A Randomized Phase 2 trial of Bortezomib–Dexamethasone versus Bortezomib–
Dexamethasone With Added Cyclophosphamide or Lenalidomide in Multiple
Myeloma Patients Achieving Stable Disease After Four Cycles of Bortezomib–
Dexamethasone Administered as Second-Line Treatment
Authors: Meletios A. Dimopoulos, 1 Huw Roddie, 2 Meral Beksac, 3 Lotfi Benboubker, 4
Romualdas Jurgutis, 5 Christian Langer, 6 Javier de la Rubia, 7 Luis Felipe Casado, 8 Kazimierz
Kuliczkowski, 9 Lena Macukanovic-Golubovic, 10 Thierry Facon 11
Affiliations:
1 Department of Clinical Therapeutics, Alexandra Hospital, University of Athens,
School of Medicine, Athens, Greece
2 Western General Infirmary, Hematology Department, Edinburgh, EX4 2HU, UK
3 Ankara Universitesi Tip Fakultesi Hastanesi, Ankara 6590, Turkey
4 Centre Régional de Cancérologie Henry Kaplan CHRU de Tours, Hôpital
Bretonneau, Service Hématologie et Thérapies Cellulaires, Tours Cedex 37044,
France
5 Klaipeda Seamen's Hospital, Haematology Department, Klapeida 92288, Lithuania
6 Medizinische Universitatsklinik, Abteilung Innere Medizin III, Ulm 89081, Germany
7 Hospital La Fe, Hematology Department, Valencia 46009, Spain
8 Hospital Virgen de la Salud de Toledo, Hematology Department, Toledo 45006,
Spain
9 Katedra i Klinika Hematologii , Nowotworow Krwi i Transplantacji Szpiku,
Haematology Department, Wroclaw 50-367, Poland
10 Clinical Center Nis, Clinic for Hematology, Nis 18000, Serbia
11 CHRU de Lille Hôpital Claude Huriez, Service des Maladies du Sang, Lille Cedex
59037, France
Bortezomib (Velcade
®
) plus dexamethasone (Vel/Dex) is known to be effective and well tolerated in patients with multiple myeloma (MM). As demonstrated in the frontline setting, the addition to Vel/Dex of cyclophosphamide (VCD) or lenalidomide
(Revlimid
®
; VRD) may lead to improved efficacy, but may be associated with increased toxicities; however, few studies have prospectively assessed Vel/Dex as second-line therapy. This randomized, open-label, parallel-group, phase 2 study in patients who have relapsed after or are refractory to primary MM therapy is designed to evaluate the safety and efficacy of an additional 4 cycles of Vel/Dex, VCD, or VDR

in patients achieving stable disease (SD) after 4 cycles of Vel/Dex. Bortezomibnaïve p atients aged ≥18 years, with measurable MM, KPS ≥60, life expectancy ≥6 months, adequate hematologic and hepatic function, and without grade ≥2 peripheral neuropathy (PN) received 4 3-week cycles of Vel/Dex (Vel 1.3 mg/m 2 IV on days 1,
4, 8, and 11, and Dex 20 mg PO on days 1, 2, 4, 5, 8, 9, 11, and 12). Patients then received a further 4 cycles of therapy as follows: patients achieving at least a partial response (PR) received Vel/Dex; patients with SD underwent central randomization to receive Vel/Dex, VCD, or VRD; patients with progressive disease (PD) discontinued treatment. Here we report efficacy and renal function improvement in patients who had the opportunity to complete the initial 4 cycles of Vel/Dex as of April
2009, and safety data for patients who received at least 1 dose of study drug.
Response was assessed by IMWG uniform response criteria based on measurement of serum and urine M-protein prior to treatment on day 1 of each cycle, at end of treatment, and monthly thereafter. Renal function as defined by calculated glomerular filtration rate (GFR; Cockcroft –Gault formula) was assessed prior to treatment on day
1 of cycles 1 –5. Adverse events (AEs) were graded using NCI CTCAE v3.0. A total of
122 patients have been enrolled; by data cut-off (July 21 2009), 24 (20%) had not completed a single treatment cycle and are excluded from the safety population
(N=98). Eighteen had received <4 cycles at data cut-off. Of the remaining 80 who were eligible for response, 63 had completed 4 cycles, 6 discontinued prior to completing 4 cycles (due to PD in 3 patients, death in 1, drug-related AEs in 2), 9 were not under treatment at data cut-off, and 2 had died. Their median age was 62 years (range 34 –86), 55% were male, 21.3% had KPS 
70; median time from prior therapy was 18.6 months. Response rate in the efficacy population was 41/80 (51%) after 4 cycles, including 8% CR. Median times to first and best response were 37 and
57 days, respectively. Patient renal function (by GFR) at baseline, median improvement in GFR, and responses achieved by the 10 patients in whom GFR improved by at least one renal function group are shown in the Table. Among the 98 patients who received at least one treatment dose, mean cumulative doses of bortezomib and dexamethasone were 14.6 mg/m 2 (4.9, 4.5, 4.4, and 4.3 mg/m 2 in cycles 1 –4) and 478 mg (151.8, 145.6, 145.4, and 144.0 mg for cycles 1–4), respectively. Most patients (90%) reported AEs, including 39% with grade 3/4 AEs and 23% with serious AEs, within the first 4 cycles. The most common grade 3/4 AEs included thrombocytopenia (13%), anemia (7%), and pneumonia (6%). AEs resulting in dose reductions/treatment stop were seen in 21%/10% of patients. Incidence of sensory PN and PN was 29% (3% grade 3/4); most PN events were reversible, with

68% resolving within a median 53 days. Updated efficacy and safety data for the first
4 cycles of Vel/Dex for all patients enrolled by July 31 will be presented.
Table: Improvement in renal function (as measured by GFR)*
Renal function group at baseline, n
†
<15 mL/min
15 –<30 mL/min
30
–<60 mL/min

60 mL/min
3
6
33
36
Median GFR (median improvement from previous cycle), mL/min
At baseline
After cycle 1
After cycle 2
After cycle 3
58.3
64.4 (4.8)
68.9 (2.9)
68.6 (9.9)
After cycle 4
Renal improvement by at least 1 grade, n (response achieved)
<15 to 15 –<30 mL/min
15 –<30 to 30–<60 mL/min
30 –<60 to 
60 mL/min
73.5 (9.4)
10
1 (1 CR)
1 (1 PR)
8 (2 CR, 1 VGPR, 3 PR, 2
SD)
*1 patient only had a baseline GFR measurement and was not included in the renal analysis
†
1 patient had no baseline GFR measurement
Supplementary information for submission:
Contact information for corresponding author:
Meletios A. Dimopoulos
Department of Clinical Therapeutics, Alexandra Hospital, University of Athens,
School of Medicine, Athens, Greece.
Tel: +30210-3381541
Fax: +30210-3381511
Email: mdimop@med.uoa.gr
Review category: 653. Myeloma – Therapy, Excluding Transplantation
Certification for human subjects: Agree

Interim analysis of clinical trial (per protocol): Not applicable
Presentation format preference: No preference
Publication preference: Publish in Blood if not accepted for presentation
Special consideration (previously published work): No
Travel and merit award application?: No
Abstract of ‘Clinical Interest’?: YES
First-time submitter to ASH?: No
Name of sponsor (ASH member): Meletios A. Dimopoulos