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Prospective Randomized Trial of Melphalan and Prednisone Versus Vincristine, Carmustine, Melphalan, Cyclophosphamide, and Prednisone in the Treatment of Primary Systemic Amyloidosis

From the Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.

Address reprint requests to Morie A. Gertz, MD, Mayo Clinic, Division of Hematology and Internal Medicine, 200 First St SW, Rochester, MN 55905; Email gertm{at}mayo.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Primary systemic amyloidosis is an immunoglobulin deposition disorder in which insoluble light chains cause organ dysfunction and death. The established conventional therapy is treatment with melphalan and prednisone. We investigated whether treatment with multiple alkylating agents improved the response rate or survival time, compared with melphalan and prednisone therapy.

PATIENTS AND METHODS: We treated 101 patients with biopsy-proven primary amyloidosis. The patients were randomly assigned to receive melphalan and prednisone (52 patients) or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (49 patients). Patients were stratified according to the presence of cardiac involvement, time from diagnosis to randomization, serum beta₂-microglobulin level, and whether peripheral neuropathy was the major manifestation of the disease.

RESULTS: The median duration of survival after randomization was 29 months, with no differences in survival time between the two groups. There were 29 patients who fulfilled the response criteria: 15 in the vincristine, carmustine, melphalan, cyclophosphamide, and prednisone arm and 14 in the melphalan and prednisone arm.

CONCLUSION: Therapy with multiple alkylating agents did not result in a higher response rate or longer survival time, compared with standard melphalan and prednisone treatment in patients with primary systemic amyloidosis.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PRIMARY SYSTEMIC AMYLOIDOSIS is an uncommon disease characterized by the deposition of a fibrillar protein composed of a monoclonal light chain or fragment thereof.¹ Involvement of the heart, kidney, or liver can result in organ dysfunction and early death. The median survival time for patients with this disease is approximately 18 months.² When only patients seen at the Mayo Clinic within 30 days after their diagnoses are included to decrease the bias caused by the overrepresentation of patients who are well enough to travel, the median survival time is 13 months.³ The current standard therapy includes the use of melphalan and prednisone to destroy the plasma cells responsible for producing the precursor light chains.^4,5

Unfortunately, despite the use of melphalan and prednisone, only a minority of patients demonstrate an objective response (30%). Problems with the use of melphalan and prednisone include the bioavailability of melphalan and the difficulty of being certain that adequate absorption occurs in any individual patient.⁶

In an Eastern Cooperative Oncology Group Multiple Myeloma Trial, a comparison of melphalan and prednisone therapy with that of vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) showed a significantly higher objective response rate with VBMCP (P < .001).⁷ Both regimens were well tolerated. Although this did not translate into survival time benefit in cases of multiple myeloma, in amyloidosis a reduction of M protein synthesis required for a response could translate into a reduced deposition of amyloid into the organs and could lead to an ultimately improved survival time.⁸ Moreover, the tumor burden in amyloidosis is substantially less than the plasma cell burden in multiple myeloma, and more intensive chemotherapy may demonstrate a higher response in patients with the reduced plasma cell load.

In this prospective study, patients with biopsy-proven primary systemic amyloidosis were stratified according to four factors known to impact survival and were then randomly assigned to one of two regimens: melphalan and prednisone or VBMCP.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Amyloidosis was confirmed histologically in all patients. Patients with secondary, familial, and localized amyloidosis were excluded. Patients with primary amyloidosis who had only cutaneous involvement, such as purpura or carpal tunnel syndrome, were excluded from participation. Patients may not have received any prior cytotoxic chemotherapy. Patients were also excluded from participation if they had a direct bilirubin concentration greater than 2 mg/dL, a serum creatinine concentration greater than 5 mg/dL, a granulocyte count less than 750/µL, or a platelet count less than 50,000/µL. Patients with overt multiple myeloma were also excluded from participation. All patients provided written informed consent before their entry onto the study, and the protocol and consent form were approved by the Institutional Review Board of the Mayo Foundation in accordance with the Declaration of Helsinki.

To ensure that they had primary systemic amyloidosis, the patients must each have satisfied one of the following three criteria: (1) they had a demonstrable light or heavy chain in their serum or urine as evident by immunoelectrophoresis or immunofixation, (2) they had a clonal population of plasma cells, which was observed by use of cytoplasmic immunoglobulin fluorescence, with clonal restriction demonstrated,⁹ or (3) any amyloid deposits present must have shown positive immunohistochemical staining with kappa or lambda immunoglobulin light chain in addition to amyloid P component immunohistochemical staining.^10,11

After their informed consent was obtained, the patients were stratified according to the following four criteria: (1) the presence or absence of cardiac amyloid as demonstrated by the presence of symptomatic congestive heart failure or echocardiographic demonstration of an interventricular septal thickness of 15 mm or more,¹² (2) a histologic diagnosis of amyloidosis established more than 6 months before study randomization, (3) a beta₂-microglobulin value of 2.7 µg/mL or more,¹³ and (4) peripheral neuropathy as the major manifestation of amyloidosis.¹⁴

The patients were assigned to treatment with melphalan (0.15 mg/kg) and prednisone (0.8 mg/kg) daily for 7 days or vincristine (1.4 mg/m²), given intravenously on day 1, carmustine (20 mg/m²), given intravenously on day 1, melphalan (8 mg/m²), given orally daily for 4 days, cyclophosphamide (400 mg/m²), given intravenously on day 1, and prednisone (40 mg/m²), given orally daily for 7 days. These cycles were repeated every 6 weeks. Leukocyte and platelet counts were monitored. If no myelosuppression was seen in the melphalan and prednisone arm, the melphalan dose was increased by 2 mg in each 6-week course until midcycle leukopenia or thrombocytopenia developed. Patients continued to receive chemotherapy for 18 cycles unless signs of serious toxicity developed. Dose modifications for melphalan, carmustine, and cyclophosphamide were incorporated in cases in which the platelet count decreased to below 100,000/µL and neutrophil count decreased to below 2,000/µL. For those patients who entered the study with a serum creatinine concentration between 2 and 5 mg/dL, the first treatment cycle was provided but with a 50% reduction in cytotoxic agents. Vincristine was omitted for all patients who had amyloid peripheral neuropathy. Because the majority of patients were treated at locations that were a great distance from the primary randomization center, accurate information regarding the specific toxicities engendered during therapy could not be obtained accurately for these patients.

Response Rate Measurements
Our response rate criteria have been defined.¹⁵ For patients with a dominant renal amyloid, a 50% decrease in their 24-hour urine albumin excretion level in the absence of an increase in the serum creatinine concentration was required. In patients with hepatic involvement, the response criterion was a 50% reduction in the serum alkaline phosphatase level with no increase in transaminase or bilirubin levels or liver size. In cases of echocardiographic regression of amyloidosis of the heart, the response criterion was a decrease of 2 mm in the thickness of the interventricular septum or an increase of 20 percentage points in the ejection fraction. Patients were monitored for the disappearance of the serum monoclonal protein or a reduction of more than 50% in the protein level, although neither was a formal response criterion. Also, the disappearance of the urinary monoclonal protein or a decrease of more than 50% in the protein level was monitored.

Baseline variables in the two treatment groups were assessed using the Mann-Whitney U test for continuous variables and 2 x 2 contingency tables for nominal variables (Fisher's exact test). Survival curves and statistical analyses were done using Kaplan-Meier and log-rank testing. A multivariate analysis of variables having an impact on survival time was performed with Cox's model. All P values were two-sided; analysis was performed using the Statview software packages (Berkeley, CA). On the basis of the median survival time of patients with amyloidosis, as previously reported,³ the study was designed to detect an improvement in median survival time from 12 to 18 months with a power of 80% at the P < .05 level. This study would not have the power to detect minimal differences in the two treatments.

	RESULTS

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Of the 101 patients enrolled in this study from August 1991 through October 1997, none were excluded from analysis, and none were lost to follow-up. All satisfied the criteria of primary amyloidosis, with 93 demonstrating a monoclonal immunoglobulin light chain in the serum or urine, five demonstrating monoclonal bone marrow plasma cells, and three having direct immunoglobulin light-chain staining of the amyloid deposits.

Table 1 shows the chief initial findings for the patients in the study. Analyses of the two treatment groups were performed for age; number of months between diagnosis and the initiation of therapy; size of the urine protein electrophoresis M spike; 24-hour urine protein, serum albumin, serum creatinine, serum cholesterol, serum alkaline phosphatase, and beta₂-microglobulin values; size of the serum M spike; C-reactive protein level; bone marrow labeling index; percentage of bone marrow plasma cells; presence of symptomatic heart failure; interventricular septal thickness; and ejection fraction. There was no statistically significant difference in these variables between the two groups, with the exception of age (age, P < .01; all others, P > .20). The median age of the VBMCP group was 60 years and that of the melphalan prednisone group was 65 years (P < .01).

Table 2 lists the various syndromes present in patients at the time they entered the study. Because many patients had more than one organ manifestation of amyloidosis, the sum is greater than 101. Of the six in the other category, all of whom had systemic amyloidosis, there was one with hemorrhage secondary to factor X deficiency, two with amyloid lymphadenopathy, two with amyloid arthropathy, and one with a resected soft tissue amyloidoma. Table 3 lists the immunoelectrophoresis and immunofixation results from the serum and urine of all 101 patients. Table 4 lists the tissues that underwent biopsy for confirmation of the diagnosis noninvasively. Of the 12 patients who had no amyloid deposits in subcutaneous fat or bone marrow, six had the diagnosis confirmed with a renal biopsy, two with an endomyocardial biopsy, two with a liver biopsy, one with pleural pericardial stripping, and one with a rectal biopsy. Eleven of the 12 who had negative fat and bone marrow amyloid stains had a monoclonal protein in the serum or urine that led to further invasive diagnostic testing to establish the diagnosis. Although the diagnosis could be established in 87% of patients from subcutaneous fat or bone marrow, endomyocardial biopsy results were positive in 14 of 14 patients, renal biopsy results were positive in 34 of 34 patients, and liver biopsy results were positive in 13 of 14 patients overall.

The time from diagnosis of amyloidosis to randomization ranged from 0 to 26.4 months. The median time from histologic diagnosis to randomization was 1.1 months, and 93 of the 101 patients were randomized to treatment within 6 months after their original diagnosis.

To detect a monoclonal protein in the serum or in the urine, immunoelectrophoresis and immunofixation were required. Of the 76 patients who had a serum monoclonal protein, the median size was 0.53 g/dL, and the protein often did not produce a visible band on the cellulose acetate or agarose electrophoresis. Thirty-four patients had Bence Jones protein present as the only immunoglobulin in the serum. Monoclonal light chains virtually never produce a detectable band on the serum protein electrophoresis. Likewise, the median size of the urine M protein in the 86 patients who had a urine light chain detected was 0.24 g/d. Because so many patients had heavy proteinuria, with a median urinary protein excretion rate of 1.8 g/d, the light chain represented only a fraction of the total urinary proteins present and, in virtually all patients with nephrotic syndrome, was hidden in the nonselective proteinuria that these patients had. Immunoelectrophoresis and immunofixation were required for the recognition of the urinary light chain.

The percentage of plasma cells was determined by a slide-based cytoplasmic immunofluorescent technique.¹⁶ The median number of cytoplasmic immunoglobulin-positive plasma cells was 10. With regard to the echocardiogram, the median interventricular septal thickness was 13 mm (normal, 12 mm or less), and 24 of the patients had an ejection fraction of less than 50% at the time of presentation.

Response to Therapy
At the time of this analysis, 55 of the 101 patients have died, and the median follow-up period of the 46 survivors is 35 months. In the melphalan and prednisone group, 14 patients fulfilled the criteria for a response. Ten patients with renal amyloidosis fulfilled the response criteria. Organ involvement resolved in two patients with renal and hepatic amyloidosis. One patient with renal and cardiac involvement responded, with an improved ejection fraction and a reduction in the interventricular septal thickness, and one patient with hepatic amyloidosis fulfilled the criteria for response.

In the VBMCP group, there were 15 responses. Ten patients had renal responses. One with combined renal and cardiac involvement showed improvement in both organs, two with hepatic-only amyloidosis showed a response, and two patients with combined renal hepatic and cardiac involvement showed a response. Overall, organ by organ, of the 101 patients, 26 showed renal improvement, seven showed improvement in the liver, and four showed improvement in their echocardiographic findings of amyloid (Table 5).

An analysis was undertaken of the hematologic responses on the basis of a greater than 50% reduction of the serum or urine M component or a complete elimination of serum and urine light chains from the patient. Hematologic responses were seen in 30 patients: 14 in the VBMCP group and 16 in the melphalan and prednisone group. There was strong concordance between a hematologic response and an organ response. Twenty patients satisfied the criteria for both a hematologic response and an organ response. Sixty-one patients showed no response either by organ function or by hematologic reduction in the serum and urine M component. There were 10 patients who showed evidence of a hematologic response but no organ response, and there were 10 patients who had an organ response but did not satisfy the criteria for a hematologic response. When these four groups were analyzed separately, patients who did not have an organ response but did have a hematologic response had a superior survival time (P = .007), and patients who had an organ response but did not have a hematologic response also had superior survival time (P = .001). When organ response and hematologic response were placed in a Cox multivariate model, both criteria were significant and independent, although organ response had a more powerful impact on survival time (P = .001), compared with hematologic response (P = .03). Both hematologic response and organ response should be considered valid criteria for assessing the impact on survival time in amyloidosis.

Four patients, two in the melphalan and prednisone group and two in the VBMCP group, developed myelodysplasia as a complication of exposure to alkylating agents. In consideration of the 3 years' median follow-up period of the survivors, this number likely represents an underestimation. In one patient, myelodysplasia developed 36 months after his first exposure to melphalan, with cytogenetic study showing a 45,XY monosomy 7 karyotype analysis. He died 11 months later of complications from myelodysplasia. In a second patient, myelodysplasia developed 35 months after her first exposure to melphalan. Cytogenetic analysis was not performed, and she died 41 months after the initiation of therapy. In a third patient, myelodysplasia developed 15 months after initial chemotherapy exposure, and the patient died 3 months later of complications of pneumonia due to severe granulocytopenia. In the fourth patient, myelodysplasia developed 16 months after initial exposure. Cytogenetic study showed a trisomy 8. This patient died 21 months after entry onto the study. In 11 patients, renal failure ultimately developed, for which dialysis was required. Ten of the 11 received hemodialysis, and 1 received peritoneal dialysis. Six of the patients died, and five remain alive. For the six patients who died, the survival time after dialysis began was 1.7 to 22.2 months.

Survival Time
The median survival time for all patients from randomization was 29 months, with no significant difference between the two groups (Fig 1). A multivariate analysis revealed that serum alkaline phosphatase and ejection fraction, both as continuous variables, were capable of predicting an adverse outcome (P < .001 for both variables). Of the 55 deaths, the cause of death was as follows: 31, cardiac-related; five, infection; four, hepatic failure; three, voluntarily cessation of dialysis; two, renal failure; four, myelodysplastic syndrome; one, respiratory failure due to pulmonary amyloid; and two, nutritional failure due to advanced intestinal amyloid. The cause of death was unknown in three patients. The presence of symptomatic congestive heart failure was a significant predictor of overall survival time. The 24 patients with overt congestive heart failure had a median survival time of 9.5 months, which was significantly different from that of patients who did not present with symptomatic congestive heart failure (P = .006). In the congestive heart failure group, there was no survival time difference between those patients treated with melphalan and prednisone versus those treated with VBMCP (P = .55).

View larger version (9K): [in this window] [in a new window]   Fig 1. Kaplan-Meier survival curve of 101 amyloidosis patients receiving either melphalan and prednisone (MP) or vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) (P = not significant).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
No great strides have been made in the treatment regimen for primary systemic amyloidosis since the first use of melphalan and prednisone was reported by Cohen et al¹⁷ in 1975.¹⁸ Natural history studies have demonstrated that the median survival time of patients who were evaluated within 30 days after their diagnosis is only 1 year.³ Despite the use of melphalan and prednisone at the Mayo Clinic for more than 20 years, median survival times of no more than 25 months and 18 months have been reported.^19,20 Although melphalan and prednisone are more effective than colchicine, only a minority of patients ultimately respond to treatment (30%), and the treatment therefore cannot have a profound impact on survival time. Therefore, better modalities are needed. Because multiagent chemotherapy has been reported to produce higher response rates, but not better survival time, in cases of multiple myeloma, it seemed reasonable to consider a multidrug regimen for patients with amyloidosis. Unfortunately, we were unable to demonstrate any difference in overall response rate or survival time in patients treated in this fashion.

One concern that we have with regard to this study is the fact that the median survival time seems to be superior to that of other studies in which melphalan and prednisone were used.^4,5,10,11 This raises the question of selection bias in the recruitment of patients onto this study. In all prior studies of therapy, the treatment was specifically oral and could be tolerated by virtually anyone. Because the study presented here involves the use of three parenteral agents with a total of five chemotherapy drugs in an already debilitated population, we are concerned that patients might have been excluded from enrollment on the basis of their physician's suspicion that the patient would be intolerant of therapy. Had this not been a prospective randomized study but a phase II trial of VBMCP, it would raise the possibility that VBMCP is a superior regimen for the management of amyloidosis, which is clearly not the case.

A second concern is the imbalance between the two treatment arms, which is related to a 5-year age difference. Unlike prior studies, age was not a stratification criterion for entry onto this study. Fortunately, in other multivariate analyses of survival time, age does not appear to be an important prognostic factor.²¹ In addition, the younger group, which might be expected to have a longer survival time, received VBMCP. Yet there was no survival time advantage to VBMCP, which suggests that the age difference, although it is significant, should not impact the interpretation of our results.

The concern alluded to above about the improved outcome in this cohort applies to all single-arm studies in amyloidosis in which patients may be selected on the basis of their ability to tolerate the therapy proposed. Recently published advances in the management of amyloidosis have included high-dose dexamethasone,²² 4'-iodo-4'-deoxydoxorubicin,²³ and stem-cell transplantation.^24,25 These innovative therapies may improve the prognosis and outcome for patients with amyloidosis, but in a single-arm study, the selection of patients eligible for enrollment will need to be considered in the interpretation of the overall results. These therapies may enhance the therapeutic options available to patients with this devastating disorder.

In conclusion, the addition of multiple alkylating agents in the treatment of patients with biopsy-proven primary systemic amyloidosis improved neither response rate nor survival time over that seen with melphalan and prednisone alone.

	ACKNOWLEDGMENTS

 
Supported in part by Research Grant CA62242 from the National Institutes of Health and QUADE Amyloidosis Research Fund

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Merlini G: Treatment of primary amyloidosis. Semin Hematol 32:60-79, 1995[Medline]

2. Kyle RA, Greipp PR: Amyloidosis (AL): Clinical and laboratory features in 229 cases. Mayo Clin Proc 58:665-683, 1983[Medline]

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4. Kyle RA, Gertz MA, Greipp PR, et al: A trial of three regimens for primary amyloidosis: Colchicine alone, melphalan and prednisone, and melphalan, prednisone, and colchicine. N Engl J Med 336:1202-1207, 1997[Abstract/Free Full Text]

5. Skinner M, Anderson J, Simms R, et al: Treatment of 100 patients with primary amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100:290-298, 1996[Medline]

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7. Oken MM, Harrington DP, Abramson N, et al: Comparison of melphalan and prednisone with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone in the treatment of multiple myeloma: Results of Eastern Cooperative Oncology Group Study E2479. Cancer 79:1561-1567, 1997[Medline]

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16. Greipp PR: Prognosis in myeloma. Mayo Clin Proc 69:895-902, 1994[Medline]

17. Cohen HJ, Lessin LS, Hallal J, et al: Resolution of primary amyloidosis during chemotherapy: Studies in a patient with nephrotic syndrome. Ann Intern Med 82:466-473, 1975

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20. Kyle RA, Greipp PR, Garton JP, et al: Primary systemic amyloidosis: Comparison of melphalan/prednisone versus colchicine. Am J Med 79:708-716, 1985[Medline]

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22. Dhodapkar MV, Jagannath S, Vesole D, et al: Treatment of AL-amyloidosis with dexamethasone plus alpha interferon. Leuk Lymphoma 27:351-356, 1997[Medline]

23. Gianni L, Bellotti V, Gianni AM, et al: New drug therapy of amyloidoses: Resorption of AL-type deposits with 4'-iodo-4'-deoxydoxorubicin. Blood 86:855-861, 1995[Abstract/Free Full Text]

24. Comenzo RL, Vosburgh E, Simms RW, et al: Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: One-year follow-up in five patients. Blood 88:2801-2806, 1996[Abstract/Free Full Text]

25. Comenzo RL, Vosburgh E, Falk RH, et al: Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: Survival and responses in 25 patients. Blood 91:3662-3670, 1998[Abstract/Free Full Text]

Submitted May 18, 1998; accepted September 30, 1998.

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