VCD) Versus Bortezomib, Doxorubicin and Dexamethasone (Pad) in Newly Diagnosed Myeloma

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ORIGINAL ARTICLE Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma

EK Mai1, U Bertsch1, J Dürig2, C Kunz3, M Haenel4, IW Blau5, M Munder6, A Jauch7, B Schurich8, T Hielscher3, M Merz9, B Huegle-Doerr1, A Seckinger1, D Hose1, J Hillengass9, MS Raab9, K Neben9, H-W Lindemann10, M Zeis11, C Gerecke12, IGH Schmidt-Wolf13, K Weisel14, C Scheid15, H Salwender16 and H Goldschmidt1

We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/ doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾ VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾ VGPR rates (37.0 versus 34.3%, P = 0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P = 0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, Po0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P = 0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P = 0.04 and 2.8 versus 0.4%, P = 0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾ VGPR rates with fewer PD and has a favorable toxicity proﬁle. Therefore, VCD is preferable to PAd as induction therapy.

Leukemia (2015) 29, 1721–1729; doi:10.1038/leu.2015.80

INTRODUCTION (GMMG, EudraCT No. 2010-019173-16) was designed to assess Induction therapy (IT) followed by high-dose melphalan (HDM) two independent primary end points: and autologous stem cell transplantation (ASCT) is the standard of 1. Demonstration of non-inferiority of bortezomib/cyclopho- care for younger multiple myeloma (MM) patients.1–3 ITs provide a sphamide/dexamethasone (VCD) IT compared to bortezomib/ crucial foundation for modern multi-drug-based myeloma treat- doxorubicin/dexamethasone (PAd) IT with respect to response rates (very good partial response (VGPR) or better, ⩾ VGPR). ment approaches, progressively inducing high rates of deep 4–8 2. Determination of the best of four treatment strategies with responses, thereby leading to prolonged progression-free fi 3,9–12 respect to PFS. The treatment strategies are de ned by PAd or survival (PFS) and overall survival (OS). VCD IT followed by standard intensification therapy (HDM+ASCT), Bortezomib/dexamethasone-based IT regimens are commonly lenalidomide consolidation and maintenance treatment with combined with either cytotoxic agents, such as doxorubicin6,7 or 5,13–16 4,17 either lenalidomide for 2 years or lenalidomide until complete cyclophosphamide, or immunomodulatory drugs (IMiDs, response (CR) is achieved. thalidomide and lenalidomide). The superiority of bortezomib- Herein we report the results of the first primary end point of the containing regimens to ITs without novel agents has been MM5 trial. demonstrated in a number of phase III trials.4,7–9,13,17 Until now, however, there has been no reported randomized phase III trial comparing a bortezomib/dexamethasone-based IT, with either PATIENTS AND METHODS doxorubicin or cyclophosphamide. Eligibility criteria The open-label, randomized, multicenter phase III clinical trial The key inclusion criteria were patients 18–70 years of age with MM5 of the German-speaking Myeloma Multicenter Group newly diagnosed MM18 who require systemic chemotherapy based on

1Department of Internal Medicine V, University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg on behalf of the German-Speaking Myeloma Multicenter Group (GMMG), Heidelberg, Germany; 2Department of Hematology, University Hospital Essen, Essen, Germany; 3Division of Biostatistics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany; 4Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany; 5Medical Clinic, Charité University Medicine Berlin, Berlin, Germany; 6Department of Internal Medicine III, University Medical Center Mainz, Mainz, Germany; 7Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; 8Coordination Centers for Clinical Trials (KKS), University Hospital Heidelberg, Heidelberg, Germany; 9Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany; 10Department of Hematology and Oncology, Katholisches Krankenhaus Hagen, Hagen, Germany; 11Department of Hematology, Asklepios Hospital St. Georg Hamburg, Hamburg, Germany; 12Department of Hematology and Oncology, Helios Hospital Berlin Buch, Berlin, Germany; 13Center for Integrated Oncology, University Hospital Bonn, Bonn, Germany; 14Department of Hematology, Oncology and Immunology, University Hospital Tübingen, Tübingen, Germany; 15Department of Internal Medicine I, University Hospital Köln, Köln, Germany and 16Department of Hematology and Oncology, Asklepios Hospital Hamburg Altona, Hamburg, Germany. Correspondence: Professor Dr H Goldschmidt, Department of Internal Medicine V, University Hospital Heidelberg and National Center for Tumor Diseases (NCT) Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail: [email protected] Received 3 November 2014; revised 12 March 2015; accepted 16 March 2015; accepted article preview online 19 March 2015; advance online publication, 8 May 2015 VCD is favorable to PAd as induction therapy in myeloma EK Mai et al 1722

Newly diagnosed symptomatic MM 18-70 years of age

A1 + B1 A2 + B2

3 x PAd 3 x VCD 1) 1)

Stem cell mobilisation (CAD + G-CSF) + leukapheresis

First ASCT (melphalan 200 mg/m2)

Second ASCT (melphalan 200 mg/m2) (if no nCR/CR)

2 x Lenalidomide

A1 B1 A2 B2

Lenalidomide Lenalidomide Lenalidomide Lenalidomide for 2 years if no CR for 2 years if no CR

1) High Risk Patients, optional in Phase II trial for auto-allo SCT

Randomized (n = 504) ineligible: VCD n =1 PAd n = 1 ITT (n = 502)

Patients not receiving PAd (n = 251) VCD (n = 251) Patients not receiving allocated intervention due allocated intervention due to: to: - myocardial infarction - non-compliance (n = 1) prior to therapy (n = 1) Received allocated Received allocated - withdrawal of consent - death (n = 1) intervention (n = 248) intervention (n = 249) (n = 2)

randomized PAd and One patient was excluded treated VCD (n = 1) from ITT due to unconfirmed diagnosis of symptomatic MM (see above) but received VCD 3 cycles n = 234 3 cycles n = 244 and was therefore 2 cycles n = 10 2 cycles n = 4 included in safety 1 cycle n = 5 1 cycle n = 1 analysis (n = 1)

Excluded from PP Excluded from PP analysis analysis - incomplete induction - incomplete induction therapy (n = 9) ITT n = 251 ITT n = 251 therapy (n = 5) - missing response Per-Protocol n = 233 Per-Protocol n = 240 - missing response assessment (n = 6) Safety n = 249 Safety n = 249 assessment (n = 3) - randomized PAd and - patient not ITT not PP treated VCD (n = 1) but Safety (n = 1, see above) CAD + G-CSF CAD + G-CSF

Stem cell collection Stem cell collection

Figure 1. Flow chart and consort diagram of the GMMG-MM5 trial. (a) Flow chart: randomization was performed prior to start of induction therapy. Maintenance therapy consisted of either lenalidomide for 2 years or lenalidomide if no complete remission (CR) was achieved. (b) Consort diagram: 502 patients were randomized and received the hence displayed treatment. Abbreviations: ASCT, autologous stem cell transplantation; CAD, cyclophosphamide/doxorubicin/dexamethasone; G-CSF, granulocyte-colony stimulating factor (lenograstim); ITT, intention-to-treat population; MM, multiple myeloma; nCR, near complete remission; PAd, bortezomib/doxorubicin/dexamethasone; PP, per-protocol population; safety, safety population; VCD, bortezomib/cyclophosphamide/dexamethasone.

‘CRAB’ criteria;18 World Health Organization (WHO) performance status Study design and treatment 19 0–2 or 3, if MM related; and measureable MM disease. Key exclusion The MM5 trial is a prospective, open-label, randomized multicenter phase criteria included: systemic light chain amyloidosis; peripheral neuro- III clinical trial (EudraCT No. 2010-019173-16). A total of 31 transplant pathy/neuropathic pain ⩾ 2° (National Cancer Institute Common centers and 75 associated sites throughout Germany are participating in Terminology Criteria for Adverse Events, NCI CTCAE, version 4.0). this trial. The study was initiated by the GMMG and approved by ethics Patients with renal impairment (RI) or renal failure were not excluded committees in the University of Heidelberg and at all participating sites. from the study. Detailed inclusion/exclusion criteria are provided in the The MM5 trial is conducted according to the European Clinical Trial study protocol (see online Supplementary Material 1). Directive (2005) and the Declaration of Helsinki.

Figure 2. Induction treatments. Schematic view of induction therapy regimens within the GMMG-MM5 trial.

Five hundred and four patients were included in the trial between July In the final analysis, the non-inferiority analysis was performed for the 2010 and October 2012. At present the study is ongoing. Patients were intention-to-treat (ITT) and the per-protocol (PP) population with a non- equally randomized to each of the four treatment arms (A1, A2, B1 and B2; inferiority margin of 10% for the difference in ⩾ VGPR rates. Therefore two- Figure 1) using block randomization, stratified by the International Staging sided confidence intervals were calculated by using the Newcombe's System (ISS) stage.20 Treatment consisted of either three 4-week cycles of hybrid score interval.23 The test of Farrington and Manning24 was used to PAd (A1+B1) or three 3-week cycles of VCD (A2+B2). Thereafter, standard test the one-sided null hypothesis of the non-inferiority of VCD to PAd. The intensification according to local protocols (GMMG standard) was two-sided significance level for this final analysis was set to 2.4%, the one- performed, including stem cell mobilization and leukapheresis followed sided level accordingly to 1.2%. To demonstrate non-inferiority of VCD, by single HDM+ASCT or, for patients not achieving near CR (nCR) or better, non-inferiority for both ITT and PP populations needs to be confirmed. ’ tandem HDM+ASCT. Subsequently, consolidation therapy consisted of two Adverse events (AEs) are summarized per patient and Fisher s exact test is cycles of lenalidomide (25 mg, days 1–21) followed by lenalidomide used to compare AE frequencies and response rates. Unless indicated maintenance (for the first 3 months 10 mg/day continuously and thereafter otherwise, numbers from the ITT population are listed. All analyses were 15 mg/day continuously) for either 2 years (A1+A2) or until CR (B1+B2). carried out using R versions 2.14.0 and 2.15.3 (www.r-project.org). The PAd IT consisted of bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11; 2 – doxorubicin 9 mg/m intravenously (i.v.) on days 1 4; and oral (p.o.) RESULTS dexamethasone 20 mg on days 1–4, 9–12 and 17–20 (240 mg/cycle, repeated every 28 days). VCD consisted of bortezomib 1.3 mg/m2 on days Patients and adherence to treatment 2 1, 4, 8 and 11; cyclophosphamide 900 mg/m i.v. on day 1; and p.o. Of the 504 patients randomized to the four treatment arms dexamethasone 40 mg on days 1–2, 4–5, 8–9 and 11–12 (320 mg/cycle, (Figure 1a), two were excluded from ITT due to a violation of repeated every 21 days; see Figure 2). Antibiotic (cotrimoxazole) and inclusion criteria. One of these patients has still been included in antiviral (acyclovir) prophylaxis was mandatory throughout IT. Intravenous the safety population. One ITT patient was randomized to PAd but bisphosphonate administration was recommended every 4 weeks. The received VCD instead and was therefore excluded from PP but route of administration of bortezomib was changed from i.v. to subcutaneous (s.c.) in all study arms following a protocol amendment in included in the ITT and the safety populations. In total, 251 February 2012 after the enrollment of 314 patients. Thereafter, equal patients were randomized to the PAd and VCD arms, respectively. numbers of patients in the VCD and PAd groups received s.c. bortezomib. In both arms, 249 patients were evaluable for the safety analysis. These results are based on the dataset as of July 2013. At that time, all Nineteen (PAd) and 12 patients (VCD) were excluded from the PP patients had completed IT and had either proceeded under maintenance/ analysis. ITT patients with less than three IT cycles due to consolidation treatment or were in follow-up. progressive disease (PD) were included in the PP assessment. A total of 233 patients in the PAd group (92.5%) and 240 patients Response assessments and end points in the VCD group (95.2%) completed all three planned IT cycles The response was assessed by a local investigator and verified by a medical and subsequent response assessment. After IT, eight patients in monitor according to Durie et al.19 (International Myeloma Working Group each treatment arm (PAd and VCD) left the study due to high-risk criteria). In addition, the European Society for Blood and Marrow Transplanta- disease and received allogeneic transplantation. The consort tion criteria21 were implemented to assess minimal response. nCR was defined diagram is displayed in Figure 1b. as the absence of serum and urine M-protein on standard electrophoresis and/ Baseline characteristics are listed in Table 1. Patients in the VCD or standard 24-h urinary measurement with a positive or missing arm were slightly younger and had a more favorable distribution immunofixation status in the serum and/or urine. For the confirmation of of WHO performance status scores. CR, negative serum and urine immunofixation as well as cytological bone marrow assessment were required. Enriched CD138+ plasma cells from bone Trial medication marrow aspirates were analyzed according to the standardized interphase fluorescence in-situ hybridization (iFISH) procedure.22 The mean delivered doses of bortezomib did not differ between treatment groups in all the three cycles (mean values (mg); cycles Statistical design and analysis I/II/III: PAd: 9.6/9.6/9.4 versus VCD: 9.6/9.5/9.9). The proportions of patients who received a scheduled or As mentioned earlier, the MM5 trial is designed to address two delayed full dexamethasone dose in the PAd and VCD arms were independent primary objectives. To guarantee a family-wise error rate of 5.0%, each primary objective is similar (% receiving full dexamethasone dose; cycles I/II/III: PAd: tested with the two-sided alpha level of 2.5%. The first primary objective 81.5/80.2/85.9 versus VCD: 81.5/82.2/84.8). was tested in a group-sequential way with a significance level split into A full doxorubicin dose was applied to 94.3/88.0/91.9% of 0.1% for the interim and 2.4% for the final analysis. The interim analysis patients in cycles I/II/III, respectively, in the PAd group. A full was based on 75 patients in each IT with the possibility to stop for futility if cyclophosphamide dose was administered to 89.9/82.6/86.4% of a single arm showed o30% response. patients in cycles I/II/III, respectively, in the VCD group.

Table 1. Baseline patient and disease characteristics 45 PAd 40 VCD Characteristic PAd (n = 251) VCD (n = 251) 35 30 n % n % 25 Sex 20 Male 147 58.6 153 61.0

Female 104 41.4 98 39.0 Percent (%) 15 10 Age in years Median (range) 59.4 (36.0–70.0) 58.7 (33.0–70.0) 5 WHO performance status 0 0 89 35.5 114 45.4 CR nCR VGPR PR MR SD PD missing 1 126 50.2 116 46.2 Response rates (ITT) 2 25 10.0 17 6.8 3 5 2.0 4 1.6 Unknown 6 2.4 0 0.0 45 PAd Heavy-chain isotype 40 VCD IgG 150 59.8 148 59.0 35 IgA 54 21.5 51 20.3 LCD 43 17.1 47 18.7 30 Other 4 1.6 5 2.0 25

Light-chain isotype 20

Kappa 177 70.5 160 63.8 Percent (%) 15 Lambda 74 29.5 91 36.2 10 4 Calcium elevation (calcium 2.65 mmol/l) 5 Yes 40 15.9 31 12.3 0 Renal insufﬁciency (creatinine 4177 μmol/l) CR nCR VGPR PR MR SD PD Yes 38 15.1 39 15.5 Response rates (PP) o o Anemia (Hb 10 g/dl or 2 g/dl normal) Figure 3. Response rates after three cycles of PAd or VCD induction Yes 124 49.4 138 55.0 therapy. ITT population consisted of 502 patients; PP population Bone disease (lytic lesionsa) consisted of 473 patients. Graphs display percentage of patients Yes 229 91.2 223 88.8 achieving the indicated response in PAd or VCD induction therapy arm for ITT population (a) and PP population (b). Abbreviations: CR, ISS stage complete remission; ITT, intention-to-treat population; missing, no I 99 39.4 94 37.5 response assessment performed; MR, minimal response; nCR, near II 80 31.9 82 32.7 complete remission; PAd, bortezomib/doxorubicin/dexamethasone; III 72 28.7 75 29.9 PD, progressive disease; PP, per-protocol population; PR, partial Adverse cytogenetics del17p response; SD, stable disease; VCD, bortezomib/cyclophosphamide/ Performed 217 100 222 100 dexamethasone; VGPR, very good partial response. Positive (% performed) 26 12.0 23 10.4

t(4;14) Performed 216 100 219 100 Primary end point Positive (% performed) 25 11.6 22 10.1 In the ﬁnal analysis of the primary objective, non-inferiority of VCD Gain 1q21 (42 copies) compared to PAd was established with the lower conﬁdence limit Performed 213 100 213 100 for the difference in ⩾ VGPR rates exceeding the non-inferiority Positive (% performed) 93 43.7 79 37.1 margin of − 10.0% in ITT (VCD-PAd: 2.8% (−6.8%; 12.3%), P = 0.001) LDH (serum) and PP analyses (VCD-PAd: 1.4% (−8.6%; 11.4%), P = 0.005). ⩽ ULN 204 81.3 207 82.5 Actual ⩾ VGPR rates were 34.3/36.9% (PAd) and 37.0/38.3% 4ULN 46 18.3 44 17.5 (VCD) for ITT and PP, respectively (Figure 3). Unknown 1 0.4 0 0.0

Calcium (serum, mmol/l) Median (range) 2.4 (1.6–3.5) 2.4 (1.7–5.4) Response rates Creatinine (serum, mg/dl) Median (range) 1.0 (0.5–7.5) 1.0 (0.4–11.3) Exploratory analyses of response rates after IT are shown in Table 2. Rates of PR or better (⩾ PR, defined as overall response Hb (g/dl) rate, ORR) did not differ in PAd 72.1% versus VCD 78.1%, P = 0.15. Median (range) 10.9 (5.8–15.9) 10.7 (6.0–16.3) PD occurred in 4.8 and 0.4% of patients within PAd and VCD Platelets (per nl) arms (P = 0.003). Among patients presenting with at least one Median (range) 238 (29–856) 240 (22–533) adverse cytogenetic aberration (del17p, t(4;14), gain 1q2142 Abbreviations: del, deletion; hb, hemoglobin; ISS, International Staging copies), PD rates were 6.2 versus 0.0% (P = 0.01, PAd versus VCD). System; LCD, light-chain disease; LDH, lactate dehydrogenase; MM, multiple Among patients with RI (serum creatinine ⩾2 mg/dl), PD rates myeloma; PAd, bortezomib/doxorubicin/dexamethasone; t, translocation; were 10.8 versus 0.0% (P = 0.05, PAd versus VCD). ULN, upper limit of normal; VCD, bortezomib/cyclophosphamide/dexa- The response rates for the PAd and VCD groups based on ISS methasone; WHO, World Health Organization. Calcium elevation, renal staging are shown in Supplementary Table 1. The PD rates for fi impairment, anemia and bone disease are de ned according to CRAB criteria patients with ISS stage III were significantly higher in the PAd for symptomatic MM.19 aOr myeloma-related osteopenia/osteoporosis. group (9.7 versus 1.3%, P = 0.03).

Table 3. AE, SAE and deaths during PAd and VCD induction therapies Table 2. Response rates after induction therapy Event PAd VCD P-value Response rates after induction PAd (n = 251) VCD (n = 251) P-value (n = 248) (n = 250)

n % n % n % n %

Overall AE CR 11 4.4 21 8.4 0.10 Any AE 152 61.3 160 64.0 0.58 ⩾ nCR 53 21.1 56 22.3 0.83 ⩾ VGPR 86 34.3 93 37.0 0.58 Non-hematological AE ⩾ PR 181 72.1 196 78.1 0.15 Infections and infestations (⩾2°) 61 24.6 56 22.4 0.60 ⩾ MR 207 82.5 232 92.4 0.001 Neuropathy (⩾2°) 37 14.9 21 8.4 0.03 SD 16 6.4 9 3.6 0.22 Thromboembolic events (⩾2°) 14 5.6 6 2.6 0.07 PD 12 4.8 1 0.4 0.003 Gastrointestinal disorders (⩾3°) 21 8.5 16 6.4 0.40 Missing 16 6.4 9 3.6 — Cardiac disorders (⩾2°) 7 2.8 6 2.4 0.79 Renal and urinary disorders (⩾3°) 4 1.6 9 3.6 0.26 Baseline creatinine ⩾ 2mg/dl n =37 n =39 CR 2 5.4 2 5.1 1.00 Hematological AE ⩾ nCR 7 18.9 12 30.8 0.29 Leukocytopenia/neutropenia (⩾3°) 28 11.3 88 35.2 o0.001 ⩾ VGPR 16 43.2 23 59.0 0.25 Thrombocytopenia (⩾3°) 18 7.3 10 4.0 0.12 ⩾ PR 22 59.5 31 79.5 0.08 Anemia (⩾3°) 19 7.7 17 6.8 0.73 ⩾ MR 27 73.0 35 89.7 0.08 SD 5 13.5 2 5.1 0.26 SAE PD 4 10.8 0 0.0 0.05 Any SAE 81 32.7 60 24.0 0.04 — Missing 1 2.7 2 5.1 Infections and infestations 32 12.9 27 10.8 0.49 Adverse cytogeneticsa n = 112 n = 101 Gastrointestinal disorders 15 6.0 8 3.2 0.14 CR 8 7.1 9 8.9 0.80 Musculoskeletal and connective 9 3.6 4 1.6 0.17 ⩾ nCR 28 25.0 24 23.8 0.87 tissue disorders ⩾ VGPR 45 40.2 39 38.6 0.89 Thromboembolic events 7 2.8 1 0.4 0.04 ⩾ PR 82 73.2 84 83.2 0.10 Cardiac disorders 5 2.0 2 0.8 0.28 ⩾ MR 94 83.9 95 94.1 0.03 Renal and urinary disorders 4 1.6 7 2.8 0.54 SD 7 6.2 3 3.0 0.34 PD 7 6.2 0 0.0 0.01 Deaths — Missing 4 3.6 3 3.0 — Any death 6 2.4 1 0.4 Infections 3 1.2 1 0.4 — Abbreviations: CR, complete remission; ITT, intention-to-treat population; Other 3 1.2 0 0.0 — missing, no response assessment performed; MR, minimal response; nCR, near complete remission; PAd, bortezomib/doxorubicin/dexamethasone; Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria for PD, progressive disease; PR, partial response; SD, stable disease; VCD, Adverse Events; PAd, bortezomib/doxorubicin/dexamethasone; SAE, ser- ‘ ’ bortezomib/cyclophosphamide/dexamethasone; VGPR, very good partial ious AE; VCD, bortezomib/cyclophosphamide/dexamethasone. Any AE ⩾ ⩾ response. ITT is shown. P-value ⩽ 0.05 was considered as statistically included all AE CTCAE grade 3or 2 for infections, cardiac disorders, significant difference. aDeletion of 17p and/or translocation (4;14) and/or neuropathy and thromboembolic events. Events with a lower CTCAE grade ⩽ fi gain of 1q21 (42 copies) are classified as adverse cytogenetics. are not considered. P-value 0.05 was considered as statistically signi cant difference.

Safety and toxicity Safety data are shown in Table 3. Application of VCD led to a DISCUSSION significant higher proportion of leukocytopenia and/or neutropenia (CTCAE ⩾ 3°, VCD 35.2% versus PAd 11.3%, P = 0.001). Since the introduction of thalidomide in 1999 ushered in the era 25 Neuropathy (CTCAE ⩾ 2°) was observed more frequently in the of novel agents in MM, treatment options and outcomes have 26 PAd arm than in the VCD arm (14.9 versus 7.6%, P = 0.03). markedly improved. New challenges, such as long-term disease 27 The number of patients with at least one serious AE (SAE) control, have been defined. The depth and duration of response 10,28–30 during IT was significantly higher in the PAd group (32.7 versus are crucial steps to achieve long-term responses. 4,17 24.0%, P = 0.04). SAEs due to thromboembolic events (including Bortezomib/dexamethasone in combination with either IMiDs, 5,13–15,31 6,7 pulmonary embolism) were significantly more frequent in the PAd alkylating agents (cyclophosphamide) or anthracyclines than in VCD arm (2.8 versus 0.4%, P = 0.04). (doxorubicin) is frequently used as IT. Decades of clinical During IT, six patients in the PAd group (2.4%) and one patient experience and lower costs support the use of classical cytotoxic in the VCD group (0.4%) died (Table 3). In the PAd group, three agents. In line with our results, using an identical VCD regimen and patients died due to infections (sepsis, pneumonia and infection 16 of an internal spinal fixation device), one due to pulmonary number of cycles, Einsele et al., reported an ORR of 84%. A phase fi 2 embolism, one because of suspected pulmonary embolism and II trial in the Mayo Clinic used an intensi ed (1500 mg/m per cycle one due to cardiac failure and concurrent PD. One patient in the cyclophosphamide) and prolonged cyclophosphamide/bortezo- VCD group died due to an infection (pneumonia). mib/dexamethasone/VCD treatment regimen that, as would be expected, resulted in a higher ORR/ ⩾ VGPR rate (88/61%)13,14,32 when compared to our study (ORR/ ⩾ VGPR rate 78/37%). Kumar Stem cell mobilization and collection et al.5 assessed two VCD regimens with 1000 mg/m2/cycle (VCD) Stem cell mobilization and collection were effective and feasible in and 1500 mg/m2/cycle (VCD-mod) cyclophosphamide. The effi- both arms: 86.9% patients (PAd group) and 88.4% (VCD group) cacy of the VCD-mod regimen (ORR/ ⩾ VGPR rate 82/41%) was collected at least one transplant (42.0 × 106 CD34+ cells per kg comparable to that of our study, which was achieved with a single bodyweight; Table 4). i.v. administration of 900 mg/m2 cyclophosphamide. However,

Table 4. Stem cell collection after induction therapy

PAd (n = 251) VCD (n = 251) P-value

CD34+ cells per kg bodyweight (×106, median) 9.7 9.3 0.24 Stem cell collection successfull, n (%) 218 (86.9) 222 (88.4) 0.68 Abbreviations: ITT, intention-to-treat population; PAd, bortezomib/doxorubicin/dexamethasone; VCD, bortezomib/cyclophosphamide/dexamethasone. ITT is shown. Numbers of collected CD34+ stem cells after induction treatment with either PAd or VCD. Successful stem cell collection was deﬁned as collection of at least 42.0 × 106 CD34+ cells per kg bodyweight. P-value ⩽ 0.05 was considered as statistically signiﬁcant difference.

Table 5. Comparison of different induction therapy regimen used in newly diagnosed multiple myeloma

IT Cycles Patients ORR ⩾ VGPR Any AE Neuropathy Leukocytopenia/neutropenia Reference nn% % % (grade) % (grade) % (grade)

VCD 3 251 78.1 37.0 64.0b 8.4 (⩾2) 35.2d/ − (⩾3) MM5 3 300 84.0 NA 52.0 (⩾3) 12.6 (⩾2) 31.0/6.0 (⩾3) 16 4 33 88.0 61.0 61.0 (⩾3) 7.0 (⩾3) − /13.0 (⩾3) 14 4a 33 63.0 13.0 79.0 (⩾3)c 9.0 (⩾3)c 9.0/30.0 (⩾3)c 5 4a 17 82.0 41.0 88.0 (⩾3)c 18.0 (⩾3)c 6.0/24.0 (⩾3)c 5 PAd 3 251 72.1 34.3 61.0b 14.9 (⩾2) 11.3/ − (⩾3)d MM5 3 413 78.0 42.0 63.0 (⩾3) 24.0 (⩾3) − /3.0 (⩾3) 7 4 102 88.0 55.0 — 16.0 (⩾3) − /10.0 (⩾3) 6 VTD 3 236 93.0 62.0 56.0 (⩾3) 10.0 (⩾3) — 17 6 130 85.0 60.0 — 14.0 (⩾3) − /10.0 (⩾3) 4 4 100 88.0 49.0 43.0 (⩾3) 3.0 (⩾3) — 35 RVD/VRD 4a 42 73.0 32.0 76.0 (⩾3)c 17.0 (⩾3)c 0.0/10.0 (⩾3)c 5 4a 66 75.0 11.0 — 7.0 (⩾3)c 3.0/10.0 (⩾3)c 33 3 31 93.0 58.0 50.0 (⩾3) 10.0 (⩾3) − /35.0 (⩾3) 34 Abbreviations: AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; IT, induction therapy; NA, not applicable; ORR, overall response rate (partial response or better); PAd, bortezomib/doxorubicin/dexamethasone; RVD, lenalidomide/bortezomib/dexamethasone; VCD, bortezomib/cyclophosphamide/dexamethasone; VRD, bortezomib/lenalidomide/dexamethasone; VTD, bortezomib/thalidomide/dexamethasone; ⩾ VGPR, very good partial response or better. Response rates and selected toxicities of induction therapies for newly diagnosed multiple myeloma. Numbers/data are based on published literature and abstracts. aNumber of cycles after which response rates shown were assessed; IT could be continued. bIncluded were any AE grade ⩾ 3or⩾2 for infections, cardiac disorders, neuropathy and thromboembolic events. AEs with a lower CTCAE grade were not recorded. cAE numbers shown also include AEs beyond the hence indicated number of IT cycles for response assessments, as indicated treatment could continue in these studies. dLeukocyto- and/or neutropenia.

these previous studies included rather small numbers of patients, achieved an ORR between 85 and 100% and ⩾ VGPR rates HDM/ASCT was not necessarily part of the first-line treatment and between 51 and 87%.5,33,34 Similarly, CRD yielded an ORR/ ⩾ VGPR IT or maintenance treatment could be applied continuously. rate of 98/58% after a median of 12 cycles.37 Whether p.o. or i.v. cyclophosphamide should be applied Of note, many of these studies permitted the continuation of IT remains difficult to determine. The applied cyclophosphamide or consolidation/maintenance treatment beyond three to six IT doses and intensities vary between the investigated VCD regimen cycles without the need for frontline or later HDM/ASCT.5,17,33,34,37 and no randomized studies exist. However, the split p.o. It is therefore difficult to compare the results and response rates of 5,14 application of cyclophosphamide might increase efficacy these studies to our present trial. In addition, PFS and OS results through a steady distribution and increased total cyclopho- from our trial remain to be seen. sphamide dose in comparison to the high blood levels achieved It should be noted that despite the high efficacy of VTD, VRD with a single i.v. injection. Further studies are required to answer and CRD, there are no data available on whether the administra- these questions. tion of two novel agents in first-line therapy has an adverse effect Combinations of an IMiD and a proteasome inhibitor (PI), on the second-line/third-line PFS and whether OS is improved in namely bortezomib/dexamethasone with either thalidomide (VTD) comparison to IT/consolidation therapies containing either an PI, or lenalidomide (RVD33,34 or VRD5) and carfilzomib/lenalidomide/ PI/alkylator or an IMiD (and spare an IMiD or PI for relapse). This is dexamethasone (CRD) are progressively used as IT. supported by the EVOLUTION trial, which demonstrates neither Three phase III trials investigating VTD IT (three to six cycles), ⩾ PFS nor OS differences between VRD and VCD/VCD-mod-treated reported higher ORR (85, 93 and 88%) and VGPR rates (60, 62 5 38 and 49%)4,17,35 compared to both IT administered in the present cohorts. Moreover, recent data from Reeder et al. demonstrate study (Table 5). No prospective trials have compared VCD versus an excellent 5-year OS of 70% for VCD-treated patients. VTD IT. The addition of cyclophosphamide to VTD, however, did Furthermore, two phase III trials investigating VTD versus not improve response rates but increased toxicity.36 bortezomib/dexamethasone or a bortezomib/dexamethasone/ RVD/VRD has been investigated in three phase I/II trials with an alkylator-containing regimen found no PFS/OS and no OS 4,35 ORR/ ⩾ VGPR rate of 73/32%,5 75/11%33 and 93/58%34 after three differences. Prospective trials with a long-term follow-up and to four cycles (Table 5). These response rates are, except for one comparable settings (for example, comparable IT/consolidation study, lower compared to the present VCD regimen. However, cycle number and rate of upfront HDM/ASCT) are therefore with increasing cycle numbers, including upfront HDM/ASCT and/ needed to determine the role of PI/alkylator versus PI/IMiD or consolidation/maintenance therapies, RVD/VRD regimens induction/consolidation therapies.

Leukemia (2015) 1721 – 1729 © 2015 Macmillan Publishers Limited VCD is favorable to PAd as induction therapy in myeloma EK Mai et al 1727 Likewise, studies evaluating VRD and CRD included relatively In the VCD group, the higher dose intensity of dexamethasone small patient numbers. Results from randomized phase III trials are (VCD 106 mg/week versus PAd 60 mg/week; Figure 2) and pending, but these regimens are cost intensive in comparison to a cyclophosphamide, both immunosuppressive agents, might have PI/alkylator-containing regimen such as VCD. conferred protection against the inflammatory component of The lower ORR/ ⩾ VGPR rates achieved with PAd in our present bortezomib-induced peripheral neuropathy.39,40 The shorter study (72/34%) when compared to PAd used in our previous scheduled bortezomib treatment-free time in the VCD arm (VCD HOVON65/HD4 study7 (78/42%), may be due to the reduced dose 10 days versus PAd 17 days; Figure 2) appears not to have offset of dexamethasone (MM5: 240 mg/cycle and HOVON65/HD4: this effect, though a reduced dose intensity of bortezomib is 480 mg/cycle). reported to result in lower neuropathy rates.32 Perhaps, the The ORR and ⩾ VGPR rates observed in our current trial and addition of doxorubicine to bortezomib might further enhance perhaps PFS might be increased upon application of more cycles. the neurotoxicity of PAd compared to VCD. Therefore, we recommend, according to recent guidelines,1,2 at In the prospective, randomized MMY-3012 trial, Moreau et al. least four cycles of VCD as pretransplantation therapy. demonstrated non-inferiority of s.c. versus i.v. bortezomib regard- The clinical value of the not significantly different ORR between ing efficacy and PFS in relapsed/refractory MM. They also the VCD and PAd IT slightly favoring the VCD IT cannot be observed fewer AE and neurotoxicity/bortezomib-induced periph- determined yet. Different cycle lengths and bortezomib dose eral neuropathy in the s.c. group.41 Based on these results, we intensities as well as the different dexamethasone doses (VCD changed the route of administration of bortezomib in the MM5 320 mg/cycle and PAd 240 mg/cycle; Figure 2) might influence trial from i.v. to s.c. The number of s.c. treated patients was comparability of efficacies in our current trial. Furthermore, an balanced between the PAd and VCD groups. earlier response assessment due to a shorter cycle length in the In a recent subgroup analysis of the MM5 trial, comparing i.v. VCD group might underestimate response in comparison to the versus s.c. application of bortezomib during IT, we demonstrated PAd group, since the half-life time of monoclonal immunoglobu- that ORR was not affected by i.v. or s.c. application of bortezomib. lins can be up to 21 days. Further, AEs were more frequently observed in i.v. treated patients We observed a significantly higher PD rate in the PAd group as well as neuropathy rates in the third cycle of IT.42 Together with (PAd: 12 patients/4.8% versus VCD: 1 patient/0.4%; P = 0.003). In limited data from other centers incorporating s.c. bortezomib in the HOVON65/GMMG-HD4 trial,7 the PD rate during the PAd IT VCD or VTD regimen,43 our data suggest that efficacy of s.c. was 1.0%. Rates of PD in trials assessing VCD IT were 0.0%5 and bortezomib is retained in newly diagnosed MM. To date, no 2.3%.16 In the current trial, 91.7% of the patients with PD in the comparison between s.c. and i.v. bortezomib in large clinical trials PAd group had either RI at diagnosis or adverse cytogenetics. In of newly diagnosed MM have been published. the VCD group, there was no PD observed in these subgroups. It should be noted that profound changes in the NCI CTCAE Among patients with RI in the PAd group, 24.3% had either PD classification of neuropathy from version 3.0 (2006, applied in the (10.8%) or stable disease (13.5%), whereas only 5.1% had stable HOVON65/GMMG-HD4 trial7) to version 4.0 (2010, applied in the disease and none had PD in the VCD group. Gain of 1q21, MM5 trial) affect comparability of neuropathy grading. However, displaying an adverse prognostic factor,22 was present in all neuropathy rate in the PAd group decreased in comparison to the patients with adverse cytogenetics in the PAd group incurring PD PAd in the HOVON65/GMMG-HD4 trial (24%)7 and is similar to a (data not shown). study using bortezomib/liposomal doxorubicin/dexamethasone Together with the improved ORR, our results provide support (Table 5).6 The increased familiarity of study site attending for the use of VCD as an IT in patients with initial RI and adverse physicians with emerging bortezomib-induced peripheral neuro- cytogenetics. However, follow-up data of this trial should be pathy may have contributed to the low neuropathy rates in the awaited to further interpret the impact of the two different IT for VCD group and the decreased rates in PAd (MM5) versus PAd patients with adverse prognostic factors. (HOVON65/GMMG-HD4) group as observed previously.44 The rates of leukocytopenia/neutropenia were significantly The increased number of thromboembolic AEs and SAEs in the higher in the VCD group compared to the PAd group (35.2 versus PAd group demonstrates the well-described pro-thrombotic 11.3%, Po0.001). The scheduled total dose of dexamethasone per activity of doxorubicin.45,46 cycle was higher in the VCD than the PAd arm (320 versus 240 mg; Cardiotoxic events were rarely observed with either IT regimen Figure 2). This did, however, not translate into higher infection and completely resolved in all but two cases. rates or infection-related SAEs (Table 3). In this study, we aimed at The higher total SAE numbers might have resulted from the reducing the infection rate (CTCAE ⩾ 2°) of 49% as seen with the prolonged duration of treatment in the PAd group. In addition, the 7 use of PAd in the HOVON65/GMMG-HD4 trial by lowering the VCD regimen is easier to deliver than the PAd regimen, with only a total dexamethasone dose. As intended, the rate fell to 24.6% in single infusion per cycle. the PAd group. The favorable toxicity profile of VCD would support the use of Cyclophosphamide is the main cause for neutropenia observed more than three cycles, for example, four to six, to further improve with VCD. The rates of leukocytopenia/neutropenia in those who pretransplantation response rates and PFS.5,14,36 received the VCD regimen were comparable to some other In summary, the MM5 trial demonstrates that VCD IT is not 5,16 14 studies. The study from Reeder et al. using a cycle length of inferior to PAd IT in terms of achieving ⩾ VGPR rates. Additional four weeks and p.o. cyclophosphamide observed lower rates of analyses revealed a trend toward higher ORR. PD rates in the VCD neutropenia (13%). Perhaps, splitting of cyclophosphamide doses group were lower, especially in patients with gain of 1q21 and RI at can reduce the depth of leukocytopenia/neutropenia. Therefore, a diagnosis. Despite higher rates of leukocytopenia/neutropenia, weekly application of cyclophosphamide p.o. appears favorable which did not translate into increased infection rates, VCD has a 5,14 and safe. favorable toxicity profile in terms of the total numbers of SAEs Neuropathy occurred more frequently in the PAd when during IT, neuropathy rates and thromboembolic events. VCD is compared to the VCD group (14.9 versus 8.4%, P = 0.03). The therefore an established standard IT in newly diagnosed transplant- applied doses of bortezomib did not differ between the two arms. eligible MM and is recommended to be preferred over PAd. Similarly, low neuropathy rates as observed in our trial were reported by other trials investigating VCD (Table 5).5,14,16 Reeder et al.32 demonstrated that neuropathy rates can even be CONFLICT OF INTEREST decreased without a loss of efficacy by a weekly (versus biweekly) EKM received travel grants from Janssen-Cilag, Celgene, Onyx and Mundipharma. JD application of bortezomib. received honoraria from Janssen-Cilag, Celgene, Roche and GSK, and compensation

© 2015 Macmillan Publishers Limited Leukemia (2015) 1721 – 1729 VCD is favorable to PAd as induction therapy in myeloma EK Mai et al 1728 for his consulting/advisory roles for Janssen-Cilag, Roche and GSK. MMu received a single-centre experience in 211 patients. Bone Marrow Transplant 2006; 37: honoraria from Celgene as well as travel grants from Mundipharma and Celgene. DH 731–737. received compensation for his consulting/advisory role from Celgene and also 12 Alvares CL, Davies FE, Horton C, Patel G, Powles R, Sirohi B et al. Long-term received research funding from Novartis and Celgene. JH received honoraria from outcomes of previously untreated myeloma patients: responses to induction Celgene and Janssen-Cilag. IGHS-W received compensation for his consulting/ chemotherapy and high-dose melphalan incorporated within a risk stratification advisroy role from Janssen-Cilag. KW received honoraria from Celgene, Janssen-Cilag model can help to direct the use of novel treatments. Br J Haematol 2005; 129: and Onyx; received compensation for her consulting/advisory role at Celgene, 607–614. Janssen, Onyx and Noxxon; and also received research funding from Celgene and 13 Khan ML, Reeder CB, Kumar SK, Lacy MQ, Reece DE, Dispenzieri A et al. A com- travel grants from Celgene and Janssen-Cilag. CS received honoraria and parison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/ compensation for his consulting/advisory role from Janssen-Cilag and Celgene. HS dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly received honoraria from Celgene, Janssen-Cilag, Chugai, Novartis, Mundipharma, diagnosed multiple myeloma. Br J Haematol 2012; 156:326–333. TEVA, Roche, Binding Site and BMS; received compensation for his consulting/ 14 Reeder CB, Reece DE, Kukreti V, Chen C, Trudel S, Hentz J et al. advisory role at Celgene, Janssen-Cilag, BMS, Novartis and TEVA; received research Cyclophosphamide, bortezomib and dexamethasone induction for newly funding from Celgene, Janssen-Cilag, Novartis and BMS; and also received travel diagnosed multiple myeloma: high response rates in a phase II clinical trial. grants from Celgene, Janssen-Cilag, Novartis, TEVA and Roche. HG received honoraria Leukemia 2009; 23: 1337–1341. from Janssen-Cilag, Celgene, Novartis, Onyx and Millennium; has a consulting/ 15 Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ. The combination of advisory role at Janssen-Cilag, Celgene, Novartis, Onyx and Millennium; received cyclophosphamide, velcade and dexamethasone (CVD) induces high response compensation as a member of the speakers bureau from Janssen-Cilag, Celgene, rates with comparable toxicity to velcade alone (V) and velcade plus Novartis, Onyx, Millennium and Chugai; and also received research funding from dexamethasone (VD). Haematologica 2007; 92:1149–1150. Janssen-Cilag, Celgene, Novartis and Chugai. UB, CK, MH, IWB, AJ, BS, TH, MMe, BH-D, 16 Einsele H, Liebisch P, Langer C, Kropff M, Wandt H, Jung W et al. Velcade, intra- AS, MSR, KN, H-WL, MZ and CG declare no conflict of interest. venous cyclophosphamide and dexamethasone (VCD) induction for previously untreated multiple myeloma (German DSMM XIa Trial). Blood 2009; 114: 59a–60a. Abstract # 131. ACKNOWLEDGEMENTS 17 Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M et al. Bortezomib We thank the investigators, the study nurses and all the members of the study teams with thalidomide plus dexamethasone compared with thalidomide plus at the participating GMMG trial sites, the teams of the myeloma research laboratory, dexamethasone as induction therapy before, and consolidation therapy after, the FISH laboratory and the central laboratory at the University Hospital Heidelberg, double autologous stem-cell transplantation in newly diagnosed multiple 376 – the coordination centers for clinical trials (KKS) in Heidelberg and Leipzig, the myeloma: a randomised phase 3 study. Lancet 2010; : 2075 2085. fi pharmacies at the trial sites and, most importantly, the participating patients and 18 Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk strati cation and 23 – their families. This study was supported by grants from Celgene, Janssen-Cilag, response assessment of multiple myeloma. Leukemia 2008; :3 9. 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