We designed a trial using two sequential cycles of modified high-dose melphalan at 100 mg/m2 and autologous SCT (mHDM/SCT) in AL amyloidosis (light-chain amyloidosis, AL), AL with myeloma (ALM) and host-based high-risk myeloma (hM) patients through SWOG-0115. The primary objective was to evaluate OS. From 2004 to 2010, 93 eligible patients were enrolled at 17 centers in the United States (59 with AL, 9 with ALM and 25 with hM). The median OS for patients with AL and ALM was 68 months and 47 months, respectively, and has not been reached for patients with hM. The median PFS for patients with AL and ALM was 38 months and 16 months, respectively, and has not been reached for patients with hM. The treatment-related mortality (TRM) was 12% (11/93) and was observed only in patients with AL after SCT. Grade 3 and higher non-hematologic adverse events were experienced by 81%, 67% and 57% of patients with AL, ALM and hM, respectively, during the first and second HDM/SCT. This experience demonstrates that with careful selection of patients and use of mHDM for SCT in patients with AL, ALM and hM, even in the setting of a multicenter study, OS can be improved with acceptable TRM and morbidity.
In AL amyloidosis (light-chain amyloidosis, AL), BM plasma cells produce monoclonal light chains that misfold and deposit in organs as amyloid fibrils, resulting in organ failure and death.1 Untreated AL patients have a median survival of 10–14 months.2 The introduction of high-dose melphalan and SCT (HDM/SCT) in the 1990s markedly improved survival.3, 4 Single and multicenter studies show hematologic complete response (CR) rates of 16–67%, organ responses in 25–45% of patients and a median OS of >5 years.5 A major issue in HDM/SCT for AL is the potential for high treatment-related mortality (TRM) because of underlying organ dysfunction. High TRM was one of the confounding factors in the single randomized phase III multicenter trial comparing HDM/SCT and oral therapy in the literature.6 However, recent reports from experienced centers have reported a TRM rate in the range of 1–15% as a result of improved patient selection and better peritransplant management.5, 7, 8 Ten-year survival was 25% for AL patients receiving HDM/SCT and 50% when hematologic CR was achieved.9 These trials have generally excluded patients with AL, who also met the criteria for symptomatic myeloma (AL with myeloma (ALM)).
The developmental approach of HDM/SCT in AL was prompted by promising results in myeloma, leading to improvement in hematologic responses, disease-free survival and OS.10, 11 This has been studied in myeloma in single and multicenter phase II and III randomized studies with benefits in newly diagnosed and relapsed settings. Studies that have shown the benefit of this therapy usually excluded patients >65 years of age and those with renal dysfunction, primarily due to concern about increased toxicities in such patients. Some trials have included patients up to 75 years old and with renal insufficiency, with promising results.12, 13 These studies suggest that non-hematologic toxicities, median disease-free survival and OS are similar for patients older and younger than 65 years of age.13 In another study, patients older than 70 years were treated with modified high-dose melphalan (mHDM) (140 mg/m2) with acceptable mortality rates.12 This has also been demonstrated for AL patients >65 years of age.14
As the median age is 65 years for myeloma, the Myeloma Committee of the SWOG cooperative group designed a trial to study SCT in patients with AL, in those with ALM and in older patients with myeloma who had renal failure (host-based high-risk myeloma, hM). The primary objective of this trial was to determine OS after HDM/SCT in these patients. Secondary objectives were to evaluate the feasibility/tolerability of this aggressive treatment in a multicenter study as well as hematologic responses.
Patients and methods
Study design and eligibility criteria
This clinical trial was approved by the Institutional Review Boards of all the participating centers in accordance with federal regulations. All patients provided written informed consent as per the Declaration of Helsinki.
The study design consisted of sequential registration to induction therapy, followed by two cycles of mHDM/SCT (MEL100) and maintenance therapy.
The eligibility criteria for participation in this study for AL patients required a tissue diagnosis of amyloidosis with evidence of underlying clonal plasma cell dyscrasia, as indicated by an abnormal clonal dominance of plasma cells in the BM and/or detection of a monoclonal gammopathy by immunofixation electrophoresis of serum and urine and/or an abnormal serum free light-chain ratio and concentration. Patients were 18 years of age or older. Previous non-transplant treatment for AL was allowed but the cumulative dose of prior oral melphalan must have been <200 mg. Other eligibility criteria included a Zubrod performance status score of ⩽2, left ventricular ejection fraction >45% and recommended carbon monoxide diffusing capacity ⩾50%. Patients requiring dialysis for end-stage renal disease were not excluded if other eligibility criteria were met. Patients with AL who also met the criteria for myeloma were included but analyzed separately.
The eligibility criteria for those with hM included age ⩾70 years and/or serum creatinine >2 mg/dL or calculated creatinine clearance <50 mL/kg/min. Other standard diagnostic criteria for the diagnosis of symptomatic stage II or III myeloma had to be met.
ALM patients were defined as those with organ damage due to amyloid fibril deposition and concomitant myeloma with hypercalcemia, lytic bone disease and BM plasmacytosis of >30%.
Treatment protocols were different for patients with AL, ALM and hM. Patients with hM and ALM received two cycles of induction therapy with thalidomide 200 mg per day along with dexamethasone 20 mg on days 1–4, 9–12 and 17–20, every 28 days. Patients with AL received no induction and maintenance therapy. PBSCs were collected following G-CSF mobilization in AL and following CY (2.5 g/m2) and G-CSF in ALM and hM patients, and a minimum yield of 7.0 × 106 CD34+ cells per kg was required. Patients then received a first cycle of mHDM (MEL100 mg/m2). At least half of the collected stem cells were infused 48 h following melphalan.
Following the first cycle of treatment, patients received a second cycle of MEL100 followed by SCT of their cryopreserved stem cells within 3–6 months of the first cycle.
Patients with ALM and hM then received maintenance treatment for 2 years, consisting of thalidomide 100 mg per day with dexamethasone 40 mg on days 1–4 every 28 days for the first year, following which they received thalidomide 50 mg/day with dexamethasone 40 mg on days 1–4 every 28 days for the second year. Patients unable to undergo a second SCT were not allowed to receive maintenance treatment on this clinical trial.
Toxicity and response criteria
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAEv3) was used to grade adverse events.
Response criteria: AL
The response criteria for hematologic and organ response in AL followed definitions by the consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis.15 At the time of commencement of this study, measurement of serum free Ig light chains was not available at many institutions, nor was it available commercially, and hence this assay was not used for eligibility or response determination in all patients.
Response criteria: ALM and hM
The response criteria for hematologic response and progression for hM were those proposed by the European Group for Blood and Marrow Transplant.16
All patients were followed for hematologic response at 3, 6 and 12 months and annually thereafter until death, 5 years after registration, or until progression, whichever occurred first.
Design and statistical analyses
The primary objective of this study was to estimate OS in patients with AL, ALM and hM treated with two cycles of mHDM/SCT. In SWOG-9210,17 the OS was 50% in hM patients aged ⩾70 years with or without renal insufficiency after 18 months of follow-up, and in SWOG-962818 the OS was 57% in AL patients after 18 months of follow-up. On the basis of these data, this regimen of mHDM/SCT would be considered promising if the true 18-month OS from registration was ⩾70%, and would be of no further interest if the true 18-month OS was 57% or less. The study was designed such that, with 100 eligible patients, the power of a one-sided test at 0.05 level of 57% versus 70% for an 18-month OS would be 86%. The Kaplan–Meier method was used to evaluate OS and PFS. Univariate and multivariate Cox regression analyses were used to determine the correlation of prognostic factors with OS and PFS.
Between 2004 and 2010, 104 patients were registered on this trial. Eleven patients were removed before receiving any protocol treatment (seven were ineligible and four withdrew consent). Thus, this analysis is restricted to the remaining 93 analyzable patients. The progression of 93 eligible patients throughout the study protocol is outlined in Figure 1. A total of 17 SWOG institutions participated in this study, with nine institutions contributing fewer than five patients, which constituted 15% of total accrual.
Patient characteristics are summarized in Table 1. There were 59 patients with AL, 9 with ALM and 25 with hM. The performance status was Zubrod 1 or better in 89% of patients. The median number of organs involved with AL was 2 (range, 1–8). Involvement of a single organ was present in 25% (24/68), with isolated renal involvement in 54% (13/24). Cardiac involvement occurred in 32% (22/68) of AL patients. The median serum creatinine level was 1.7 mg/dL (range, 0.8–10.0) for hM patients. There were five patients with hM (20%) with creatinine clearance of <10 mL/kg/min and on dialysis. Seventy-two patients registered to the transplant phase of the trial, of whom 67 were eligible. Forty-one patients completed two cycles of SCT.
Treatment experience: AL
Of the 65 patients registered with AL, 4 were ineligible and 2 withdrew consent. Overall, 32 patients were removed from the study because of toxicity (11), disease progression (1), death (3), patient refusal (1), other reasons (7) and reason not specified (9).
Fifty eligible patients (85%) received an initial cycle of MEL100. There were three deaths (6%) within 100 days of the first mHDM/SCT.
Twenty-eight patients received a second cycle of MEL100. Twenty-two did not receive a second cycle because of toxicity (9), death (2), disease progression (1), patient choice (1), other reasons (5) and reasons not specified (4). There was one death (4%) within 100 days of the second mHDM/SCT.
Treatment experience: hM and ALM
Of the 39 patients registered with hM and ALM, 3 were ineligible and 2 withdrew consent. Overall, 38 patients were removed from the protocol because of progression (5), death (3), patient choice (2), toxicity (7), other reasons (8) and reasons not specified (3). Eighteen patients registered to the transplant phase, of whom 17 were eligible. There were no deaths within 100 days of the first mHDM/SCT.
Thirteen patients received a second cycle of mHDM/SCT. Four patients did not receive a second cycle because of progression (1), patient refusal (1), other reasons (1) and reason not specified (1). Twelve patients initiated maintenance therapy. Among them, three completed therapy, two remained on therapy and seven were removed from treatment for the following reasons: toxicity (3), progression (1), death (1) and other reasons (2).
TRM was defined as death occurring within 100 days of registration, during the stem cell collection and mobilization phase and within 100 days of mHDM/SCT. Overall TRM was 12% (11/93). Seven deaths (8%, 7/93) occurred during the stem cell mobilization and collection phase and three deaths (4%, 3/67) occurred within 100 days of the first SCT and one death (2%, 1/41) occurred within 100 days of initiation of the second SCT. Seven deaths during the stem cell mobilization and collection phase were reported in AL (3), hM (2) and ALM (2) patients. All four deaths after SCT occurred in AL patients. TRM occurred in 4 of the 22 (18%) patients with cardiac involvement.
Treatment-related adverse events
Grade 3 or higher non-hematologic adverse events occurred in 81% (39/48), 67% (2/3) and 57% (8/14) of AL, ALM and hM patients, respectively, during first and second mHDM/SCT. Grade 3 and 4 non-hematologic adverse events occurred in 60% patients during induction, 33% during maintenance in hM patients and in 56% patients during induction, and none of the two evaluable patients during maintenance phases of treatment in ALM patients. (Table 2)
Hematologic responses (partial hematologic response or better) after two cycles of MEL100 occurred in 3 of 14 evaluable patients with AL, in 1 of 2 evaluable patients with ALM and in 4 of 7 evaluable patients with hM. Overall, hematologic progression occurred in 35% of patients. Among the six hM and ALM patients evaluable for response during the maintenance phase, one patient had a response that improved from stable disease to partial hematologic response.
Clinical and organ responses were also evident at 1 year following mHDM/SCT in patients with AL. Four of the 10 evaluable AL patients (40%) experienced a cardiac response. Two of the three evaluable AL patients experienced a renal response.
The median OS for AL patients is 68 months with a median follow-up for surviving patients of 51 months. Similarly, the median OS for ALM patients is 47 months, with a median follow-up for surviving patients of 54 months. The median OS for hM patients has not yet been reached (Figure 2). The estimated 2- and 5-year OS for AL, ALM and hM was 69%, 56% and 80%, and 56%, 42% and 55%, respectively. The estimated 18-month OS for AL, ALM and hM was 73%, 56% and 88%, respectively.
Progression was considered to occur when there was hematologic or organ disease progression, additional therapy was initiated or when death occurred. The median PFS for AL and ALM was 38 months and 16 months, respectively, and has not yet been reached for hM (Figure 2). The estimated 2- and 5-year PFS for AL, ALM and hM was 59%, 44% and 55%, and 50%, 30% and 50%, respectively.
Prognostic factors for OS and PFS
Univariate Cox proportional hazards regression showed that timely initiation of the first and second transplants was significantly associated with improved OS and PFS outcomes (P<0.05). Furthermore, urine protein excretion >0.5 g per day was associated with shorter PFS. In a multivariate model that considered all variables with a univariate P-value ⩽0.1, timely initiation of first transplant and total urine protein excretion >0.5 g per day were highly associated with PFS (Table 3). From the variables examined, no multivariate model for OS could be constructed on the basis of the stepwise selection criteria implemented.
This trial was designed to learn about applying HDM/SCT, an effective therapy for plasma cell diseases, in high-risk patients in a multicenter trial with two cycles of MEL100. Overall TRM was 12% from registration, and similar between the AL, ALM and hM groups. This compares favorably with TRM of 26% in the multicenter IFM trial involving patients with AL undergoing SCT,6 perhaps reflecting patient selection and the use of mHDM.
Median OS was 5.7 years in AL, 3.9 years in ALM and has not been reached in the hM group. PFS was poorest in the ALM group, at only 1.3 years, compared with 3.1 years for the AL group and has not been reached for the hM group.
Overall TRM was 12% in this trial, with 8% occurring during the stem cell mobilization and collection phase. This is higher than expected and was mostly in patients with AL amyloidosis. This reflects the challenges of complexity of this disease; possibly, careful cardiac monitoring, fluid and electrolyte balance, careful selection of patients and referral to experienced centers would decrease this initial higher treatment-related complications.
This study represents one of the largest US multicenter national cooperative group efforts to treat patients with AL. The feasibility of such collaborative efforts, as shown here, demonstrates that, despite careful selection of patients, many patients do not complete the entire proposed protocol-directed treatment. Nonetheless, mHDM/SCT in patients with AL can improve OS with acceptable TRM and morbidity.
Similarly, hM patients, defined by age >65 years and renal dysfunction, have been excluded from most clinical trials demonstrating the efficacy of HDM/SCT. However, myeloma is a disease of older patients, and in this study these patients performed quite well, calling into question whether they should automatically be excluded from transplant clinical trials. A risk-adapted approach is feasible and effective in the hM group. Of note, hM in this trial was defined on the basis of host factors rather than on gene expression profiling, cytogenetics or FISH analysis.
Use of mHDM (MEL100) before SCT has not been studied widely. A small series of 30 AL patients, who were ineligible to receive 200 mg/m2 of HDM/SCT because of age, lower ejection fraction and poor performance status, were treated with two cycles of MEL100 at a single center.19 The TRM in this study was 20%, and on a median follow-up of 27 months 57% of patients were alive and 17% achieved a hematologic response and 40% achieved an organ response. Only 5 of the 30 patients (17%) received a second course of SCT. The patients undergoing a second course of SCT in this study were possibly sicker than those in the current study because of advanced cardiac involvement with lower ejection fraction. Furthermore, results of mHDM/SCT (MEL100) in myeloma have been promising as they have shown prolonged OS in older patients20, 21, 22 (Table 4). It is of note that these studies did not use maintenance treatment. In current study, use of planned two cycles of mHDM/SCT led to manageable toxicities and prolonged OS in hM as well as AL patients. Of note, only 56% of AL patients received a second cycle of SCT compared with 72% of hM patients, again emphasizing the complexity and medical frailty of patients with AL and organ dysfunction.
There are several limitations of our current study: (1) The distinction between different categories of clonal plasma cell diseases, AL, hM and ALM, is arbitrary. ALM patients were defined as those with organ damage due to amyloid fibril deposition and concomitant myeloma with hypercalcemia, lytic bone disease and BM plasmacytosis of >30%. (2) Patient attrition rate was very high because of ineligibility, toxicity and other reasons. (3) At the time of designing the trial in 2001, second-generation immunomodulatory agents, as well as proteasome inhibitors, were not available, and hence the choice of induction and maintenance regimens. Further, data on patients who received novel agents for progression are not available, as this may have contributed to prolonged OS. Moreover, the toxicities and adverse events associated with high-dose thalidomide and dexamethasone could be the reasons for the patient attrition in this study. (4) Contemporary testing of cardiac biomarkers and serum free light chain assay were not included in this trial because of the conception of trial design before the advent of these tests for staging in AL. (5) OS prolongation could be the effect of the use of novel agents at the time of progression and is in comparison with traditional treatments and not novel agents. (6) Only 21% of evaluable AL patients and 57% of evaluable hM patients achieved a hematologic PR or better. These rates are much lower than those in other reports, possibly because of the use of a lower dose of melphalan and because only 41 patients (60%) received two cycles of planned SCT. Furthermore, even fewer patients received maintenance treatment for hM for 2 years, now considered standard.23, 24 As there are no data supporting the use of induction and maintenance in AL patients, these were not used.
In conclusion, despite the use of mHDM/SCT in this multicenter trial, many patients did not complete the entire protocol-directed treatment. Nonetheless, MEL 100 can improve OS and PFS, with acceptable treatment-related complications in AL, ALM and hM. This is a cooperative group-designed trial that has completed accrual and has long-term follow-up. Recently, the E4A08 trial of the Eastern Cooperative Oncology Group studying a combination of bortezomib, melphalan and dexamethasone in AL was closed prematurely because of slower-than-expected accrual. Improved accrual on and enrollment into these national multicenter clinical trials is of crucial importance in studying various treatment options in these rare diseases. This trial represents an important collaborative effort. Timing and sequencing of regimens containing novel agents, and comparison with or combination with one or two cycles of HDM/SCT, will be determined in future trials.
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This investigation was supported in part by the following PHS Cooperative Agreement grant numbers awarded by the National Cancer Institute, DHHS: CA32102, CA38926, CA37981, CA76448, CA35431, CA20319, CA76132, CA04919, CA46441, CA14028, CA58861, CA58416, CA12644, CA22433, CA46368, CA45377, CA35090 and CA46113.
VS received research funding from Celgene, Onyx and Millennium; DCS received research funding from Celgene; and RZO received research funding from Celgene, Onyx, Johnson and Johnson and Millennium. Other authors declare no conflict of interest.
VS: concept and design, data analysis and interpretation, manuscript writing; AH: concept and design, collection and assembly of data, data analysis and interpretation, final approval of manuscript; DCS: data analysis and interpretation, final approval of manuscript; KTF: collection and assembly of data, data analysis and interpretation, final approval of manuscript; SAF: collection and assembly of data, data analysis and interpretation, final approval of manuscript; RS: concept and design, collection and assembly of data, data analysis and interpretation, concept and design, data analysis and interpretation; BM: final approval of manuscript; HFS: final approval of manuscript; LAH: final approval of manuscript; RMD: final approval of manuscript; ROZ: final approval of manuscript; and BB: concept and design, data analysis and interpretation, final approval of manuscript.
About this article
High-dose melphalan and autologous peripheral blood stem cell transplantation in patients with AL amyloidosis and cardiac defibrillators
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