Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial
© Huang et al.; licensee BioMed Central Ltd. 2014
Received: 20 September 2013
Accepted: 6 December 2013
Published: 6 January 2014
Although the use of bortezomib alone and in combination with steroids has shown efficacy in AL amyloidosis, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT.
This was a single-center, prospective, randomized controlled trial comparing induction therapy consisting of two BD cycles followed by HDM/SCT (BD + HDM/SCT) with HDM/SCT alone in the treatment of patients with newly diagnosed AL amyloidosis. The hematological and organ responses of the patients were assessed every three months post HDM/SCT.
Fifty-six patients newly diagnosed with renal (100%), cardiac (57.1%), liver (7.1%), or nervous system (8.9%) AL amyloidosis were enrolled in this study; 28 patients were assigned to each arm. Two patients died within 100 days of HDM/SCT (3.6% treatment-related mortality). The overall hematologic response rates in the BD + HDM/SCT arm and HDM/SCT arm at three, six and twelve months were 78.5% versus 50%, 82.1% versus 53.5% and 85.7% versus 53.5%, respectively. In the BD + HDM/SCT arm, 15 (53.5%) patients achieved a hematologic response after BD and before HDM/SCT. An intention-to-treat analysis revealed a higher rate of complete remission in the BD + HDM/SCT arm at both 12 and 24 months (67.9% and 70%, respectively) than with the HDM/SCT-only therapy (35.7% and 35%, respectively, P = 0.03). After a median follow-up of 28 months, the survival rates at 24 months post-treatment start were 95.0% in the BD + HDM/SCT group and 69.4% in the HDM/SCT alone group (P = 0.03).
Our preliminary data suggest that the outcome of treating AL amyloidosis with BD induction and HDM/SCT was superior to the outcome of the HDM/SCT treatment alone.
This trial has been registered at clinicaltrials.gov with the number NCT01998503.
KeywordsAL amyloidosis Bortezomib Autologous stem cell transplantation
AL amyloidosis is the most common form of systemic amyloidosis, and it arises from the production of monoclonal free light chains (FLCs) by a pathological plasma cell clone . The deposition of insoluble amyloid fibrils in vital organs, such as the heart, kidney, liver, and nerves, can lead to progressive organ dysfunction and death . AL amyloidosis is often devastating, and the median survival rate of untreated patients with this lethal disease is only 10 to 14 months from diagnosis . The treatment for AL amyloidosis is aimed at reducing FLCs by eradicating the plasma cells  that produce them, although the options currently available for this treatment are limited .
AL amyloidosis treatments are based on existing multiple myeloma therapies. Melphalan (MEL) and prednisone administration was the first effective regimen developed for AL amyloidosis; however, the treatment responses are typically slow and rarely result in complete remission [6, 7]. An Italian study combining MEL with high-dose dexamethasone (MDex) noted an impressive hematologic response rate of 67%  and long-term remissions in AL amyloidosis , and MDex is still considered a standard for non-study, non-transplant intervention because of its low toxicity profile . Alternatively, intensive therapy with high-dose MEL and autologous stem cell transplantation (HDM/SCT) is effective in AL amyloidosis and can offer durable remission in some patients [11, 12]. However, only 25% of affected patients are eligible for this approach [13, 14], and the treatment-related mortality (TRM) with HDM/SCT is high [11, 15, 16]. Accordingly, it is necessary to identify modifications to the HDM/SCT procedure that could improve outcomes in patients with AL amyloidosis.
Novel drugs, including thalidomide [17, 18], lenalidomide  and bortezomib  (alone or in combination with dexamethasone), have recently proven to be effective in the non-transplantation setting. Bortezomib is a reversible proteasome inhibitor that has shown significant activity in patients with multiple myeloma [21, 22]. Indeed, several studies have confirmed that bortezomib combined with dexamethasone (BD) is an active and fast-acting regimen for AL amyloidosis, even in pretreated patients [20, 23–25]. However, the data regarding the toxicity and efficacy of BD chemotherapy prior to HDM/SCT are limited for patients with AL amyloidosis. Thus, to determine whether induction therapy with BD is advantageous in patients with AL amyloidosis, we prospectively evaluated a therapeutic regimen consisting of two cycles of BD chemotherapy followed by HDM/SCT in a single-center study.
Patients with newly diagnosed AL amyloidosis were enrolled in this trial, which was approved by the institutional ethical review board of Jinling Hospital. The participants or their guardians provided written informed consent. All patients had amyloid disease, which was confirmed by renal biopsy and documented plasma cell dyscrasia; the AL amyloidosis diagnosis and the assessment of organ involvement were based on consensus criteria . Patients who met the three criteria for multiple myeloma (MM) diagnosis, that is, clonal bone marrow plasma cells ≥10%, the presence of serum and/or urinary monoclonal protein and evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, were excluded . The following HDM/SCT inclusion criteria were applied: age between 18 and 65 years, performance status of 0 to 2 according to Eastern Cooperative Oncology Group (ECOG) criteria , a left ventricular ejection fraction (LVEF) >45%, a serum bilirubin level ≤2.0 mg/dl, a pulmonary diffusion capacity ≥50% and a serum creatinine level ≤2 mg/dl. Patients were excluded if they had uncompensated congestive heart failure, symptomatic cardiac arrhythmia, or cardiac syncope.
Hematologic and organ response criteria
Hematologic and organ responses were evaluated according to the novel criteria of the International Society of Amyloidosis [30, 31] . Hematologic complete response (CR) was defined as normalization of the FLC levels and ratio, negative serum and urine immunofixation. A hematologic very good partial response (VGPR) was defined as a reduction in dFLCs (difference between involved FLCs and uninvolved FLCs) to <40 mg/L. A hematologic partial response (PR) was defined as a greater than 50% reduction in dFLCs. No response (NR) was defined as less than PR. A hematologic progression has three situations: from CR, any detectable monoclonal protein or abnormal FLC ratio (the light chain must double); from PR, a 50% increase in serum M protein to >0.5 g/dl or 50% increase in urine M protein to >200 mg/day (a visible peak must be present); and an FLC increase of 50% to >100 mg/l. The hematological and organ responses were assessed every three months following HDM/SCT.
The protocol was designed as a superiority trial to demonstrate that BD induction followed by HDM/SCT is superior to HDM/SCT alone for treating AL amyloidosis. The working hypothesis was that the BD induction, followed by the HDM/SCT, would improve the hematologic CR rate (estimated to be 30% in the group assigned to receive the HDM/SCT alone) by 40% at 12 months. The sample size necessary to detect a significant difference (α = 0.05, 2-sided) was calculated to be 23 on the basis of 0.8 power. To compensate for the non-assessable patients, we planned to enroll a minimum of 28 patients per group.
The primary end point for this study was a hematologic CR rate 12 months after HDM/SCT. The secondary end points included the organ response rate, overall survival (OS), and progression free survival (PFS) for all patients. OS was defined as the time from the randomization to the date of death from any cause. The survival time was censored at the date of the last contact for the patients who were still alive or lost to follow-up. PFS was defined as the time from the randomization until date of progression, death, or last follow-up. The PFS and OS between the groups were compared using the Kaplan-Meier method. The start date was the date of randomization, and the cutoff date was June 30, 2013.
The t-test for independent samples or the Mann–Whitney U test was used to compare the continuous data between the groups. The differences between the categorical variables were assessed using Fisher’s exact test. Cox proportional hazards were used to calculate the hazard ratios (HRs) for each variable. The P value reported was 2-sided, and P <0.05 was considered to be statistically significant. All analyses were performed using SPSS software (version 13.0, SPSS Inc., Chicago, IL, USA).
BD + HDM/SCT (number = 28)
HDM/SCT (number = 28)
Organ involvement, number (%)
>1 organ involved
Cardiac stage, number (%)a
Involved FLC, number (%)
Abnormal FLC κ-to-λ ratio number (%)
ECOG PS (0/1/2), number (%)
24-hour urine protein (g/24 hour)
4.6 ± 2.2
5.8 ± 4.1
26.8 ± 6.1
25.7 ± 4.9
0.8 ± 0.3
0.8 ± 0.4
89.0 ± 19.6
85.1 ± 25.6
Marrow plasma cells (%)
3.2 ± 2.7
2.8 ± 2.1
Echocardiogram septal thickness (mm)
11.7 ± 2.4
11.1 ± 1.8
Ejection fraction (%)
60.8 ± 6.5
62.7 ± 6.1
Alkaline phosphatasea (U/L)
23 to 321
33 to 661
55.5 to 13,730
15.2 to 7,709
>8500 ng/L (%)
22 to 3,261
17 to 3,078
0 to 0.15
0 to 0.12
25 to 516
24 to 204
14 to 471
14 to 163
>180 mg/L (%)
Of the 28 patients who underwent BD induction, 24 completed the treatment in accordance with the standard dose; four patients developed neuropathy and one patient experienced thrombocytopenia resulting in a dose reduction of bortezomib in the second cycle. Five patients developed grade 3 edema, resulting in a dose reduction of dexamethasone to 20 mg. A total of 14 patients in the BD + HDM/SCT group and 13 patients in the HDM/SCT group received 200 mg/m2 MEL whereas the other patients received 140 mg/m2 MEL (Figure 1). The median number of stem cells collected was 5.5 × 106 CD34+/kg (range: 2 to 13.7 × 106 CD34+/kg) in the BD + HDM/SCT group and 3.5 × 106 CD34+/kg (range: 2.0 to 14.2 × 106CD34+/kg) in the HDM/SCT group (P = 0.13). The median granulocyte and platelet engraftment was 10 days and 13 days, respectively.
Hematologic and organ responses
Hematological and organ responses
Months post HDM/SCT
BD + HDM/SCT
BD + HDM/SCT
BD + HDM/SCT
Number = 28
Number = 28
Number = 28
Number = 28
Number = 20
Number = 23
The ITT analysis of organ response (OR) between the two groups is also summarized in Table 2. A total of 65.2% (n = 15) of the patients in the BD + HDM/SCT group and 39.1% (n = 9) of patients in the HDM/SCT group experienced improvements in at least one involved organ by twelve months. When assessed by individual organ, the response rates of the kidneys and hearts in the BD + HDM/SCT patients were higher than those of the HDM/SCT patients. However, the response rates of the liver and nervous system were similar between the two groups. In both groups, the OR rates of the surviving patients gradually increased with follow-up time.
Survival and progression
Factors associated with survival of all patients
Without BD induction
Urine protein >3.5 g/24 hour
Cardiac stage III
Baseline BNP >170 ng/L
The use of MEL 140
Treatment-related mortality and toxicity
Adverse events possibly related to HDM/SCT (Grade >2)
BD + HDM/SCT (n = 28)
HDM/SCT (n = 28)
Nausea or vomiting
Adverse events possibly related to BD induction
Thrombocytopenia, number (%)
Neutropenia, number (%)
Anemia, number (%)
Gastrointestinal, number (%)
Cardiac, number (%)
Infection, number (%)
Acute kidney injury, number (%)
Hepatic, number (%)
The HDM/SCT procedure for AL amyloidosis was introduced in 1998 by Comenzo et al., and represented a major breakthrough for AL amyloidosis . Indeed accumulating data have indicated that HDM/SCT can suppress underlying monoclonal plasma cell disease and improve the patient’s quality of life . The purpose of induction chemotherapy is to reduce the light chain load and to improve organ function prior to HDM/SCT. Amyloidosis is characterized by a relatively small tumor mass, so small that induction chemotherapy is often not necessary before proceeding directly to high-dose therapy. To date, the use of induction chemotherapy prior to HDM/SCT has been evaluated in a few studies, which have reported negative results. Pretreatment with two cycles of oral melphalan/prednisone prior to the transplantation did not improve the results of a prospective randomized trial . Similarly, the data from Perz et al.  indicated that administering vincristine, doxorubicin and dexamethasone (VAD) before HDM/SCT did not increase the hematologic response rate. Nonetheless, the outcome of BD induction prior to HDM/SCT has remained unknown.
Several studies have reported the results of adjuvant BD combination with HDM/SCT, and the addition of bortezomib to the HDM used as a conditioning regimen prior to stem-cell transplantation is feasible and well-tolerated by patients with AL amyloidosis . The BD regimen has also been used following HDM/SCT to improve the depth of the response for patients who achieve less than VGPR. Nineteen of 28 patients received post-transplant BD chemotherapy, with 67% of these achieving CR and 60% organ responses . A complementary approach of administering two cycles of BD prior to and as conditioning for HDM/SCT also yielded very good response rates of hematological remission in 9/18 patients after the induction, and all 11 patients evaluable after HDM/SCT attained CR/VGPR . The combination of BD with cyclophosphamide has also shown encouraging response rates in patients with AL amyloidosis, even without high-dose therapy [40, 41]. Additionally, most of the patients in these two series were either transplant ineligible or relapsed. Therefore, based on the current knowledge regarding the use of BD in the treatment of AL amyloidosis, it is clear that the BD regimen is effective and fast acting in patients with AL amyloidosis. Our data also show that BD therapy prior to HDM/SCT can quickly reduce the FLC level and the tumor burden and can furthermore delay the progress of involved organs, thus improving the safety and efficiency of HDM/SCT. Therefore, the BD regimen is an appropriate therapy before HDM/SCT. For patients who have already achieved CR prior to HDM/SCT, it is difficult to assess whether HDM/SCT was necessary, and only a clinical trial can provide an answer. Regardless, we believe that additional therapy with HDM/SCT may be able to improve the depth of the response and further extend PFS of those patients.
Our data demonstrate that BD induction followed by risk-adapted HDM/SCT is a more effective strategy than HDM/SCT alone for treating newly diagnosed patients with AL amyloidosis. The majority of patients (85.7%) in the BD induction group achieved hematological responses, including more than half (67.9%) who achieved CR at one year post-therapy. The BD induction group also displayed better PFS and OS rates than the group that received HDM/SCT alone. HDM/SCT treatment in patients with cardiac involvement remains challenging, particularly for patients with stage III cardiac involvement. In our series, 44.4% (4/9) of the patients with stage III cardiac involvement died during follow-up, but the median survival time was more favorable than previously reported .
The disadvantages of induction chemotherapy in patients with AL amyloidosis include the potential risk of side effects, the risk of further worsening organ function and the consequent delay of HDM/SCT. Our data demonstrate that the majority of patients can tolerate two cycles of BD treatment, and that the toxicity of the BD regimen is moderate and manageable. All toxicities were reversible and did not influence the subsequent HDM/SCT procedure because MEL toxicity differs from that of bortezomib. However, additional attention should be given to some toxicities that can result in bortezomib or dexamethasone dose reduction, including edema, peripheral neuropathy, and thrombocytopenia. Edema is a common toxicity for high-dose dexamethasone, particularly in patients with renal involvement and low serum albumin levels. Because the serum albumin levels of all five patients who developed grade 3 edema were lower than 2 g/dl, support treatment with diuretics and serum albumin is important for these patients. Peripheral neuropathy also needs to be carefully monitored during BD induction, as 18% of the patients developed grade 3 neuropathy in this study, apparently higher than in other studies [24, 25]. One study demonstrated that 1.6 mg/m2 once-weekly bortezomib dosing can reduce toxicity compared to 1.3 mg/m2 twice-weekly dosing . Subcutaneous bortezomib is another option to reduce the incidence of peripheral neuropathy and has been confirmed in a randomized, phase 3 study for multiple myeloma patients  and was also proven in a small series of AL amyloidosis patients . In addition, we observed a high incidence of herpes zoster infection during BD induction; thus, anti-virus prophylaxis appears to be necessary for these patients. In our study, the occurrence of TRM in our study population of 56 patients was 3.6% (2/56), a lower value than in most reports. Moreover, no patients in the BD induction group died because of treatment-related complications. The possible reasons for the relatively low TRM observed include the risk-adapted approach of HDM/SCT, the induction chemotherapy used in half of the patients, the small proportion of patients with severe cardiac involvement and racial differences.
This study has several limitations. First, all of the patients had renal involvement, which most likely constitutes a selection bias because the study was conducted in a nephrology institution. Second, neither group met the median PFS and OS rates, and the long-term patient prognosis requires further study. Third, it is unclear whether the PFS rate of the patients who achieved CR after the BD induction following HDM/SCT is equivalent to the CR achieved with BD therapy alone. Fourth, the sample size of this trial is too small to allow patient stratification based on known risk factors, as well as to allow a subgroup analysis, so the results for stratification or subgroup analysis cannot match the results of other studies. We will continue this study and enroll more patients to make this stratification or subgroup analysis more clear. Additionally, the appropriate salvage regimen for patients who had no response to BD induction following HDM/SCT is also unclear.
In conclusion, our preliminary data suggest that induction therapy with BD followed by HDM/SCT is an effective and tolerable regimen for treating patients with AL amyloidosis. This protocol can significantly improve both the hematological and organ response rates, and the risk of the BD + HDM/SCT regimen is apparently comparable to that of HDM/SCT. Although HDM/SCT remains a high-risk treatment modality for AL amyloidosis, new agents, such as bortezomib, may alter this therapeutic approach and improve patient outcomes. Further study will be required to establish the long-term benefits of this treatment.
bortezomib in combination with dexamethasone
brain natriuretic protein
Eastern Cooperative Oncology Group
free light chains
high dose melphalan and autologous stem cell transplantation
intention to treat
overall response rate
progression free survival
vincristine doxorubicin and dexamethasone
very good partial response.
Part of this work was presented as a poster at the 2013 World Congress of Nephrology in Hong Kong, China, 31 May to 4 June 2013. This work was supported by the National Key Technology R&D Program (No. 2013BAI09B04) and the Clinical Research Program of Jiangsu Province (No. BL2012007).
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