Efficacy of VRD (Bortezomib, Lenalidomide, and Dexamethasone) Consolidation Therapy and Maintenance Therapy with Immunomodulatory Agents (Thalidomide or Lenalidomide) after Autologous Peripheral Blood Stem Cell Transplantation in the Era of Bortezomib-Containing Induction Therapy: A Single Institution Experience

Research Article

Ann Hematol Oncol. 2019; 6(5): 1249.

Efficacy of VRD (Bortezomib, Lenalidomide, and Dexamethasone) Consolidation Therapy and Maintenance Therapy with Immunomodulatory Agents (Thalidomide or Lenalidomide) after Autologous Peripheral Blood Stem Cell Transplantation in the Era of Bortezomib-Containing Induction Therapy: A Single Institution Experience

Tanimura A¹*, Hirai R¹, Nakamura M², Takeshita M¹, Togano T², Sekine R², Hagiwara S³ and Miwa A¹

¹Department of Hematology, Tokyo-Kita Medical Center, Tokyo, Japan

²Division of Hematology, National Center for Global Health and Medicine, Tokyo, Japan

³Division of Hematology, Tokyo Women’s Medical University, Tokyo, Japan

*Corresponding author: Akira Tanimura, Department of Hematology, Tokyo-Kita Medical Center. 4-17-56 Akabanedai, Kita-Ku, Tokyo, Japan

Received: March 18, 2019; Accepted: April 19, 2019;Published: April 26, 2019


Autologous Stem Cell Transplantation (ASCT) for Newly-Diagnosed Multiple Myeloma (NDMM) has underwent recent improvements in combination with novel agents-containing induction and post-ASCT therapy. Since the approval of bortezomib for NDMM in Japan, we conducted the following regimen (BD arm) in transplant-eligible patients with NDMM: BD (bortezomib and dexamethasone) induction, ASCT, VRD consolidation, and maintenance therapy with Immunomodulatory Agents (IMIDs). The efficacy and safety of the BD arm were compared to those of patients treated with VAD (vincristine, doxorubicin, and dexamethasone) induction followed by ASCT (VAD arm) retrospectively. Thirty-three patients were treated with the BD arm, and 92 patients with the VAD arm. Thirty-one patients in the BD arm proceeded to ASCT. Thereafter, 23 and 17 patients received VRD consolidation and IMIDs maintenance therapy, respectively. The rates of complete response (CR)/=Very Good Partial Response (VGPR) after ASCT, consolidation, and maintenance therapy were 43%/61%, 76%/90% and 87%/93%, respectively. The response rates after ASCT did not differ between BD and VAD arms. The median progression-free survival (PFS) was 46.2 months (BD arm) and 30.6 months (VAD arm) (p=0.0106). The median Overall Survival (OS) was not-reached (BD arm) and 90.6 months (VAD arm) (p=0.0172).VRD consolidation and IMIDs maintenance therapies improved disease status after ASCT and prolonged PFS and OS.

Keywords: Multiple myeloma; Consolidation therapy; Maintenance therapy


ASCT/SCT: Autologous Stem Cell Transplantation; NDMM: Newly-Diagnosed Multiple Myeloma; MM: Multiple Myeloma; BD: Bortezomib and Dexamethasone; VRD: Bortezomib; Lenalidomide; and Dexamethasone; IMIDs: Immunomodulatory Drugs; PFS: Progression-free Survival; OS: Overall Survival; VAD: Vincristine; Doxorubicin, and Dexamethasone; HD-CY: High Dose Cyclophosphamide; PR: Partial Response; VTD-PACE: Bortezomib; Thalidomide; Dexamethasone; Cis-Platin; Doxorubicin; Cyclophosphamide; and Etoposide; VGPR: Very Good Partial Response; CR: Complete Response; AE: Adverse Events; SPM: Second Primary Malignancy; MRD: Minimal Residual Disease; iFISH: Interphase Fluorescence in Situ Hybridization; DS: Durie-Salmon Stage; ISS: International Scoring System; ASCH/SCH: Autologous Stem Cell Harvesting; SD: Stable Disease, PD: Progressive Disease; NC: No Change; SCR: Stringent Complete Response


Autologous Hematopoietic Stem Cell Transplantation (ASCT) prolongs the survival of patients with multiple myeloma (MM) who are up to 65 years of age, compared to conventional chemotherapy [1,2]. Because significant survival improvements can be afforded with new agents (proteasome inhibitors, immunomodulatory drugs, his tone deacetylase inhibitors and antibodies), up-front ASCT combined with new agent-containing induction therapies has become standard and the most important treatment option for patients with MM [3,4].

the introduction of new agents, VAD therapy (vincristine, doxorubicin, and dexamethasone) was the standard induction therapy for patients who were ASCT-eligible. Since the advent of bortezomib, bortezomi/dexamethasone-containing induction therapies became standard [3-9]. Because improvements in induction therapy response rate were projected to the prolong survival after ASCT, the effectiveness of 3-drug or 4-drug induction regimens containing bortezomib and IMIDs have been investigated.

Many studies of post-ASCT therapies (consolidation and/ or maintenance therapy) that contain new agents have been reported. Several reports indicate Progression-Free Survival (PFS) prolongation due to consolidation therapy [10-12]. However, only a few studies have shown overall survival benefits [13]. In maintenance therapy, there are concerns increased Second Primary Malignancy (SPM) frequencies after the long long-term use of Lenalidomide after high-dose and standard-dose melphalan [14-18]. With regard to the combination of agents with post-ASCT therapies, the patients who are suitable for therapy administration and the appropriate therapy durations await further determinations.

Our institute administered BD (bortezomib and dexamethasone) induction therapy, high-dose melphalan with stem cell support, VRD (bortezomib, lenalidomide and dexamethasone) consolidation therapy, and IMIDs maintenance therapy for the symptomatic and fit patients with MM patients who were under 66 years old. Here, we report the outcomes of 33 consecutive patients who received this regimen series and compare our results with those of a historical control study of VAD induction therapy followed by ASCTs from our institute.

Materials and Methods

Study design

This study was conducted at a single center, retrospectively. Response rates after BD induction therapy, stem cell harvesting by high dose cyclophosphamide + G-CSF, ASCT with high-dose melphalan, VRD consolidation therapy, and IMIDs maintenance therapy were accessed. The response rates, Progression-Free Survival (PFS) and Overall Survival (OS) of this study group (BD arm) were compared with those of a historical control group (VAD arm) who previously received VAD induction and ASCT in the same institute.


Patients were 65 years of age or younger, with newly diagnosed myeloma and without severe infections, uncontrolled diabetes, or severe organ dysfunctions. Patients were consecutively treated as candidates for ASCT in our hospital. From December 2009, these patients received BD induction therapy, high dose cyclophosphamidecontaining stem cell harvesting regimens (HD-CY + G-CSF), and high-dose melphalan supported with autologous hematopoietic stem cells, followed by VRD consolidation and IMIDs maintenance therapies. The historical control group was composed of patients, who had been treated in our hospital from January 2000 to November 2009 and received VAD therapy, HD-CY + G-CSF, or G-CSF alone harvesting regimens and ASCT, but did not receive planed post- ASCT therapy.


BD arm: Four cycles of tri-weekly administration of bortezomib (1.3 mg/m2, subcutaneous injection on days 1, 4, 8, and 11) combined with oral dexamethasone (20mg, on days 1, 2, 4, 5, 8, 9, 11, and 12) were administered. The HD-CY containing regimen consisted of 2 doses of 2g/m2 cyclophosphamide, which were intravenously injected on 2 continuous days, followed by G-CSF. High dose melphalan (200mg/m2) was administered intravenously, divided into 2 days, and autologous stem cells were infused 2 or 3 days after the completion of melphalaninjection. As consolidation therapy, four cycles of triweek VRD administration (subcutaneously injected bortezomib (1.0mg/m2) on days 1, 4, 8, and 11, oral lenalidomide (15mg) days1- 14, and oral dexamethasone (20mg) days 1, 2, 4, 5, 8, 9, 11, and 12) were given. For IMIDs maintenance therapy, lenalidomide (5-10mg) or thalidomide (100mg), which were preferentially chosen by the attending physician, were given until Progressive Disease (PD) or unacceptable adverse events.

VAD arm (the historical control arm): Three or four cycles of 35- days of VAD, which consisted of continuous intravenous infusion of vincristine (0.4mg) days 1-4, doxorubicin (9mg/m2) days 1-4, and oral dexamethasone (40mg) days 1-4, 9-12, and 17-20) were administered. As a harvesting regimen, the HD-CY + G-CSF regimen was given from January 2000 to June 2009, and the G-CSF alone regimen was adapted from July 2009 to November 2009. ASCT was performed in the same way as described above for the BD arm. No planed posttransplant therapy was administered to the patients in the VAD arm.


All patients from each arm provided written informed consent, which was performed according to the Helsinki Declaration principles.


The response rates after induction therapy, harvesting, and ASCT, and the survivals rates in the BD arm were compared with those of the VAD arm. The efficacy and toxicity of consolidation and maintenance therapies were evaluated in the BD arm.


Differences between groups were evaluated using the Fisher’s exact test for categorical variables and the Mann-Whitney U-test for continuous variables. PFS was calculated as the time from treatment initiation to the first documentation of PD or death due to any cause. OS was calculated as the time from treatment initiation to death.PFS and OS were calculated using the Kaplan-Meier method. To evaluate the influence of the factors upon survival, the log-rank test was used.

All statistical analyses were performed with EZR (Saitama Medical Centre, Jichi Medical University), which is a graphical user interface of R (The R Foundation for statistical Computing, version 3.0.2) [19].


Patient characteristics

Thirty-three and 92 patients in BD and VAD arms, respectively, were analyzed. There were no significant differences in patient backgrounds at the time of induction therapy initiation between both groups, except for the levels of hemoglobin and calcium, which were higher in the BD group than in the VAD group (Table 1).