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Haematologica. Dec 2011; 96(12): 1890–1892.
PMCID: PMC3232278

Bortezomib and high-dose melphalan conditioning for stem cell transplantation for AL amyloidosis: a pilot study

Treatment with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) can induce hematologic responses, organ responses and lead to improvement in survival in selected patients with AL (immunoglobulin light chain) amyloidosis.1 The depth of hematologic response, in particular the achievement of complete hematologic response (CR), has been shown to be predictive of clinical response, quality of life and improvement in survival.13 The median survival of patients achieving hematologic CR after HDM/SCT in a landmark analysis of patients alive at one year following treatment exceeds ten years compared to 50 months for those not achieving a hematologic CR.4

The proteasome inhibitor bortezomib has been approved for treatment of myeloma. Recent studies demonstrate high response rates when bortezomib is used in combination with oral melphalan and prednisone.5 While the mechanism of action is still not completely understood, in vitro, bortezomib senstitizes myeloma cells to DNA-damaging agents such as melphalan, and overcomes chemoresistance.6 It also acts upon the bone marrow microenvironment, inhibiting nuclear factor-κB activation in bone marrow stromal cells. This leads to a reduction in interleukin-6 production and enhanced apoptosis of myeloma cells.7 Recently, bortezomib has been incorporated into HDM conditioning for SCT in myeloma.8 Pre-clinical and phase I/II data have suggested that the optimal timing of administration of a single dose of bortezomib is 24 h after melphalan.6,9

Because hematologic CR is a critical determinant of treatment outcome following HDM/SCT, we hypothesized that the addition of bortezomib to HDM/SCT could increase hematologic CR rates in patients with AL amyloidosis. This hypothesis led us to conduct a prospective feasibility pilot study of bortezomib-HDM/SCT for the treatment of AL amyloidosis (ClinicalTrials.gov: NCT00790647). The objective of this trial was to determine whether the addition of bortezomib to HDM/SCT has the potential to improve hematologic CR rates in patients with AL amyloidosis undergoing HDM/SCT. Additional objectives were to evaluate the tolerability of the combination and its impact upon clinical responses.

This clinical trial was approved by the Institutional Review Board of the Boston University Medical Campus. Eligibility criteria for participation in this clinical trial were as described in previous HDM/SCT protocols.1 Patients with grade 3 peripheral sensory neuropathy from AL amyloidosis were excluded. Peripheral blood stem cells were mobilized with G-CSF, and a minimum of 2.5×106 CD 34+ cells/kg were required for transplantation. Bortezomib was administered at 1 mg/m2 on Days -6, -3, +1, and +4 and HDM was administered at 140 or 200 mg/m2 in two divided doses on Days -2 and -1, depending upon age and co-morbidities. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3, was used to grade adverse events. Treatment-related mortality was defined as death occurring from the time of stem cell mobilization through Day +100 following HDM/SCT. Hematologic and clinical responses were assessed six and 12 months after HDM/SCT. The response criteria for hematologic and clinical/organ response used were standards defined by the consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis.10

Ten subjects with AL amyloidosis were enrolled in this clinical trial from October 2008 to November 2009. The median age was 65 years (range 46–68) and 60% were men. The median number of organs involved was 2 (range 1–4). Two patients (20%) had cardiac involvement; both had elevated BNP (B-type natriuretic peptide) and troponin I levels (Mayo clinic cardiac stage III).11 The median BNP level for all patients was 84 pg/mL (range 8–325). Two patients (20%) had received prior treatment with 2 cycles of bortezomib and dexamethasone. Other patients’ characteristics are shown in Table 1.

Table 1.
Patients’ characteristics.

Of the 10 subjects enrolled, one was removed from the study prior to treatment because of cardiac arrhythmias during stem cell collection that precluded HDM/SCT. This patient subsequently underwent orthotopic heart transplantation followed by HDM/SCT. Of the 9 remaining subjects on the trial, 8 received 200 mg/m2 of HDM and one received 140 mg/m2, being over 65 years of age. There was no treatment-related mortality. The median times to neutrophil and platelet engraftment were Days +10 and +14 after SCT, respectively. One of the 9 subjects developed grade 4 mucositis, one developed grade 3 renal failure not requiring dialysis, and 3 developed grade 3 infectious complications (enterococcus urinary tract infection, clostridium difficile colitis, and influenza A pneumonia).

Hematologic responses were achieved in 89% of treated subjects (8 of 9), of which 6 (67%) were hematologic CRs. Thus, according to intention-to-treat, 80% (8 of 10) had a hematologic response to treatment. Only one treated subject presented with worsening of hematologic parameters, necessitating additional treatment. There have been no hematologic relapses at a median follow up of 23 months (range 18–31). Seventy-eight percent of treated patients (7 of 9) had an organ response at one year following bortezomib-HDM/SCT; 6 with renal and one with hepatic response (Figure 1). All subjects are alive and well after a median follow up of 29 months from the time of diagnosis and 23 months from study enrollment.

Figure 1.
Renal response with improvement in urine protein excretion at one year after Bz-HDM/SCT.

In conclusion, this pilot study demonstrates that the addition of bortezomib to the conditioning regimen for HDM/SCT is feasible and well tolerated by patients with AL amyloidosis. The combination resulted in no increase in adverse events over those typically seen with HDM alone. Furthermore, this combination produced a high rate of hematologic and organ responses. Although this pilot study only included a small number of highly selected patients, the CR rate of 67% of treated patients compares favorably with that of 40% seen in previous series using melphalan alone for conditioning.5 This suggests that there may be additive or synergistic activity of bortezomib and melphalan, due to the activity of bortezomib as a chemosensitizer6 and its effect on the bone marrow microenvironment.7 We plan to carry out a second clinical trial using bortezomib for initial induction therapy as well as incorporating it into the conditioning regimen. Based upon the results of these two studies, the regimen with superior phase II results will be compared to a standard melphalan-based SCT in a randomized phase III study, with the goal of determining whether the addition of bortezomib leads to a higher rate of hematologic and clinical responses, and better progression-free and overall survival.


We gratefully acknowledge our colleagues in the Clinical Trials Office, specifically Anthony Shelton, RN, Carol Antonelli, and Kathleen T. Finn, NP, and the staff of the Solomont Center for Cancer and Blood Disorders at Boston Medical Center who assisted with the multidisciplinary evaluation and treatment of the patients. We also thank Dr. Gheorghe Doros for assistance with statistical design.


The information provided by the authors about contributions from persons listed as authors and in acknowledgments is available with the full text of this paper at www.haematologica.org.

Financial and other disclosures provided by the authors using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are also available at www.haematologica.org.


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