Japanese Journal of Clinical Oncology Advance Access originally published online on December 21, 2007
Japanese Journal of Clinical Oncology 2007 37(12):961-968; doi:10.1093/jjco/hym126
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© 2007 Foundation for Promotion of Cancer Research
Bortezomib in Combination with Conventional Chemotherapeutic Agents for Multiple Myeloma Compared with Bortezomib Alone
1 Department of Hematology, The Catholic University of Korea, Seoul
2 Department of Emergency Medicine, St. Mary's Hospital, Seoul
3 Department of Clinical Pathology, St. Mary's Hospital, Seoul, Korea
For reprints and all correspondence: Yonggoo Kim, Department of Clinical Pathology, St. Mary's Hospital, #62 Yeouido-Dong, Youngdungpo-Gu, Seoul 150-713, Korea. E-mail: yonggoo{at}catholic.ac.kr
Received July 12, 2007; accepted August 13, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: Recent studies have demonstrated synergy between bortezomib and a number of conventional cytotoxic agents. This study examined whether or not the speed of the response, progression and safety from a combination treatment of bortezomib with common chemotherapeutic drugs is superior to bortezomib monotherapy.
Methods: Fifty-seven patients with relapsed, refractory multiple myeloma (MM) who had received at least two cycles of treatment including bortezomib were enrolled in this study. The median age was 56 (35–79) years and 49.1% were male. Thirty-two patients were treated with bortezomib alone and 25 were treated with chemotherapeutic agents that were given in combination with bortezomib. The monoclonal immunoglobulin (mIg) or free light chain (FLC) concentrations were determined in the sera before and after two cycles of bortezomib treatment. The adverse events were assessed and graded according to the NCI Common Toxicity Criteria (version 2.0).
Results: Thirty-one of the 57 patients (54.4%) attained an early objective response (EOR) after the second bortezomib treatment, defined as a 
50% decrease in the serum mIg or FLC concentration. Improvements in the response were observed when common chemotherapeutic agents were added to bortezomib monotherapy. In patients who received bortezomib combined with chemotherapeutic agents, 19 out of 25 patients (76%) showed an EOR, whereas 12 out of 32 patients (37.5%) given bortezomib monotherapy achieved an EOR after the second cycle of bortezomib treatment (P = 0.004); the median decrease from the baseline in the paraprotein level was 74.6 ± 5.9 and 39.7 ± 4.2%, respectively (P = 0.003).
A statistically significant elevation of serum lactic dehydrogenase (P = 0.007) and alkaline phosphatase (P = 0.027) from baseline within two cycles of bortezomib treatment was observed in responding patients. With the combination treatment, peripheral neuropathy of Grade II occurred in 12 out of 25 patients (48%) compared with 12 of 32 (37.5%) in those given bortezomib alone (P = 0.589). The median time to progression of disease was similar in the two groups (359 ± 43.5 versus 365 ± 103.5, P = 0.688). The multivariate Cox regression model showed that a high serum albumin and low β2-microglobulin are favorable factors for the progression-free survival following bortezomib treatment.
Conclusions: Bortezomib in combination with common chemotherapeutic agents is more active in the treatment of relapsed, refractory MM than with bortezomib alone. However, more effective post-bortezomib treatment is needed to reduce the rate of disease progression particularly in patients with high tumor burden.
Key Words: bortezomib • multiple myeloma • combination therapy • free light chain • progression-free survival
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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With conventional treatments, multiple myeloma (MM) remains an essentially incurable disease with a median survival of 3–4 years (1,2). Even if the superiority of high-dose therapy with stem cell support over conventional chemotherapy has been established, the response to induction therapy in previously untreated myeloma patients is associated with prolonged survival in patients receiving autologous stem- cell transplantation (SCT) (3,4). Bortezomib is a first-in-class proteasome inhibitor that induces apoptosis and growth arrest and reverses chemoresistance in MM cells (5,6). In addition, bortezomib offers a novel approach to the treatment of MM in Phase 2 or 3 clinical trials producing rapid control (7–9). The achievement of a complete or partial response (PR) to bortezomib as a salvage treatment is associated with a significantly longer survival (7). Therefore, the initial decrease in the myeloma burden is the primary goal for all patients and may translate into an improved survival benefit.
Recent laboratory and clinical studies have demonstrated synergy between bortezomib and a number of conventional cytotoxic agents (10–15). The addition of dexamethasone to bortezomib in patients showing a suboptimal response to bortezomib alone was associated with improvement in the response without excessive toxicity (16). However, there are no reports of a comparison of bortezomib monotherapy with bortezomib combination treatment in patients who previously did not receive bortezomib.
This study examined whether or not the speed of response, progression and safety of combination treatment of bortezomib with common chemotherapeutic drugs including thalidomide is superior to those of bortezomib alone by examining the outcome of the two treatments in MM patients who had not been previously treated with bortezomib. Prompt chemosensitivity to bortezomib in combination with common chemotherapeutic agents compared with bortezomib monotherapy was observed. However, in our patients, the combination treatment with bortezomib did not lengthen the time to progression compared with those administered with bortezomib alone.
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PATIENTS AND METHODS |
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Patients and Disease Characteristics
From August 2004 to April 2007, 57 consecutive MM patients with refractory or relapsed MM from a single institution were treated with bortezomib. All patients who had received at least two cycles of treatment including bortezomib were analyzed in this retrospective study. The patients were required to have symptomatic MM diagnosed using the standard criteria, with measurable disease. All patients had a measurable level of monoclonal (M) protein. Measurable disease was defined as a monoclonal immunoglobulin (Ig) level on serum electrophoresis of at least 1 g/dl of IgG or 0.5 g/dl of IgA or 0.2 g/dl of IgM. Patients with light chain disease (LCD) or non-secretory MM, who did not show any M protein at diagnosis, had measurable serum free light chain (SFLC) according to the FreeLite test as defined elsewhere (17). The reference range for the SFLC concentrations were 3.3–19.4 mg/l for
and 5.7–26.3 mg/l for 
, respectively. The monoclonal Ig or SFLC concentrations and biochemical markers such as lactic dehydrogenase (LDH) and alkaline phosphatase (ALP) were determined in the sera at baseline and 2 weeks after the second cycle of bortezomib treatment. At the same time, blood and urine samples were collected to perform an immunofixation test. The other inclusion criteria were a Karnofsky performance status 50%, a serum concentration of aspartate aminotransferase or alanine aminotransferase no higher than three times the upper limit of the normal range, a serum total bilirubin concentration no higher than twice the upper limit of the normal range, a measured or calculated creatinine clearance of more than 10 ml/min, granulocytes 0.5 x 109/l and platelets 30 x 109/l. All the patients provided written informed consent before entering treatment.
Treatment
Thirty-two patients were treated with bortezomib alone (1.3 mg/m2 intravenously twice weekly for 2 weeks in a 21-day cycle) and 25 were treated with bortezomib (1.3 mg/m2 intravenously twice weekly for 2 weeks in a 21- or 28-day cycle) in combination with the other chemotherapeutic agents including oral dexamethasone (n = 7), or oral dexamethasone + doxorubicin or thalidomide (n = 18). All patients received bortezomib alone from August 2004 to July 2005. The combination treatment was started from August 2005 in our institute. Since then addition of the chemotherapeutic agents to bortezomib was determined based on the presence of morbidity including diabetes mellitus, hypertension or other chronic illness in patients. The combination treatment regimens are follows.
- Bortezomib + dexamethasone; oral dexamethasone 20 mg on the day and day after bortezomib administration for all cycles (21-day cycle). Patients aged 60 years or older received reduced dose 10 mg.
- Bortezomib + oral dexamethasone + doxorubicin or thalidomide; the addition of either intravenous infusion doxorubicin at 4.5 mg/m2 on days 1–4 of the first cycle or thalidomide 100 mg on days 1–28 of the second cycle.
The patient was evaluated for possible toxicity according to the National Cancer Institute Common Toxicity Criteria version 2. If the patient experienced febrile neutropenia, Grade 4 hematological toxicity or any Grade 3 or higher non-hematological toxicity considered to be related to bortezomib, bortezomib was withheld until toxicity returned to Grade 
1 (excluding peripheral neuropathy). If the toxicity did not resolve within 2 weeks, bortezomib was discontinued. If the toxicity resolved, bortezomib was restarted at a dose reduced by 25% (1.3–1.0 mg/m2 and 1.0–0.7 mg/m2). Patients willing to undergo, and eligible for, an SCT received bortezomib treatment until the maximal response was achieved. Patients who are not eligible for transplant received additional two cycles of bortezomib treatment after a Complete response (CR) was obtained. Patients who did not achieve 25% reduction of M-protein after the second cycle of bortezomib therapy received dexamethasone for all remaining cycles. Post-bortezomib treatment consisted of autologous or allogeneic SCT, conventional treatment including melphalan, thalidomide and/or glucocorticoids or a follow-up without further treatment.
Evaluations
The primary end points of this retrospective study were the early response and safety. An early objective response (EOR) was defined as a 50% reduction in the monoclonal Ig or SFLC level when assessed after the second bortezomib treatment. The EOR included both a CR and PR. CR was defined as the disappearance of the monoclonal band in the immunofixation test in serum or urine. A PR was defined as the presence of a monoclonal band in the immunofixation test in serum or urine. The minimal response (MR) was defined as a 25–49% reduction of monoclonal Ig or SFLC concentrations and stable disease (SD) as <25% reduction of the measurable monoclonal protein. The secondary objective was to identify the factors associated with disease progression after bortezomib therapy. The patients were evaluated monthly after the last bortezomib treatment. Progression was defined as a relapse or a 25% increase in the level of the measurable M protein. The progression-free survival (PFS) or time to progression was calculated from the beginning of the bortezomib treatment until the time of relapse, disease progression or death or the date the patient was last known to be in remission.
Statistical Analysis
For the response category, the groups were compared using a 
2 test (or Fisher's exact test). The logistic regression model was used to estimate the hazard ratios (HRs) and the 95% confidence intervals (95% CI) for the treatment and some prognostic factors. The time-to-event analysis was performed using the Kaplan–Meier method. The differences in PFS were compared using a log rank or generalized Wilcoxon tests and, for multivariate survival analyses, by the Cox proportional hazard model to identify the prognostic factors.
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Patient Characteristics
The median age was 56 (35–79) years and 49.1% were male. The demographics and disease characteristics of all 57 patients at the enrollment were similar between the two groups including prior treatment before bortezomib administration (Table 1). The median number of previous therapies was 2 (range, 1–5). Nineteen (59.4%) out of 32 patients with available cytogenetic results using fluorescence in situ hybridization or the conventional technique were reported to be abnormal; del(13) was present in nine, the hyperdiploid abnormality was reported in four, t(11;14) in two, del(17p) in two and 7+ in two.
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Early Response
Seven patients whose disease belonged to LCD and two patients with non-secretory MM showed an elevated concentration of SFLC (
100 mg/l). The response to treatment could be measured by SFLC in those patients. The other 48 patients had a measurable monoclonal Ig in the sera. Overall, 31 of the 57 patients (54.4%) showed an EOR after the second bortezomib treatment according to the change in the monoclonal Ig or SFLC concentration. The improvement in the response was higher in patients who had bortezomib in combination with the chemotherapeutic agents than in those given bortezomib monotherapy. In the patients with bortezomib monotherapy, 12 (37.5%) out of 32 patients showed an EOR, whereas 19 (76%) out of 25 patients with bortezomib in combination achieved an EOR (P = 0.004). Table 2 shows response to bortezomib alone in comparison with the combination treatment. Eight (32%) patients given the combination treatment obtained an early conversion of immunofixation negativity that was compatible with a CR compared with six (18.8%) patients given bortezomib alone (P = 0.03). Multivariate logistic-regression analysis was performed using all the major clinical prognostic factors affecting EOR (prior treatment, age, gender, stage at diagnosis, serum albumin and β2-microglobulin and cytogenetics) but failed to identify a significant factor except for the treatment group (HR = 0.136, 95% CI 0.032–0.588, P = 0.008). An EOR was obtained regardless of type of previous treatment (SCT versus chemotherapy, P = 0.716). Among the patients with abnormal cytogenetics, there was a trend toward a lower EOR rate compared with normal cytogenetics (6 of 19 versus 9 of 13, respectively, P = 0.07).
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The data on change in the M-protein level were analyzed. Figure 1 shows the results of early reduction of M protein in each treatment group. The data were examined to assess the relative impacts of bortezomib alone and the combination treatment. In the patients given bortezomib monotherapy, the median reduction (mean ± SE) in the paraprotein level was 39.7 ± 4.2% compared with a median reduction of 74.6 ± 5.9% after the combination treatment (P = 0.003) (Fig. 1a). The data on the change in the M-protein levels were analyzed according to the response to the bortezomib therapy (Fig. 1b). In patients who obtained an EOR in each treatment group, the median reduction (mean ± SE) in the M-protein level was 79.9 ± 4.4 or 77.6 ± 3.8%, respectively (P = 0.693). However, in the patients who did not show an improved response in each treatment group, the median reduction (mean ± SE) in the M-protein level was 19.3 ± 4.2 or 36.3 ± 6.1%, respectively (P = 0.043).
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The change in biochemical markers (the ratio of the highest concentration within two cycles of the bortezomib treatment compared with the pretreatment levels) including serum LDH and ALP according to obtainment of an EOR was determined. A statistically significant elevation of LDH (P = 0.007) and ALP (P = 0.027) from baseline within two cycles of bortezomib treatment was observed in the responding patients compared with the patients without an EOR (Table 3).
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Toxicity
Table 4 lists the common treatment-emergent adverse events by the bortezomib treatment reported with or without the addition of other chemotherapeutic agents including thalidomide. The adverse event profile of all the patients was similar to that reported previously. Peripheral neuropathy (37.5 versus 48%), thrombocytopenia (84.4 versus 52%), granulocytopenia (34.4 versus 24%), constipation (21.9 versus 24%), fatigue (21.9 versus 29.2%), vomiting (21.9 versus 16.7%), diarrhea (18.8 versus 20.8%) and skin rash (9.4 versus 0%) were the most commonly reported
Grade 2 adverse events in patients receiving the bortezomib monotherapy versus the combination treatment, respectively. In both groups, thrombocytopenia was cyclical, occurring during the administration of bortezomib but recovered toward the baseline during the remaining period of each cycle. The addition of glucocorticoid to patients receiving bortezomib treatment appeared to be associated with a reduction in the reporting of skin rash. One patient given the combination treatment died from pneumonia. One patient given bortezomib alone died from acute renal failure caused by tumor lysis syndrome (TLS).
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The Post-Bortezomib Therapies and Progression
The median number of bortezomib treatment was 4 (range, 2–9) in the patients with bortezomib alone and 3 (2–6) in those given the combination treatment at the time of this analysis (P = 0.349). With a median follow-up duration of 289 days (range, 41–511), 17 (54.8%) of 31 evaluable patients who received bortezomib alone exhibited disease progression while 14 (58.3%) of 24 evaluable patients with the combination treatment progressed (P = 0.796). The median time to disease progression for all treated patients of each cohort was 365 days (95% CI, 162–568 days) in patients with bortezomib alone and 359 days (95% CI, 274–444 days) in those given the combination treatment (P = 0.688). The post-bortezomib treatment consisted: stem cell transplantation using either high-dose therapy with autologous stem-cell support (n = 12) or reduced-intensity allogeneic transplant (n = 5) as described elsewhere (18); melphalan + prednisolone (MP, n = 16); thalidomide + dexamethasone (TD, n = 9); dexamethasone (D, n = 5) and no further treatment after bortezomib treatment (n = 8). The two patients who died immediately after the second bortezomib treatment were excluded. The numbers of patients with either bortezomib alone versus combined treatment who received each post-bortezomib treatment were 10 versus 7 with SCT, 21 versus 4 with MP, 3 versus 6 with TD, 2 versus 3 with D and 4 versus 4 in follow-up without treatment, respectively.
Univariate analysis revealed that six factors, including a previous SCT (versus conventional treatment), serum albumin (<3.5 versus 3.5 g/dl), β2-microglobulin (5.5 versus <5.5 mg/l), ISS (III versus I–II) and bone lesions (presence versus absence) were associated with a significantly higher risk of progression. The achievement of EOR after the second cycle of bortezomib was not associated with the prolonged PFS (HR = 0.68; 95% CI 0.29–1.57, P = 0.368). As shown in Table 5, multivariate Cox regression analysis revealed a high serum albumin (P < 0.001) to be a favorable factor for PFS. High β2-microglobulin levels (5.5 mg/l) were marginally associated with a poor PFS (P = 0.065). Figures 2a and b show the PFS after bortezomib therapy according to the two significant factors including serum albumin and β2-microglobulin levels, respectively. PFS was not different between the two bortezomib treatment groups (Fig. 2c).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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This study evaluated the efficacy of bortezomib alone versus bortezomib in combination with common chemotherapeutic agents in patients with MM, who had been previously bortezomib naive. In this study, the EOR (CR and PR after the second cycles) was 54.4%. There was an almost two-fold increase in the median reduction of the paraprotein levels early after bortezomib in combination with other drugs when compared with bortezomib alone. Patients treated with bortezomib in combination showed higher response rate but not a longer time to progression. The occurrence of the treatment-emergent adverse events reported was similar between the two groups.
Bortezomib, a potent and reversible proteasome inhibitor, offers a novel approach to the treatment of MM in Phase 2 or 3 clinical trials, and is known to produce rapid control (7–9). After a combination treatment of bortezomib and dexamethasone, improved responses were observed in 18 and 33% of the pretreated patients in the SUMMIT and CREST trial, respectively (16). In the aforementioned studies (7,8,19), the addition of dexamethasone, at an intensity similar to that used in standard high-dose pulse therapy, was chosen in case the patients showed suboptimal responses to bortezomib only. The potential benefit of the up-front combination with bortzomib and common chemotherapeutic agents could not be assessed. In addition, in the absence of a control group, the possibility that some of the improved responses may have represented a late response to a previous bortezomib treatment could not be excluded. A trend towards a greater sensitivity to bortezomib combined with common chemotherapeutic agents than with bortezomib monotherapy is noteworthy despite it being an uncontrolled study because all the patients of this study had not been previously treated with bortezomib.
There is no generally accepted standard therapy using bortezomib for patients with newly diagnosed or relapsed MM, and the ultimate choice of treatment with bortezomib will be balanced by the efficacy, convenience, disease status and clinical trial results. More study will be needed to assess the efficacy of this and other combinations as well as to identify patients most likely to benefit from these combinations. In vitro studies have laid the foundation for several phase I/II trials investigating combinations of bortezomib with melphalan, prednisone, pegylated liposomal doxorubicin or thalidomide in patients with relapsed and refractory MM (12,13,20). Two recent Phase 2 trials also assessed bortezomib-based regimens for previously untreated patients with myeloma. The proven efficacy of bortezomib in advanced MM, the additive effect of dexamethasone and the potent synergy with doxorubicin together provide the rationale for combination therapy with bortezomib, doxorubicin and dexamethasone (PAD) (15). PAD, as induction therapy, achieves a high CR and an overall response rate (CR + PR) of 95%. The Intergroupe Francophone du Myelome study administered bortezomib and high-dose dexamethasone, and achieved an overall response rate of 66% with a CR rate of 21% (21). It was reported that the addition of high-dose dexamethasone after a second cycle of bortezomib monotherapy was associated with manageable adverse events that did not usually interfere with the ability to continue therapy (16). Our data also demonstrate that adding the chemotherapeutic agents did not appear to alter the type of myelosuppression and thrombocytopenia or increase their incidence compared with those associated with bortezomib alone.
This study evaluated the efficacy and toxicity after a second cycle of bortezomib in each treatment group with or without dexamathasone-based combination treatment. Determining the EOR after the bortezomib treatment might be critical for the overall outcomes. The SUMMIT study showed that the median time to the first response was 1.3 months and the achievement of an objective response to bortezomib alone after two cycles was associated with a significantly longer survival than in all other patients (7). The early response to bortezomib treatment in our patients was not influenced by gender, type of myeloma, serum level of albumin or β2-microglobulin, stage and previous treatments. Moreover, the responses seemed to occur regardless of any abnormalities in the cytogenetics. A combination of bortezomib with common chemotherapeutic agents showing a clear synergy was a unique factor associated with the achievement of an EOR in our patients. The amount of M-protein reduction after the second cycle of bortezomib was more markedly different between the treatment groups in the patients without an EOR, while similar in those with an EOR. It is likely that the patients who have a resistance to bortezomib seemed to respond to simultaneous administration of the combined agents.
It has been shown that increased ALP in patients responding to bortezomib was associated with a parallel increase in bone-specific ALP and parathyroid hormone, suggesting that response to bortezomib in MM is closely associated with osteoblastic activation (22). In our patients, early response to bortezomib has been related to a significant increase in serum ALP concentrations. TLS is exceedingly rare in MM because of the relatively slow proliferation and response of the malignant cells. Bortezomib therapy, due to the rapidity of its action, may result in TLS in myeloma patients who have rapidly proliferative disease with a high tumor burden (23). The patients with an EOR showed a remarkable elevation of serum LDH levels that is able to be transiently observed in TLS. These findings suggest that TLS, a bortezomib-induced rapid reduction in tumor burden and variation in markers of osteoblastic activation (such as ALP) have also predicted an early response in patients with myeloma treated with bortezomib.
The time to progression was not significantly improved in the combination group compared with in the monotherapy group even though the rate of EOR was significantly higher. In the SUMMIT and CREST trial, the median time to progression was shorter in the patients for whom dexamethasone has been added to the treatment regimen (7,8). In our patients, the interval between the beginning of the bortezomib treatment and the first occurrence of progression correlated with the clinical factors including serum albumin and β2-microglobulin levels, suggesting that a tumor burden at the time of bortezomib treatment is important for the progression.
Measurements of the SFLC have greater sensitivity than protein electrophoresis and/or immunofixation to detect M protein (24). SFLC concentrations may be a more accurate tumor marker. This method has been shown to be useful in patients with light chain only or non-secretory myeloma as well as intact Ig myeloma. SFLC has a short serum half-life so that the changes in SFLC can provide a rapid indication of the treatment response. In this study, two patients with non-secretory MM and seven with LCD showed elevated concentrations (100 mg/l) in one type of SFLC (involved type), which could be used to determine the EOR. An early indication of resistance to treatment using measurements of the SFLC would allow the administration of an ineffective chemotherapy drugs to be minimized and be a valuable aid when selecting the appropriate treatment regimens.
In conclusion, more rapid tumor control was achieved in the resistant or relapsed myeloma patients by bortezomib in combination with other drugs with a completely different mechanism of action than by bortezomib monotherapy. The potent synergy with the chemotherapeutic agents provides the rationale for combination therapy with bortezomib, even though more study will be needed to determine which regimen is the best according to response and adverse reaction. Moreover, therapeutic trials aimed at effectively reducing the disease progression after bortezomib treatment will be needed for patients with improved responses.
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Acknowledgment |
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The authors wish to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year of 2007.
Conflict of interest statement
None declared.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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