Randomized Phase II Study of Bortezomib, Thalidomide, and Dexamethasone With or Without Cyclophosphamide As Induction Therapy in Previously Untreated Multiple Myeloma

Ludwig, Heinz; Viterbo, Luísa; Greil, Richard; Masszi, Tamás; Špıčka, Ivan; Shpilberg, Ofer; Hájek, Roman; Dmoszyńska, Anna; Paiva, Bruno; Vidriales, María‐Belén; Esteves, Graça; Stoppa, Anne Marie; Robinson, Don; Ricci, Deborah; Cakana, Andrew; Enny, Christopher; Feng, Huaibao; Velde, Helgi van de; Harousseau, Jean Luc

doi:10.1200/jco.2011.39.5137

Cited by 71 publications

(79 citation statements)

References 35 publications

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“…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][10][11][12][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.…”

Section: Discussionmentioning

confidence: 89%

“…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.…”

Section: Discussionmentioning

confidence: 99%

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CyBorD induction therapy in clinical practice

Areethamsirikul

Masih‐Khan

Chu

et al. 2015

Bone Marrow Transplant

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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. INTRODUCTIONCurrently, 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][2][3][4][5][7][8][9][10][11][12][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/m 2 (days 1, 4, 8 and 11), weekly cyclophosphamide (Cy) 300 mg/m 2 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/m 2 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 hig...

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

CyBorD induction therapy in clinical practice

Areethamsirikul

Masih‐Khan

Chu

et al. 2015

Bone Marrow Transplant

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“…Several studies have reported encouraging results for MM patients with BCD regimen [19,[24][25][26], in both newly diagnosed and relapsed/refractory patients, including patients of all ages. The ORR ranged from 69 to 96 %.…”

Section: Discussionmentioning

confidence: 99%

“…Bortezomib was also evaluated in combination with cyclophosphamide and dexamethasone (BCD) in newly diagnosed MM patients, both eligible and ineligible for ASCT [18]. Nevertheless, BCD regimens were inevitably associated with increased toxicity, resulting in a transient decrease in the global health score [19].…”

Section: Introductionmentioning

confidence: 99%

Once-Weekly 1.6 mg/m2 Bortezomib BCD Regimen in Elderly Patients with Newly Diagnosed Multiple Myeloma Who are Unfit for Standard Dose Chemotherapy

Tang

Yao

et al. 2016

Indian J Hematol Blood Transfus

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Bortezomib has shown anti-myeloma effects in combination with alkylating agents, but clinical benefits can be limited by neurotoxicity. There is less information on the efficacy and tolerability of once-weekly 1.6 mg/m 2 bortezomib combined with cyclophosphamide and dexamethasone (BCD) regimen in elderly patients with newly diagnosed multiple myeloma who are unfit for standard dose chemotherapy. Here, we report our experience of weekly 1.6 mg/m 2 intravenous bortezomib in this group of patients. Between March 2010 and February 2015, we treated 34 newly diagnosed elderly patients with the combination of bortezomib 1.6 mg/m 2 intravenously on days 1 and 8; cyclophosphamide 200 mg/m 2 intravenously on days 1-4; dexamethasone 20 mg intravenously on days 1-4, and 8-11. Among the 34 patients, 14 (41 %) responded with complete response (CR), 6 (18 %) with very good partial response (VGPR) and 10 (29 %) with partial response (PR). The overall response rates were 88 %. After 2 cycles of treatments, the survival of patients who attained a response of VGPR or CR was significantly longer than those with PR or resistance to BCD, for both progression-free survival (PFS) (21.4 vs. 10.6 months, p = 0.002) and overall survival (OS) (23.0 vs. 16.8 months, p = 0.043). The 2-year PFS and OS were 26.5 and 64.7 % respectively in these elderly multiple myeloma patients in our study. Grade 1/2 neuropathy was observed in 20 % of the cycles while grade 3/4 neuropathy was not observed. No patients withdrew due to neuropathy or other side effects. Onceweekly bortezomib at 1.6 mg/m 2 BCD regimen is both effective and safe in elderly patients with newly diagnosed multiple myeloma who are unfit for standard dose chemotherapy.

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“…There is no evidence that 4-drug regimens are superior and they may be more toxic. 19,20 The better response rate observed with new regimens is 21 36 38 n/a related to a better efficacy across all prognostic subgroups, including ISS 3 and poor-risk cytogenetics. 6,12 There is currently no direct evidence that the higher CR plus n-CR rate achieved with these new regimens translates into a longer PFS since in all of these studies, there were different post-ASCT treatments.…”

Section: What Is the Best Induction Treatment Prior To Autologous Stementioning

confidence: 99%

Treatment of autologous stem cell transplant-eligible multiple myeloma patients: ten questions and answers

Mohty

Harousseau

2014

Haematologica

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F e r r a t a S t o r t i F o u n d a t i o nics and renal impairment. In the era of novel agents, the role of transplant itself is being questioned and trials are ongoing to establish whether transplant can be delayed until after relapse in some patients. The current ongoing studies are aimed towards improving the different steps of the procedure with the aim of further improving efficacy and tolerability. This review addresses a number of questions surrounding the different steps of the transplant procedure and summarizes the available research evidence as a basis for decision making. Is high-dose therapy plus autologous stem cell transplantation superior to conventional chemotherapy?The concept of high-dose therapy (HDT) plus autologous stem cell transplantation (ASCT) was developed in the 1980s. The objective of ASCT was to support highdose therapy (HDT) in order to reduce the duration and toxicity of severe myelosuppression. The Intergroupe Francophone du Myelome (IFM) was the first to conduct a randomized trial showing the superiority of HDT/ASCT over conventional chemotherapy in patients under 65 years of age regarding response rate, event-free survival (EFS) and overall survival (OS).1 These findings were confirmed seven years later in a larger study conducted by the UK Medical Research Council (MRC Myeloma VII trial). 2Following these results, HDT/ASCT became the standard of care in patients without severe comorbidities and under 65 years of age.Overall, 7 randomized studies have compared ASCT/HDT to conventional chemotherapy. 3 While EFS was superior with HDT/ASCT in 5 of 7 trials, OS was significantly prolonged in only 3 trials. These results were confirmed by a meta-analysis that showed a significant benefit for HDT/ASCT in terms of EFS but no benefit in terms of OS. 4 This was partly explained by the impact of ASCT at relapse in patients initially treated with conventional chemotherapy. Therefore, although the majority of myeloma experts recommend HDT/ASCT as part of initial therapy, some experts consider that delaying ASCT until relapse remains a valuable approach.Importantly, the use of HDT/ASCT was the major cause of OS improvement observed in younger patients before the introduction of novel agents, such as immunomodulatory drugs (IMIDs) and proteasome inhibitors. 5 However, despite the demonstrated efficacy of the procedure, relapses ultimately occurred in the vast majority of patients and long remissions (and possible cures) remained rare. The introduction of several new agents (thalidomide, lenalidomide and bortezomib) has substantially changed treatment strategies in the transplant setting. The addition of novel agents before and/or after HDT/ASCT has dramatically increased the post-ASCT complete response (CR) rate and the CR plus very good partial response (VGPR) rate.6,7 Maybe more importantly, the level of CR has been up-graded with the achievement of stringent CR (s-CR) with a normal κ/λ ratio (serum free light chain assessment), 8 of immunophenotypic CR (with multiparameter flow cytome...

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Randomized Phase II Study of Bortezomib, Thalidomide, and Dexamethasone With or Without Cyclophosphamide As Induction Therapy in Previously Untreated Multiple Myeloma

Abstract: Both VTD and VTDC are highly active induction regimens producing high combined CR/nCR and MRD-negative rates; however, VTDC was associated with increased toxicity and suggestion of transient decreases in Global Health score, without an increase in activity.

Cited by 71 publications

References 35 publications

CyBorD induction therapy in clinical practice

CyBorD induction therapy in clinical practice

Once-Weekly 1.6 mg/m2 Bortezomib BCD Regimen in Elderly Patients with Newly Diagnosed Multiple Myeloma Who are Unfit for Standard Dose Chemotherapy

Treatment of autologous stem cell transplant-eligible multiple myeloma patients: ten questions and answers

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