economical. Given these lofty aspirations, the optimal induction regimen has not yet been identified. CyBorD has gained popularity as an induction regimen given its ease of administration and excellent safety profile; however, efficacy has been extrapolated into real-life practice only from data generated by phase 2 trials. In our evaluation of CyBorD use in a non-trial setting, we were able to confirm the high efficacy of once weekly CyBorD with an ORR 95% and ⩾ VGPR rate of 66%, comparable to results from the original CyBorD phase 2 data published by Reeder et al. (Table 4), as well as to other three- and four-drug combinations in the literature.9–13,16 Of note, CyBorD outcomes appear comparable to that of VRD (bortezomib, lenalidomide and dexamethasone) and VTD (bortezomib, thalidomide and dexamethasone), two of the most effective induction regimens reported with ORR of 100 and 93–95%; ⩾ VGPR of 67% and 60– 62%, respectively.3,9,10 Comparison of induction response among three- and four-drug regimens is summarized in Table 6. In the EVOLUTION trial, the four-drug regimen, bortezomib, lenalidomide, Cy and dexamethasone (VDCR), failed to show benefit over other three-drug regimens including a regimen with similar components to CyBorD.12 Fewer toxicities and drug © 2015 Macmillan Publishers Limited
CyBorD induction therapy in multiple myeloma N Areethamsirikul et al
5 discontinuations with the three-drug versus four-drug combinations suggest that ‘more’ is not necessarily better. In our study, CyBorD toxicities were manageable, with few grade 3–4 hematologic adverse events and no compromise in ability to mobilize stem cells. The absence of grade 3–4 peripheral neuropathy is remarkable and compares favorably with rates of this complication associated with other novel agent combinations, specifically 10% with VTD (bortezomib, thalidomide and dexamethasone), 13% with VRCD, and 8% with VTCD (bortezomib, thalidomide, Cy and dexamethasone).3,12,16 CyBorD is convenient and easy to administer with the bortezomib in a once-weekly schedule. Moreover, the current standard of care has moved from an i.v. to a s.c. mode of administration for bortezomib, associated with further reduction of the incidence of peripheral neuropathy with similar efficacy to the i.v. route.17 In addition, the use of a higher single dose of s.c. bortezomib (with volumes up to 3 ml) is feasible, with limited skin reactions, and eliminates the need to administer at two injection sites in 81% of patients.18 The s.c. route further enhances the convenience of this regimen. Without the constraints of clinical trial eligibility, our real-life experience with CyBorD included the treatment of patients with high-risk features, including PCL and severe renal impairment (including dialysis-dependency). All PCL patients in our series responded to CyBorD and those with renal impairment appeared to tolerate the regimen well, with a high rate of renal improvement. No renal dose adjustment is required with bortezomib even in dialysis-dependent patients19,20 and Cy requires dose reduction only with severely impaired creatinine clearance of 10 ml/min or less. Therefore, this induction regimen is well-suited for use in newly diagnosed myeloma patients in whom renal impairment is common. Finally, it is worth commenting that CyBorD is a relatively costeffective regimen. When compared with VRD induction, VCD (a similar regimen of bortezomib, Cy and dexamethasone) led to similar survival outcomes and manageable toxicities, but at a significant cost differential ($29 468 USD less per treatment course for VCD compared with VRD).21 CONCLUSION CyBorD using weekly bortezomib as a three-drug induction regimen before ASCT is highly effective in real-life clinical practice. We demonstrated efficacy similar to the data from phase 2 studies of CyBorD and other novel three/four-drug regimens. CyBorD is well-tolerated with routine administration of a single higher dose given weekly s.c. and represents a convenient and relatively costeffective induction regimen. CONFLICT OF INTEREST CC received honoraria from Janssen and Celgene. ST received honoraria from Celgene. VK received honoraria form Celgene and Lundbeck. RT received honoraria from Janssen and Celgene. DR received research funds from Millinneum, Janssen and Celgene, honoraria from Janssen, Celgene and Amgen, Consulting fees from Janssen and Celgene. The remaining authors declare no conflict of interest.
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