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Bortezomib-thalidomide-dexamethasone (VTD) is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma

Leukemia volume 29, pages 2429–2431 (2015)Cite this article

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Integration of novel agents into first-line therapy for newly diagnosed multiple myeloma (MM) patients who are eligible to receive an autologous stem cell transplantation (ASCT) has led to unprecedented rates of high-quality responses.1 Based on the results of several phase III trials,2, 3, 4, 5 a three-drug induction regimen including bortezomib and dexamethasone (VD) is currently considered the standard of care in preparation for ASCT. The European Medicines Agency recently approved the combination of bortezomib with thalidomide and dexamethasone (VTD) for this use. However, alternative triplet therapies built on the backbone of VD, including VD plus either lenalidomide (VRD) or cyclophosphamide (VCD), are commonly given in routine practice, although their use is not supported by results of phase III studies. Our involvement over the past years in the design and coordination of two consecutive large phase III trials incorporating either VTD or VCD as induction therapy for ASCT-eligible MM patients, prompted us to perform a retrospective case-matched analysis aimed to evaluate the efficacy and toxicity of these two popular regimens in a representative sample size. For this purpose, 236 patients who were randomly assigned to the VTD arm of the GIMEMA-MMY-3006 study (registered with ClinicalTrials.gov, number NCT01134484), were compared with an equal number of pair mates who were enrolled in the European Myeloma Network (EMN)-02 study (registered with ClinicalTrials.gov, number NCT01208766). By study design, these latter patients were planned to be treated with VCD induction and subsequent cyclophosphamide to collect peripheral blood stem cells before randomization to receive either ASCT upfront or bortezomib-melphalan-prednisone followed by ASCT at the time of relapse. Case matching was performed with respect to the following patient characteristics at baseline: age (±2 years), international staging system (ISS) stage (1 vs 2 vs 3) and presence or absence of t(4;14) (⩾10 vs <10%) and/or del(17p) (⩾20 vs <20%) detected by fluorescence in situ hybridization analysis of CD138+ bone marrow plasma cells. The two groups were also comparable with respect to additional prognostic variables. In both studies, induction treatment with either VTD, as reported elsewhere,2 or VCD consisted of three 21-day cycles. In VCD, the dosing schedules of VD were the same than in VTD (for example, bortezomib, 1.3 mg/m2 intravenously (i.v.), twice-weekly, and dexamethasone, 320 mg per cycle) with the addition of cyclophosphamide, 500 mg/m2 i.v. on days 1 and 8. Responses evaluated by investigators after the three cycles of induction therapy or the last cycle actually received in case of early treatment discontinuation were centrally reassessed by the study coordinating team according to the IMWG criteria6 and analyzed on an intention-to-treat basis. Overall, the rates of complete response (CR), very good partial response (VGPR) or higher and at least partial response were significantly higher with VTD vs VCD (Table 1). In particular, VTD increased by more than three times the rate of CR in comparison with VCD (19 vs 6%, P<0.001), a gain retained across subgroups of patients with ISS stage 2+3 (20 vs 4%, P<0.001) and high-risk cytogenetics, as defined by the presence of t(4;14) and/or del(17p) (23 vs 8%, P=0.030) (Table 1). By the opposite, the probability to achieve less than partial response was threefold lower with VTD vs VCD; in particular, no patient assigned to VTD experienced disease progression during induction therapy vs 3% in the VCD-treated group (P=0.015). Adverse events (AEs) were graded by use of NCI-CTCAE version 3.0 and were grade 3–4 in 27% of patients in the VTD group and 26% of those in VCD. Of the most common grade 3–4 AEs recorded during induction therapy and listed in Table 2, peripheral neuropathy (PN)7 and skin rash occurred more frequently with VTD compared with VCD (7 vs 2%, P=0.009, and 8 vs 1%, P<0.001, respectively). By the opposite, VCD was associated with a higher probability of severe anemia (7 vs 0%, P=0.003), neutropenia (8 vs 2%, P<0.001) and thrombocytopenia (4 vs <1%, P=0.006) than VTD. Overall, the probability to discontinue induction therapy and to go off-study due to any of the reasons listed in Table 2 was 4% in both treatment groups. Patients assigned to VTD or VCD received 95% and 96% of the planned dose of bortezomib, respectively.

Table 1 Response to VTD and VCD induction therapy
Full size table
Table 2 Grade 3 or 4 adverse events reported in at least 2% of patients during induction therapy with VTD or VCD
Full size table

Comparisons between published studies of VCD induction therapy are difficult owing to the limited sample size of patients enrolled in most of them, heterogeneities in patient characteristics and differences in treatment outlines.8, 9, 10, 11, 12, 13 In particular, major treatment differences across the studies included dosing, route and schedule of bortezomib administration (from 1.3 to 1.5 mg/m2 either i.v. or subcutaneously, twice-weekly or once-weekly), dosing of cyclophosphamide (between 300 and 500 mg/m2/once a week for 2, 3 or 4 weeks per each 21-day or 28-day cycle, corresponding to a total dose per cycle between 900 and 1500 mg/m2, either i.v. or orally), dosing of dexamethasone (from 160 to 480 mg per cycle), and the number of planned cycles (generally, in the 3–4 range). Despite these differences, the rate of CR after 3–4 cycles reported in most of these studies was in a close range, between 3 and 8%,8, 10, 13 while VGPR or higher was observed in 16–41% of patients.10, 13 Notably, in the phase II EVOLUTION study aimed at evaluating eight cycles of induction therapy with either VCD or VRD or VRD plus cyclophosphamide, the best response observed after a median of six cycles of VCD among patients younger than 66 years was 10% CR and 24% VGPR or better. The small number of patients enrolled in the VCD arm of this study precludes any possible conclusion about the optimal number of cycles to be given in preparation for ASCT. Although cross trial comparisons are inadequate, the rates of response reported in the studies mentioned above are consistent with those found in our case-matched analysis. Results of a large phase III study aimed at demonstrating the non-inferiority of VCD compared with bortezomib-doxorubicin-dexamethasone (PAD) were recently published.13 The 8 and 38% rates of CR and ⩾VGPR seen among 251 patients who were randomly assigned to receive three cycles of VCD comprising VD at the same dosing planned in the EMN-02 study and cyclophosphamide at 900 mg/m2 on day 1 are almost superimposable to our data. Differently, another group who treated two small cohorts of patients with different dosing schedules of bortezomib and weekly cyclophosphamide administered in a continuous manner reported that the probability to achieve at least VGPR after four cycles of VCD was 60%, albeit the CR rate was unsatisfactory low, at 3%.8, 9 In our analysis, VCD was more frequently associated with severe hematological toxicity than VTD which, by the opposite, induced more often severe PN compared with VCD. Differently, the rate of grade ⩾3 PN reported in two studies of VCD incorporating standard-dose bortezomib given i.v. twice-weekly was 7 and 9%.8, 10 It is important to highlight that in the GIMEMA-MMY-3006 study, complete resolution of grade 2 or higher PN occurred in 88% of VTD-treated patients, whereas 94% improved to at least grade 1.7 As a result, the probability to discontinue induction therapy and not proceed throughout the subsequent treatment phases including ASCT was the same in both the same in both VTD- and VCD-treated groups. Highly active novel agent-based treatments incorporating first or second generation proteasome inhibitors combined with an immunomodulatory drug and, eventually, the addition of a monoclonal antibody targeting antigens expressed on the surface of myeloma cells support the current treatment approach to MM, which is aimed at maximizing the depth of response and minimizing the burden of tumor cells, particularly in early treatment phases. Given the possible coexistence of multiple clones with different genotypic and phenotypic characteristics, even at the onset of the disease, it is possible that the combination of multiple drugs with different mechanisms of action might inhibit clonal evolution, although this hypothesis needs to be backed by confirmatory clinical studies.14 In addition, a growing body of evidence suggests that improvements in the depth of response are consistently associated with better outcomes across all phases of MM and regardless of the use of less or more intensive treatments.15 In particular, attainment of high-quality responses to induction therapy before ASCT is an early predictor of prolonged progression-free survival after ASCT. Therefore, the choice of the most effective induction regimen to be used in preparation for high-dose melphalan is of primary importance for ASCT-eligible MM patients and should be carefully balanced with toxicity. Results of our analysis, as well as of other studies aimed at exploring, although not in a head-to-head manner, the role of VCD induction therapy, support the activity of this latter regimen which, however, is likely to be inferior compared with that of a three-drug regimen incorporating a proteasome inhibitor and an immunomodulatory drug, like VTD. In our study, VTD effected a threefold or higher increase in the CR rate compared to VCD and this gain was retained across subgroups of patients at high-risk, such as those with advanced ISS stage or an unfavorable cytogenetic profile. Importantly, VTD was not associated with a higher probability of any grade 3-4 AE in comparison with VCD. These data, if confirmed by the results of a phase III study conducted by the Intergroup Francophone du Myelome and aimed at prospectively comparing VTD with VCD induction therapy, might support the preferential use of a more expensive, but more active, regimen like VTD rather than VCD in preparation for ASCT in newly diagnosed MM patients.

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References

  1. Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 2011; 117: 6063–6073.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatmentbeforeautologous stem cell transplantation in newlydiagnosed multiple myeloma. Blood 2011; 118: 5752–5758.

    Article  CAS  Google Scholar 

  4. Rosiñol L, Oriol A, Teruel AI, Hernández D, López-Jiménez 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.

    Article  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. Durie BG, Harousseau JL, Miguel JS, Bladé J, Barlogie B, Anderson K et alInternational Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia 2006; 20: 1467–1473.

    Article  CAS  Google Scholar 

  7. Tacchetti P, Terragna C, Galli M, Zamagni E, Petrucci MT, Pezzi A et al. Bortezomib- and thalidomide-induced peripheral neuropathy in multiple myeloma: clinical and molecular analyses of a phase 3 study. Am J Hematol 2014; 89: 1085–1091.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Laumann K, Hentz J et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood 2010; 115: 3416–3417.

    Article  CAS  Google Scholar 

  10. 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.

    Article  CAS  Google Scholar 

  11. Leiba M, Kedmi M, Duek A, Freidman T, Weiss M, Leiba R et al. Bortezomib-cyclophosphamide-dexamethasone (VCD) versus bortezomib-thalidomide-dexamethasone (VTD)-based regimens as induction therapies in newly diagnosed transplant eligible patients with multiple myeloma: a meta-analysis. Br J Haematol 2014; 166: 702–710.

    Article  CAS  Google Scholar 

  12. Areethamsirikul N, Masih-Khan E, Chu CM, Jimenez-Zepeda V, Reece DE, Trudel S et al. CyBorD induction therapy in clinical practice. Bone Marrow Transplant 2015; 50: 375–379.

    Article  CAS  Google Scholar 

  13. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW et al. Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia 2015; 29: 1721–1729.

    Article  CAS  Google Scholar 

  14. Brioli A, Melchor L, Cavo M, Morgan GJ . The impact of intra-clonal heterogeneity on the treatment of multiple myeloma. Br J Haematol 2014; 165: 441–454.

    Article  Google Scholar 

  15. Lonial S, Anderson KC . Association of response endpoints with survival outcomes in multiple myeloma. Leukemia 2014; 28: 258–268.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Seràgnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy

    M Cavo, L Pantani, A Pezzi, G Marzocchi, E Zamagni, P Tacchetti & A Brioli

  2. Azienda Policlinico Umberto I, University La Sapienza, Roma, Italy

    M T Petrucci

  3. Hematology and Bone Marrow Transplant Unit, Udine, Italy

    F Patriarca

  4. Department of Clinical and Molecular Bio-Medicine, University of Catania, Catania, Italy

    F Di Raimondo

  5. Hematology, Papa Giovanni XXIII Hospital, Bergamo, Italy

    M Galli

  6. Hematology-Bone Marrow Transplantation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

    V Montefusco

  7. Arcispedale S. Maria Nuova, Hematology, Reggio Emilia, Italy

    B Gamberi

  8. University of Torino, Azienda Ospedaliero-Universitaria (AOU) S. Giovanni Battista Torino, Torino, Italy

    A Palumbo

  9. Department of Hematology, Erasmus MC, Rotterdam, The Netherlands

    P Sonneveld

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  1. M Cavo
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Correspondence to M Cavo.

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Competing interests

MC has received honoraria from Janssen, Celgene, Amgen, Bristol–Myers Squibb and Millennium Pharmaceuticals; has served on speakers' bureaux for Janssen and Celgene; has been a consultant for Janssen, Celgene, Amgen and Millennium. MTP has received honoraria from Janssen and Celgene. FP has received honoraria from Janssen and Celgene. FDR has received honoraria and served on speakers’ bureaux for Celgene and Janssen. EZ has received honoraria from Janssen and Celgene. AP has received honoraria from Celgene, Janssen, Amgen, Bristol-Myers Squibb, Merck and Millennium; has been a consultant for Celgene, Janssen, Amgen, Bristol–Myers Squibb and Millennium. PS has received research support and honoraria from Celgene, Janssen, Onyx and Millennium. All other authors declare that they have no conflicts of interest.

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Cavo, M., Pantani, L., Pezzi, A. et al. Bortezomib-thalidomide-dexamethasone (VTD) is superior to bortezomib-cyclophosphamide-dexamethasone (VCD) as induction therapy prior to autologous stem cell transplantation in multiple myeloma. Leukemia 29, 2429–2431 (2015). https://doi.org/10.1038/leu.2015.274

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