Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Melphalan and prednisone were more effective than colchicine for primary amyloidosis

ACP J Club. 1997 Nov-Dec;127:71. doi:10.7326/ACPJC-1997-127-3-071


Source Citation

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. 1997 Apr 24;336: 1202-7.


Abstract

Objective

To assess the effectiveness of combinations of colchicine, melphalan, and prednisone in patients with primary amyloidosis.

Design

Randomized controlled trial.

Setting

Mayo Clinic, Minnesota, United States.

Patients

220 patients (median age 64 y) who had biopsy-confirmed primary systemic amyloidosis. Exclusion criteria were secondary, familial, senile, or localized amyloidosis; overt symptomatic multiple myeloma or diarrhea; or previous receipt of alkylating drugs or colchicine.

Intervention

Patients were stratified according to age, sex, and major clinical manifestations and were allocated to colchicine, 0.6 mg twice daily (n = 72); melphalan, 0.15 mg/kg of body weight, and prednisone, 0.8 mg/kg daily, for 7 days every 6 weeks (n = 77); or melphalan, prednisone, and colchicine at the same doses and frequencies (n = 71). The doses of colchicine and melphalan were increased until adverse effects developed.

Main outcome measures

Duration of survival and treatment response. Treatment response was assessed by repeated measurements of abnormal protein levels (increase ≥ 1 g in serum albumin, ≥ 50% decrease in serum monoclonal protein, ≥ 50% decrease in urinary monoclonal protein, and ≥ 50% decrease in urinary protein in the absence of worsening renal insufficiency).

Main results

The median duration of survival in patients who received colchicine alone; melphalan and prednisone; and melphalan, prednisone, and colchicine was 8, 18, and 17 months, respectively (P < 0.001). Response to therapy occurred in more patients who received melphalan and prednisone or mel-phalan, prednisone, and colchicine than in patients who received colchicine alone (P < 0.001) (Table).

Conclusion

Patients with primary amyloidosis who received melphalan and prednisone had a greater response to treatment and longer survival than patients who received colchicine.

Sources of funding: In part, National Institutes of Health and Quade Amyloidosis Research Fund.

For article reprint: Dr. R.A. Kyle, Mayo Clinic, 200 First Street South West, Rochester, MN 55905, USA. FAX 507-266-4972.


Table. Melphalan and prednisone (MP) and melphalan, prednisone, and colchicine (MPC) vs colchicine (C)*

Treatment response at 2 y EER CER RBI (95% CI) ABI |EER-CER| NNT (CI)
MP vs C 29% 2.8% 929% (185 to 3770) 26% 4 (3 to 7)
MPC vs C 28% 2.8% 914% (179 to 3729) 25% 4 (3 to 7)

*Treatment response defined in Main outcome measures. Abbreviations defined in Glossary; RBI, ABI, NNT, and CI calculated from data in article.


Commentary

The trial by Kyle and colleagues shows no role for colchicine in the management of patients with primary amyloidosis. An important observation in this study is the improved overall median survival in the patients who achieved a serum or urinary monoclonal protein response (50 vs 36 mo, P = 0.03). This encouraging result supports the need to investigate more intensive therapy, such as high-dose chemotherapy followed by rescue therapy with peripheral stem cells (1) or intensive high-dose dexamethasone (2).

The evaluation of organ function in amyloidosis helps define the extent of disease and prognosis. Cardiac complications of amyloidosis are the most frequent cause of death (3). The best predictor of cardiac death is the early-to-late peak diastolic flow velocity ratio (E/A); in fact, the E/A ratio and the deceleration time, both simple measures of diastolic filling function, are more predictive of cardiac death than are the typical echocardiographic variables of mean ventricular wall thickness used in this study (4). Future studies should consider using the E/A ratio and decelerating time to evaluate the cardiac status of patients with primary amyloidosis.

Patients with primary amyloidosis should be entered into studies for the evaluation of novel and innovative therapies. In the meantime, treatment with melphalan and prednisone should be considered.

Mohamad Hussein, MD
Cleveland Clinic Myeloma ProgramCleveland, Ohio, USA


References

1. Comenzo RL, Vosburgh E, Sarnacki DL, et al. Blood. 1995;86(Suppl 1):206A.

2. Chidiac TA, Bukowski RM, Klein AL, Hussein MA. Proceedings of the American Society of Clinical Oncology. 1997;16:41A.

3. Kyle RA, Greipp PR. Mayo Clinic Proceedings. 1983;58:665-83.

4. Klein AL, Hatle LK, Taliercio CP, et al. Circulation. 1991;83:808-16.