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Keywords:

  • autologous transplantation;
  • myeloma;
  • bortezomib;
  • arsenic trioxide;
  • melphalan

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

BACKGROUND:

Bortezomib is active for newly diagnosed and relapsed multiple myeloma, and it has synergistic activity with melphalan. The authors of this report conducted a randomized trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA), and melphalan.

METHODS:

Among 60 patients who enrolled between October 2006 and September 2007, 58 patients underwent autologous transplantation with a preparative regimen of melphalan 200 mg/m2 intravenously, AA 1000 mg daily intravenously for 7 days, and ATO 0.25 mg/kg intravenously for 7 days. Patients were randomized to receive no bortezomib (Group 1), bortezomib 1 mg/m2 × 3 doses (Group 2), and bortezomib 1.5 mg/m2 × 3 doses (Group 3). Primary endpoints were complete response (CR), grade IV toxicity, and 90-day treatment-related mortality (TRM). Secondary endpoints were progression-free survival (PFS) and overall survival (OS).

RESULTS:

The median follow-up of all surviving patients was 36 months (range, 20-43 months). The CR rates in Groups 1, 2, and 3 were 20%, 10%, and 10%, respectively. Grade 3 and 4 nonhematologic toxicities and TRM were comparable. The median OS was not reached in the groups, whereas the median PFS in Groups 1, 2, and 3 was 17.8 months, 17.4 months, and 20.7 months, respectively. PFS and OS were significantly shorter in patients who had high-risk cytogenetics (P = .016 and P = .0001, respectively) and relapsed disease (P = .0001 and P = .0001, respectively) regardless of the treatment group.

CONCLUSIONS:

Adding bortezomib to a preparative regimen of ATO, AA, and high-dose melphalan was safe and well tolerated in patients with multiple myeloma. There was no significant improvement in the CR rate, PFS, or OS in the bortezomib groups. Cancer 2012;. © 2011 American Cancer Society.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Multiple myeloma (MM) is the second most common hematologic malignancy and is responsible for approximately 1% of all cancer-related deaths in Western countries.1 Current treatment options include induction therapy followed by consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) in eligible patients.2 At least 2 randomized trials have demonstrated that auto-HCT results in a significantly prolonged event-free survival and overall survival (OS) compared with conventional chemotherapy in patients with MM.3, 4 Although auto-HCT is safe with a transplantation-related mortality (TRM) rate of <2%, it is associated with a continuing risk of disease relapse.5 Attempts at improving outcomes with more intensive regimens have not been successful.5-8 Thus, further exploration of novel preparative regimens is warranted.

Bortezomib, a proteasome inhibitor, is an active agent in newly diagnosed as well as relapsed and refractory MM. Several large clinical trials have demonstrated the safety and efficacy of bortezomib in MM.9-11 In vitro exposure of melphalan-resistant myeloma cell lines to noncytotoxic concentrations of bortezomib increased sensitivity to melphalan.12, 13 In 1 preclinical study, subtoxic concentrations of bortezomib potently sensitized MM cell lines and patient cells to the DNA-damaging activity of melphalan, including cells that were resistant to melphalan.13 In addition, combining bortezomib with oral melphalan produced acceptable toxicity and encouraging responses in patients who were resistant to either agent alone.14

Bortezomib has been used in combination with high-dose melphalan as part of conditioning regimens in at least 2 clinical trials.14, 15 We previously demonstrated the feasibility of combining arsenic trioxide (ATO) with ascorbic acid (AA) and high-dose melphalan in patients with relapsed MM.16 This combination was well tolerated and resulted in a response rate of 87%. On the basis of these data, we conducted a randomized phase 2 clinical trial assessing the safety and efficacy of bortezomib in combination with high-dose melphalan, AA, and ATO. We postulated that the combination of these antimyeloma drugs would improve the complete response (CR) rate, which is a surrogate for improved disease-free survival and OS.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patients

Patients were enrolled from October 2006 to September 2007. The inclusion criteria were a diagnosis of MM, age ≤75 years, Zubrod performance status <2, left ventricular ejection fraction >40% with no uncontrolled arrhythmia or unstable cardiac disease, a corrected QT interval <470 milliseconds, adequate pulmonary function test results with no symptomatic pulmonary disease, serum bilirubin <2 times the upper limit of normal, and serum glutamic pyruvic transaminase <4 times the upper limit of normal with no evidence of chronic active hepatitis or cirrhosis. Other inclusion criteria were the absence of effusions or ascites >1 L before drainage, negative human immunodeficiency virus testing, a negative pregnancy test in a woman with child-bearing potential, and the willingness of the patient or guardian to provide informed consent.

Treatment Plan

Peripheral blood stem cells were mobilized and collected after granulocyte-colony–stimulating factor (G-CSF) alone or chemotherapy plus G-CSF according to standard institutional guidelines. Patients were randomized to 1 of the 3 treatment groups in a 1:1:1 ratio. Table 1 depicts the treatment schema. All patients received ATO 0.25 mg/kg intravenously on days −9 to −3 over 2 hours, AA 1000 mg intravenously on days −9 to −3 over 30 minutes, and melphalan 100 mg/m2 intravenously on days −4 and −3 over 30 minutes. The dose of ATO was administered after melphalan in all patients. Group 1 did not receive bortezomib and served as a control. Patients received supportive care according to established departmental guidelines. Patients received G-CSF 5 μg/kg daily from day +1 until the absolute neutrophil count (ANC) was 0.5 × 109/L for 2 consecutive days. Oral levofloxacin, acyclovir, and fluconazole were given for the duration of neutropenia. Blood products were given for hemoglobin levels <8 g/dL and platelet counts <20 × 109/L.

Table 1. Treatment Schemaa
TreatmentGroup 1Group 2Group 3
  • Abbreviations: IV, intravenous.

  • a

    Groups 1, 2, and 3 were randomized to receive no bortezomib, 1 mg/m2 bortezomib, and 1.5 mg/m2 bortezomib, respectively.

Melphalan   
 Dose100 mg/m2 IV100 mg/m2 IV100 mg/m2 IV
 ScheduleDays −4, −3Days −4, −3Days −4, −3
Ascorbic acid   
 Dose1000 mg IV1000 mg IV1000 mg IV
 ScheduleDays −9 to −3Days −9 to −3Days −9 to −3
Arsenic trioxide   
 Dose0.25 mg/kg0.25 mg/kg0.25 mg/kg
 ScheduleDays −9 to −3Days −9 to −3Days −9 to −3
Bortezomib   
 DoseNone1 mg/m21.5 mg/m2
 ScheduleDays −9, −6, −3Days −9, −6, −3

Response Criteria

The primary endpoints were CR, time to grade IV toxicity, and death. The secondary endpoints were response rate, progression-free survival (PFS), and OS. Toxicity was graded according to National Cancer Institute Common Terminology Criteria (version 3.1; Bethesda, Md). Engraftment was defined as an ANC of 0.5 × 109/L for 2 consecutive days. Response was defined according to the criteria of the International Myeloma Working Group.17 PFS was calculated from the date of auto-HCT to the date of disease progression or the time last known alive. OS was calculated from the date of auto-HCT to the date of death or time last known alive.

Prognostic Factors

High-risk cytogenetics and molecular characteristics were defined as: deletion 13 (del13) or hypodiploidy on conventional cytogenetics; and as translocation t(4;14), t(14;16), or del(17p) on conventional cytogenetics or fluorescence in situ hybridization.18

Statistical Analyses

Patient characteristics were summarized using the mean and standard deviation for numerical valued variables and frequencies with percentages for categorical variables. Differences in the distributions of patient characteristics between the 3 treatment groups and associations between variables were assessed using the Kruskal-Wallis test for numerical variables19 or generalized Fisher exact tests20, 21 for categorical variables. Unadjusted probabilities of OS and PFS were estimated using the method of Kaplan and Meier.22 The log-rank test23 was used to compare unadjusted OS and PFS between subgroups. Bayesian regression models24 were fit to assess the joint effects of patient covariates and treatment arms on both OS and PFS, and the best fitting model was chosen for each outcome from the exponential, Weibull, log-logistic, log-normal, and gamma distributions using Bayesian Information Criterion.25 In each multivariate regression model, the covariates included treatment arm, sex, race, age, disease stage, diagnostic status (defined by the 3 subgroups: first remission consolidation without progressive disease [PD] as a baseline group, no first remission consolidation without PD, and PD), cytogenetics (high risk or standard risk),26 and prior response category (PD, partial response/very good partial response [PR/VGPR], stable disease). For each model fit, we assumed that each parameter in the linear term followed a noninformative, normal prior with mean of 0 and variance of 10,000. All frequentist statistical analyses were carried out in R (The R Project for Statistical Computing, Vienna, Austria) and Bayesian computations in Open BUGS version 3.1.2 (Mathstat, Helsinki, Finland).27

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

Patients

From October 2006 to September 2007, 60 patients were assigned randomly to 3 treatment groups with 20 patients enrolled in each group. Table 2 summarizes the characteristics of the 60 patients enrolled in this study, including 58 patients who eventually underwent auto-HCT. One patient in treatment Group 3 developed deep venous thrombosis before completing the preparative regimen and was withdrawn from the study. A second patient in Group 1 developed pneumonia and sepsis before receiving high-dose melphalan and died 2 months later of multiorgan failure. The mean age (±standard deviation) of patients at the time of transplantation was 60 years (±6.5 years), 57 years (±6.1 years), and 63 years (±7.9 years) in treatment Groups 1, 2, and 3, respectively. The patients were well matched clinically, whereas high-risk cytogenetic abnormalities were present in 1 patient (5%) in Group 1, 4 patients (15%) in Group 2, and 4 patients (20%) in Group 3. Fifteen patients (25%) developed recurrent disease before auto-HCT (6 patients in Group 1, 6 patients in Group 3, and 3 patients in Group 3), and 6 patients had undergone previous auto-HCT. The median interval between diagnosis and auto-HCT was 12 months, 9 months, and 10 months in Groups 1, 2, and 3, respectively. Sixteen patients (6 patients in Group 1, 6 patients in Group 2, and 4 patients in Group 3) had >10% plasma cells in the bone marrow at the time they underwent auto-HCT.

Table 2. Descriptive Statistics for Categorical Variablesa
 No. of Patients (%)b 
VariableGroup 1Group 2Group 3TotalP
  • Abbreviations: ISS, International Staging System; PD, progressive disease; PR, partial response; SD, stable disease; VGPR, very good partial response.

  • a

    Each cell contains the number and percentage in each of the variable's subgroups.

  • b

    Groups 1, 2, and 3 were randomized to receive no bortezomib, 1 mg/m2 bortezomib, and 1.5 mg/m2 bortezomib, respectively.

Sex     
 Women12 (60)9 (45)6 (30)27 (45).184
 Men8 (40)11 (55)14 (70)33 (55) 
Race     
 Asian0 (0)1 (5)1 (5)2 (3).201
 Black1 (5)2 (10)5 (25)8 (13) 
 Mixed1 (5)4 (20)3 (15)8 (13) 
 Other0 (0)1 (5)0 (0)1 (2) 
 White18 (90)12 (60)11 (55)41 (68) 
ISS stage     
 I7 (35)2 (10)8 (40)17 (28).401
 II4 (20)5 (25)5 (25)14 (23) 
 III5 (25)6 (30)3 (15)14 (23) 
 Unknown4 (20)7 (35)4 (20)15 (25) 
High-risk cytogenetics     
 No19 (95)16 (80)13 (65)51 (85).166
 Yes1 (5)4 (20)4 (20)9 (15) 
Disease status at transplantation     
 First remission14 (70)14 (70)17 (85)45 (75).499
 Relapsed6 (30)6 (30)3 (15)15 (25) 
Response to last treatment before transplantation     
 PD3 (15)2 (10)0 (0)5 (8).292
 PR/VGPR16 (80)14 (70)18 (90)48 (80) 
 SD1 (5)4 (20)2 (10)7 (12) 
Bone marrow plasma cells     
 >106 (30)6 (30)4 (20)16 (27).99
 <1014(70)14 (70)16 (80)43 (73) 

Stem Cell Mobilization and Engraftment

Forty-nine patients (81%) were mobilized with G-CSF 10 μg/kg daily or with pegylated G-CSF alone given subcutaneously. Eleven patients (18%) with high tumor burden received chemotherapy and G-CSF 10 μg/kg daily using the modified CVAD regimen (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) to achieve cytoreduction and mobilization.28 The median CD34 cell dose in Groups 1, 2, and 3 was 4.2 × 106/kg, 4.1 × 106/kg, and 3.6 × 106/kg, respectively. All patients were engrafted with a median time to neutrophil engraftment (ANC >500/dL) of 10 days in each group, and there were no engraftment failures or delays in any of the 3 cohorts. The median time to a platelet count of >20 × 109/L was 10 days (range, 7-17 days), 11 days (range, 7-31 days), and 10 days (range 5-17 days), respectively, for the 3 groups.

Induction Therapy

In the 45 newly diagnosed patients who proceeded to auto-HCT to consolidate the initial response, the following induction regimens were used: thalidomide plus dexamethasone (14 patients), lenalidomide plus dexamethasone (12 patients), bortezomib plus dexamethasone (14 patients; 10 received had thalidomide, and 2 received lenalidomide added to the combination), and other (5 patients). None of the patients were in CR before auto-HCT because of the existing institutional practice of delaying the auto-HCT until a relapse occurred in patients who achieved a CR to induction. In the 15 patients who had relapsed disease at the time of auto-HCT, the initial induction therapies were thalidomide plus dexamethasone (6 patients); bortezomib plus dexamethasone (4 patients; 3 received thalidomide, and 1 had lenalidomide added to the combination); vincristine, doxorubicin, and dexamethasone (2 patients); and others (3 patients). Six patients with relapsed disease also received fractionated cyclophosphamide as salvage before proceeding to auto-HCT.

Treatment-Related Mortality and Adverse Events

One patient in Group 1 died of treatment-related causes within 90 days with an overall TRM rate of 1.6%, and the TRM rates were 5%, 0%, and 0% in Groups 1, 2, and 3, respectively, with no significant difference between the 3 groups (P = 1.0). Grade 3-4 toxicities were similar and were observed in 10 patients (50%) in Group 1 (mucositis in 3, tachycardia in 2, chest pain in 1, venous thrombosis in 1, dyspnea in 1, acute renal failure in 1, and pleural effusion in 1), 10 patients (50%) in Group 2 (mucositis in 2, tachycardia in 1, hypotension in 1, pneumonia in 1, and pulmonary edema in 1), and 12 patients (60%) in Group 3 (left ventricular dysfunction in 1, chest pain in 1, hypertension in 1, pulmonary edema in 2, pleural effusion in 1,dyspnea in 1, mucositis in 1, intestinal obstruction in 1, and elevated transaminases in 1) (Table 3). The most common adverse events were fluid retention (78%), nausea (65%), and diarrhea (63%). Grade 1 and 2 weight gain because of fluid retention was observed in 75%, 70%, and 90% of patients in Groups 1, 2, and 3, respectively.

Table 3. Grade 3 and 4 Adverse Events
 No. of Adverse Eventsa
Type of Adverse EventGroup 1Group 2Group 3
  • Abbreviations: GI, gastrointestinal.

  • a

    Groups 1, 2, and 3 were randomized to receive no bortezomib, 1 mg/m2 bortezomib, and 1.5 mg/m2 bortezomib, respectively.

Total grade 3 and 4251816
Cardiac   
 Grade 3514
 Grade 4110
Gastrointestinal   
 Grade 3442
Pulmonary   
 Grade 3124
 Grade 4200
Infection   
  Grade 3330
Grade 4010
Neutropenic fever   
 Grade 3565
Other   
 Grade 3200
 Grade 4201

Response

CR rates at 100 days after auto-HCT in Groups 1, 2, and 3 were 20%, 10%, and 10%, respectively. The combined CR + VGPR rates at 100 days in Groups 1, 2, and 3 were 60%, 60%, and 65%, respectively. The overall response rate at 100 days was 85%, 90%, and 95% for Groups 1, 2, and 3, respectively. Taken together, there was no significant difference in response rates between the 3 groups.

Maintenance

Only 10 of the 60 patients (4 in Group 1, 2 in Group 2, and 4 in Group 3) on the study received post-transplant maintenance therapy. Four patients received lenalidomide, 4 received thalidomide, 1 received curcumin, and 1 received dexamethasone. There was no significant difference in PFS or OS in patients who received maintenance therapy (P = .16 and P = .17, respectively).

Survival

The median follow-up in all surviving patients was 36 months (range, 20-43 months), and the median PFS in Groups 1, 2, and 3 was 19.5 months, 17.2 months, and 20.5 months, respectively (Fig. 1, top).The median OS has not been reached in any of the 3 groups (Fig. 1, bottom). No significant difference in PFS or OS was observed between the 3 treatment groups (P = .51 and P = .88, respectively).

thumbnail image

Figure 1. (Top) Progression-free survival and (Bottom) overall survival are illustrated according to randomization group.

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Prognostic Factors

We analyzed the impact of several patient characteristics on PFS and OS, including age, serum albumin, beta-2 microglobulin, lactate dehydrogenase level, disease stage, remission versus relapsed disease at auto-HCT, high-risk chromosomal abnormalities, prior autologous transplantation, and plasmacytosis (>10%) on bone marrow biopsy before auto-HCT. On multivariate analysis for both PFS and OS, only high-risk cytogenetics and relapsed disease at auto-HCT emerged as predictors of poor outcome (Table 4). Fifty-one patients had standard-risk cytogenetics, and 9 patients had high-risk cytogenetics based on published criteria.26 The median PFS for patients with high-risk cytogenetics versus patients with standard-risk cytogenetics was 5.7 months versus 21.8 months (P = .016), and the median OS for patients with high-risk cytogenetics versus patients with standard-risk cytogenetics was 15.9 months (P = .0001) (Fig. 2). Furthermore, the median PFS (P = .0001) and the median OS (P = .0001) were significantly shorter in patients with recurrent disease (Fig. 3). There was no significant difference in terms of response rate or PFS between growth factor versus chemotherapy plus growth factor mobilization. Thirty-5 of the 60 patients had received bortezomib as part of their induction or salvage therapy. There was no significant difference in CR + VGPR, PFS, or OS between those who received bortezomib before auto-HCT versus those who did not.

Table 4. Multivariate Analysis of Prognostic Factors for Progression-Free Survival and Overall Survival
 OSPFS
VariableMean±SD95% CIPr (Beneficial Effect)Mean±SD95% CIPr (Beneficial Effect)
  1. Abbreviations: CI, confidence interval; OS, overall survival; PFS, progression-free survival; SD, standard deviation.

Intercept1.02±0.340.38, 1.680.89±0.330.25, 1.55
Age−0.008±0.02−0.06, 0.04.381−0.02±0.02−0.07, 0.03.215
Race: Nonwhite0.11±0.33−0.52, 0.76.6270.19±0.35−0.48, 0.88.701
Bortezomib (1.0 mg) vs no bortezomib0.14±0.36−0.57, 0.82.6530.05±0.35−0.64, 0.72.56
Bortezomib (1.5 mg) vs no bortezomib0.21±0.38−0.53, 0.95.7160.1±0.38−0.64, 0.84.602
Sex: Men−0.05±0.32−0.68, 0.57.439−0.1±0.31−0.72, 0.51.378
Stage II vs I0.01±0.41−0.79, 0.82.5140.17±0.42−0.64, 0.97.651
Stage III vs I−0.15±0.43−1.01, 0.68.366−0.28±0.44−1.16, 0.58.266
Unknown stage vs stage I−0.25±0.41−1.02, 0.55.267−0.5±0.41−1.29, 0.30.11
High-risk cytogenetics−0.71±0.44−1.54, 0.18.058−0.98±0.43−1.79, −0.10.016
Maintenance therapy before transplantation0.07±0.42−0.71, 0.94.5550.14±0.43−0.66, 1.02.618
Chemomobilization before transplantation0.08±0.38−0.64, 0.85.571−0.14±0.38−0.84, 0.63.351
thumbnail image

Figure 2. (Top) Progression-free survival and (Bottom) overall survival are illustrated according to cytogenetic status at the time patients underwent autologous hematopoietic stem cell transplantation

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thumbnail image

Figure 3. (Top) Progression-free survival and (Bottom) overall survival are illustrated according to disease status at the time patients underwent autologous hematopoietic stem cell transplantation.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

We report here the results of the first randomized phase 2 trial incorporating the proteasome inhibitor bortezomib into the conditioning regimen for auto-HCT in MM. Melphalan 200 mg/m2 is considered the standard conditioning regimen. Attempts to intensify this regimen have not been successful because of increased toxicity.5-8, 16 On the basis of antimyeloma activity exhibited by bortezomib in combination with alkylating agents, we designed this randomized phase 2 trial to test the safety and efficacy of bortezomib in combination with high-dose melphalan.12-15, 29 Patients in the 3 randomized groups were comparable. There were no patients in CR at the time of auto-HCT, although 80% had at least a PR. There was no difference in the time to neutrophil or platelet engraftment, and comparable grade III and IV toxicities were observed between the 3 treatment groups. The TRM rate was 1.6% with only 1 death in Group 1. At a median follow-up of 36 months, the primary endpoint of CR was achieved in 20%, 10%, and 10% of patients in Groups 1, 2, and 3, respectively. There was no significant improvement in median PFS or OS in the groups that received bortezomib. Patients with relapsed disease and high-risk cytogenetic abnormalities had significantly shorter PFS and OS.

Historic data from our institution suggest a median PFS of 21 months after auto-HCT performed immediately after induction therapy.6 The PFS in relapsed patients who undergo auto-HCT at our institution is approximately 12 months.30 The lack of benefit in the bortezomib-treated groups in the current study may be attributed to several factors, such as the possibility that concomitant administration of AA may have compromised the efficacy of bortezomib, as reported by several investigators.31, 32 Also, the inclusion of a large proportion of patients (25%) with relapsed disease who are known to have worse outcome most likely also contributed.30

We identified 2 previous clinical trials that studied the incorporation of bortezomib into a melphan-based conditioning regimen for myeloma.15, 29 The first study was a single-arm trial by the French Myeloma Intergroup (IFM) that used a matched historic control design.15 The conditioning regimen included bortezomib 1 mg/m2 given on days −6, −3, +1, and +4, and melphalan 200 mg/m2 given on day −2, and autologous cell reinfusion on day 0. Fifty-four patients (median age, 58 years; range, 40-65 years) were treated on that trial. Fifty-four percent of patients received induction therapy with combined vincristine, doxorubicin, and dexamethasone; 33% received induction therapy with bortezomib and dexamethasone; and 13% received >2 lines of therapy. After auto-HCT with the bortezomib-melphalan conditioning, 32% achieved a CR, and 70% were had a CR + VGPR at 3 months after autologous stem cell transplantation. In a matched control analysis with patients from the IFM 2005-01 trial of high-dose melphalan only, the CR rate was higher in the bortezomib-melphalan group versus the melphalan only group (35% vs 11%; P = .001), regardless of induction therapy. Compared with the IFM study, more patients (25%) in our trial had relapsed disease, and no patient was in CR at the time of auto-HCT. Although the CR rate was lower in our study, perhaps because we included patients with more advanced disease, the CR + VGPR rate of >60% was not much different from the 70% rate reported in the IFM trial. Although the IFM study did report cytogenetic abnormalities, no information was available regarding the outcome of high-risk patients.

The second study evaluated the synergy between bortezomib and melphalan in the high-dose setting, the maximum tolerated dose of bortezomib in combination with melphalan, and the timing bortezomib administration (before or after melphalan).29 Only patients with <VGPR after 1 or more induction regimens were enrolled and were randomized to receive a single escalating dose of bortezomib (1.0 mg/m2, 1.3 mg/m2, or 1.6 mg/m2) either 24 hours before or 24 hours after high-dose melphalan. Bone marrow was collected before the initiation of therapy and at the time of transplantation to evaluate the sequence associated with maximal plasma cell apoptosis. Among 39 randomized patients, 19 received bortezomib before melphalan, and 20 patients received bortezomib after melphalan. Toxicity and post-transplantation hematopoietic recovery were similar in both arms. The overall response rate was 87%, and 51% of patients achieved a VGPR or better. Pharmacodynamic studies revealed greater plasma cell apoptosis among patients who received bortezomib after melphalan. Unlike the IFM study, patients aged >65 years were included; patients were heavily pretreated, including with prior autologous transplantation; and no patients were in CR or VGPR at the time of auto-HCT. The TRM rate was 5%, and there was 1 death from severe ileus and another from Para influenza virus infection. The median time to engraftment of neutrophils and platelets was 12 days and 16 days, respectively. At a median follow-up of 17.3 months, the overall response rate was 87%, and with 72% of patients achieved a >VGPR post-transplantation. Among the patients who had previous exposure to bortezomib, 57% achieved >VGPR post-transplantation. Although the dose and frequency of bortezomib in that trial were different from ours, the patient population was relatively comparable. Like our study, the trial by Lonial et al also included heavily pretreated patients, none of whom was in CR before transplantation. The CR + VGPR rates were comparable to our trial. Even with the inclusion of patients who had advanced disease, the PFS was 15.3 months, which was comparable to the PFS of 17 to 20 months in our trial.

We conclude that adding bortezomib to a preparative regimen of ATO, AA, and high-dose melphalan is safe and well tolerated in patients with MM with no increase in grade III and IV toxicity or TRM. However, there was no significant improvement in CR, PFS, or OS at either dose level (1 mg/m2 or 1.5 mg/m2) in this group of patients. A prospective study of bortezomib and high-dose melphalan without AA and ATO that excludes patients with relapsed disease may better define the role of bortezomib in this setting.

FUNDING SOURCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES

This work was partly supported by a research grant from Cephalon Oncology.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. FUNDING SOURCES
  8. REFERENCES
  • 1
    Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004; 351: 1860-1873.
  • 2
    Kyle RA, Rajkumar SV. Treatment of multiple myeloma: a comprehensive review. Clin Lymphoma Myeloma. 2009; 9: 278-288.
  • 3
    Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996; 335: 91-97.
  • 4
    Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med. 2003; 348: 1875-1883.
  • 5
    Kazmi SM, Saliba RM, Donato M, et al. Phase II trial of high-dose topotecan, melphalan and CY with autologous stem cell support for multiple myeloma. Bone Marrow Transplant. 2011; 46: 510-515.
  • 6
    Anagnostopoulos A, Aleman A, Ayers G, et al. Comparison of high-dose melphalan with a more intensive regimen of thiotepa, busulfan, and cyclophosphamide for patients with multiple myeloma. Cancer. 2004; 100: 2607-2612.
  • 7
    Moreau P, Facon T, Attal M, et al. Comparison of 200 mg/m2 melphalan and 8 Gy total body irradiation plus 140 mg/m2 melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood. 2002; 99: 731-735.
  • 8
    Christoforidou AV, Saliba RM, Williams P, et al. Results of a retrospective single institution analysis of targeted skeletal radiotherapy with Holmium-DOTMP as conditioning regimen for autologous stem cell transplant for patients with multiple myeloma. Impact on transplant outcomes. Biol Blood Marrow Transplant. 2007; 13: 543-549.
  • 9
    Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003; 348: 2609-2617.
  • 10
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