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Long-term, disease-free survival in a patient with IgA multiple myeloma
BRIEF CLINICAL
OBSERVATIONS
TABLE I Gastric Emptying Results Cisapride
10 mg Three Times a Day*
Baseline
WWW Solid lag phase (minutes) Retention of the solid meal at 100 minutes (%) Liquid 50% emptying time (minutes)
8/31/88
5/17/89
Normal
Range [1,2,5]
24
<65
9”:
z:
14
<61
45
22
15
<31
Begun on April 27, 1988.
s9mT~ sulfur colloid-chicken liver, and the liquid meal was 150 mL of 10% dextrose labeled with 113mInDTPA. The time taken for esophageal emptying of a bolus of the solid meal was also measured [1,2,4,5]. The gastric emptying test was performed at 10 A.M., after the patient had fasted overnight. This test demonstrated a gross delay in gastric emptying of both solid and liquid meals (Table I). Esophageal emptying was also delayed at 186 seconds (normal, less than 90 seconds) [1,2,5]. Treatment with cisapride (Janssen Pharmaceutics Inc.) in a dose of 10 mg orally three times a day, 30 to 60 minutes before meals, was commenced on April 27, 1988, and continued since that time. The patient has had no further hospital admissions or severe hypoglycemic episodes, and his gastrointestinal symptoms have totally resolved. Subsequent gastric emptying measurements, obtained on August 31, 1988, and May 17, 1989, at 10 A.M., after the patient had taken cisapride 10 mg orally at 9 A.M., demonstrated a considerable and sustained improvement in solid and liquid gastric emptying (Table I). Although the dramatic fluctuations in blood glucose are no longer observed, there has been no significant change in glycosylated hemoglobin measurements. Our previous study [5] demonstrated that cisapride, when administered for four weeks, is effective in the treatment of diabetic gastroparesis. This observation is in contrast to the gastrokinetic effects of metoclopramide [3] and domperidone [4] in diabetic gastroparesis, which are not sustained. The rate of gastric emptying of indigestible solid particles in patients with diabetic gastroparesis is also improved by cisapride [6]. In the current case, we have demonstrated that the beneficial effect of cisapride may be maintained for at 196
February
1990
The American
Journal
least 12 months and that it therefore appears to be the first effective long-term treatment for diabetic gastroparesis. We suspect that the improvement in our patient’s glycemic control was related to the use of cisapride, but clearly cannot be certain on this point. Nevertheless, we would suggest that type I diabetic patients with unexplained poor glycemic control should be screened for gastric emptying abnormalities. M. HOROWITZ. M.B.B.~., Ph.D., F.i.A.C.P: 4.P. ROBERTS, M.B.B.s., F.R.A.C.P. Royal Adelaide Hospital Adelaide, Australia 1. Horowitz M, Harding PE. Maddox A, et al: Gastric and oesophageal emptying in insulin-dependent diabetes mellitus. J Gastroenterol Hepatol 1986; 1: 97113. 2. Horowitz M, Harding PE, Maddox AF. et al: Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1989; 32: 151-159. 3. Schade RR, Dugas MC, Lhotsky DM, Gavaler JS, van Thiel DH: Effect of metoclopramide on gastric liquid emptying in patients with diabetic gastroparesis. Dig Dis Sci 1985; 30: lCL15. 4. Horowitz M. Harding PE, Chatterton BE, Collins PJ, Sherman DJC: Acute and chronic effects of domperidone on gastric emptying in diabetic autonomic neuropathy. Dig Dis Sci 1985; 30: l-9. 5. Horowitz M, Maddox A, Harding PE, et al: Effect of cisapride on gastric and oesophageal emptying in insulin-dependent diabetes mellitus. Gastroenterology
1987; 92: 1899-1907. 6. Feldman M, Smith HJ: Effect of cisapride on gastric emptying of indigestible solids in patients with gastroparesis diabeticorum. A comparison with metoclopramide and placebo. Gastroenterology 1987; 92: 171-174. Submitted August 23, 1989, and accepted September 7. 1989
LONG-TERM DISEASE-FREE SURVIVAL Id A PATIENT WITH IgA MULTIPLE MYELOMA Multiple myeloma is a disease characterized by the proliferation of neoplastic plasma cells. Many patients initially respond to cheof Medicine
Volume
88
motherapy and enter a plateau phase of variable duration; their mean survival is usually two to three years. The presence of severe anemia, hypercalcemia, or moderate degrees of azotemia before treatment is often associated with a significantly worse prognosis [l]. The presence of pleural effusion due to plasma cell invasion is also considered to indicate a poor prognosis [2]. Moreover, the prognosis is usually found to be poorer in patients who respond rapidly to therapy than in those showing a slow response [3]. We herein report on a patient with IgA myeloma who has no evidence of residual disease except persistent osteolytic lesions after 11 years of follow-up, despite the initial presence of features usually associated with a poor prognosis-severe anemia, malignant pleural effusion, and a rapid response to chemotherapy. To our knowledge, this is the first patient with IgA myeloma who has survived for longer than 10 years without evidence of disease. In March 1978, a 43-year-old woman was admitted because of bilateral exophthalmos, diplopia, and dyspnea. Physical examination disclosed three tumors of the anterior chest wall and dullness in the left lower lung field. Laboratory study showed the following values: hemoglobin 8.4 g/dL, serum creatinine 1.7 mg/dL, and serum calcium 11.2 mg/dL. Serum protein electrophoresis showed a monoclonal spike of 4.3 g/dL in the /3 region. Subsequent immunoelectrophoresis revealed an IgA X monoclonal protein. The 24-hour urinary excretion of protein was 10.2 g. Bone marrow aspiration showed 58% abnormal plasma cells. Bone radiographs demonstrated multiple lytic lesions in the skull and ribs. Chest roentgenograms disclosed a left-sided massive pleural effusion, and pleurocentesis was performed. The aspirated pleural fluid was found to contain many abnormal plasma cells (Figure 1). The patient underwent chemotherapy with 500 mg of cyclophosphamide given as a one-hour intravenous infusion every two to three weeks, plus 40 mg of prednisolone daily for two weeks. Dyspnea, diplopia, subcutaneous tumors, and the pleural effusion had virtually disappeared by the end of May 1978. No protein was detectable in a 24-hour urine specimen collected on June 24,1978, and no spike was
BRIEF CLINICAL OBSERVATIONS
Figure 1. Atypical plasma cells in the pleural effusion (Wright-Giemsa stain; original magnification X400, reduced by 10%).
visible on serum protein electrophoresis. Long-term follow-up of the patient was subsequently performed on an outpatient basis. Cyclophosphamide was continued orally, at a dosage ranging from 50 to 100 mg daily, until January 1, 1985. She has currently survived 11 years since the diagnosis of myeloma and four years since discontinuing her medication, and has no evidence of disease. Protein electrophoresis, immunoelectrophoresis, and immunofixation of the serum and urine have shown normal results, the most recent series of tests being in January 1989. Repeated bone marrow aspirations have revealed no evidence of multiple myeloma. The bone surveys remain unchanged, with minimal evidence of recalcification of the lytic lesion. A few patients with symptomatic multiple myeloma have survived for 10 years or longer, Kyle [4] reported that 19 (2.2%) of a series of 870 patients with overt multiple myeloma survived for longer than 10 years. In a series of 305 patients, Alexanian [5] reported 13 (4.3%) who survived longer than 10 years. Most patients with overt myeloma who survive 10 years or longer have persistent symptoms requiring chemotherapy, and only occasionally do patients with multiple myeloma become asymptomatic after they respond to chemotherapy. However, even these patients still tend to have evidence of residual myeloma after many years. Only two patients with symptomatic multiple myeloma (one with IgG
myeloma, the other with IgD myeloma) have ever been reported who showed a complete response to treatment with alkylating agents and had no evidence of multiple myeloma more than 10 years after diagnosis [6,7]. Although patients with multiple myeloma usually survive only two to three years, it is important for physicians to realize that some patients can show an impressive response to chemotherapy, resulting in long survival and even cure. However, the following problems remain to be solved before this fact becomes clinically significant: (1) Are there any characteristics common to patients in whom longterm, disease-free survival is possible with the appropriate therapy? (2) Can the prognosis of the subgroup of patients defined by these characteristics be improved by the use of aggressive treatment? HIROSHI KAMESAKI, M.D. HIROYUKI AMANO,M.D. SHI~EMI TOYODA, Ph.D. YOHICHIRO OHNO, M.D. TAKANOBU IMANAKA, M.D. YUTAKA TAKAHASHI, M.D. Tenri Hospital Mishima 200 Tenri, Nara, Japan 1. Alexanian R, Balcerzak S, Bonnet JD, et a/; Prognosticfactors In multiple myeloma. Cancer 1975: 36: 1192-1201. 2. Hughes JC, Votaw ML: Pleural effusion in multiple myeloma. Cancer 1979; 44: 1150-1154. 3. Hansen OP, Jessen B, Videbaek A: Prognosis of myelomatosis on treatment wtth prednisone and cytostatics. Stand J Haematol 1973; 10: 282-290. 4. Kyle RA: Long-term survival in multiple myeloma. N Engl J Med 1983: 308: 314-316. 5. Alexanian R: Ten-year survival in multlple myeloma. Arch Intern Med 1985; 145: 2073-2074. 6. Dutcher JP, Wiernik PH: Long-term survival of a
February
1990
patient with multiple myeloma-a cure? Cancer 1984; 53: 2069-2072. 7. Kyle RA: IgD multiple myeloma: a cure at 21 years. Am J Hematol 1988; 29: 41-43. Submitted
July 13. 1989, and accepted in revised form September 7, 1989
CHRONIC MYELOGENOUS LEUKEMIA COMPLICATED BY fJJ;;MUNE HEMOLYTIC Autoimmune hemolysis is a frequent complication of certain diseases with abnormal immunologic reactivity. Systemic lupus erythematosus and malignant lymphoproliferative disorders are the most common entities associated with autoimmune hemolysis. Autoimmune hemolytic anemia is a rare feature of chronic myelogenous leukemia and is even denied by some authors [l]. However, a few cases have been reported [2,3], and we herein report another one. The patient was a 55-year-old black man who in January 1985 sought medical attention because of heartburn after spicy foods. His white blood cell count was 109,000/ mm3 and he had an enlarged spleen. The leukocyte alkaline phosphatase score was 5 (normal, 16 to 120), and the result of a bone marrow examination was compatible with the diagnosis of chronic myelogenous leukemia. The patient was treated with busulfan intermittently. The patient was first seen in our Hematology Unit in September 1985. The white blood cell count was 85,000/mm3, and busulfan
The American
Journal
of Medicine
Volume
88
197
OBSERVATIONS
TABLE I Gastric Emptying Results Cisapride
10 mg Three Times a Day*
Baseline
WWW Solid lag phase (minutes) Retention of the solid meal at 100 minutes (%) Liquid 50% emptying time (minutes)
8/31/88
5/17/89
Normal
Range [1,2,5]
24
<65
9”:
z:
14
<61
45
22
15
<31
Begun on April 27, 1988.
s9mT~ sulfur colloid-chicken liver, and the liquid meal was 150 mL of 10% dextrose labeled with 113mInDTPA. The time taken for esophageal emptying of a bolus of the solid meal was also measured [1,2,4,5]. The gastric emptying test was performed at 10 A.M., after the patient had fasted overnight. This test demonstrated a gross delay in gastric emptying of both solid and liquid meals (Table I). Esophageal emptying was also delayed at 186 seconds (normal, less than 90 seconds) [1,2,5]. Treatment with cisapride (Janssen Pharmaceutics Inc.) in a dose of 10 mg orally three times a day, 30 to 60 minutes before meals, was commenced on April 27, 1988, and continued since that time. The patient has had no further hospital admissions or severe hypoglycemic episodes, and his gastrointestinal symptoms have totally resolved. Subsequent gastric emptying measurements, obtained on August 31, 1988, and May 17, 1989, at 10 A.M., after the patient had taken cisapride 10 mg orally at 9 A.M., demonstrated a considerable and sustained improvement in solid and liquid gastric emptying (Table I). Although the dramatic fluctuations in blood glucose are no longer observed, there has been no significant change in glycosylated hemoglobin measurements. Our previous study [5] demonstrated that cisapride, when administered for four weeks, is effective in the treatment of diabetic gastroparesis. This observation is in contrast to the gastrokinetic effects of metoclopramide [3] and domperidone [4] in diabetic gastroparesis, which are not sustained. The rate of gastric emptying of indigestible solid particles in patients with diabetic gastroparesis is also improved by cisapride [6]. In the current case, we have demonstrated that the beneficial effect of cisapride may be maintained for at 196
February
1990
The American
Journal
least 12 months and that it therefore appears to be the first effective long-term treatment for diabetic gastroparesis. We suspect that the improvement in our patient’s glycemic control was related to the use of cisapride, but clearly cannot be certain on this point. Nevertheless, we would suggest that type I diabetic patients with unexplained poor glycemic control should be screened for gastric emptying abnormalities. M. HOROWITZ. M.B.B.~., Ph.D., F.i.A.C.P: 4.P. ROBERTS, M.B.B.s., F.R.A.C.P. Royal Adelaide Hospital Adelaide, Australia 1. Horowitz M, Harding PE. Maddox A, et al: Gastric and oesophageal emptying in insulin-dependent diabetes mellitus. J Gastroenterol Hepatol 1986; 1: 97113. 2. Horowitz M, Harding PE, Maddox AF. et al: Gastric and oesophageal emptying in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1989; 32: 151-159. 3. Schade RR, Dugas MC, Lhotsky DM, Gavaler JS, van Thiel DH: Effect of metoclopramide on gastric liquid emptying in patients with diabetic gastroparesis. Dig Dis Sci 1985; 30: lCL15. 4. Horowitz M. Harding PE, Chatterton BE, Collins PJ, Sherman DJC: Acute and chronic effects of domperidone on gastric emptying in diabetic autonomic neuropathy. Dig Dis Sci 1985; 30: l-9. 5. Horowitz M, Maddox A, Harding PE, et al: Effect of cisapride on gastric and oesophageal emptying in insulin-dependent diabetes mellitus. Gastroenterology
1987; 92: 1899-1907. 6. Feldman M, Smith HJ: Effect of cisapride on gastric emptying of indigestible solids in patients with gastroparesis diabeticorum. A comparison with metoclopramide and placebo. Gastroenterology 1987; 92: 171-174. Submitted August 23, 1989, and accepted September 7. 1989
LONG-TERM DISEASE-FREE SURVIVAL Id A PATIENT WITH IgA MULTIPLE MYELOMA Multiple myeloma is a disease characterized by the proliferation of neoplastic plasma cells. Many patients initially respond to cheof Medicine
Volume
88
motherapy and enter a plateau phase of variable duration; their mean survival is usually two to three years. The presence of severe anemia, hypercalcemia, or moderate degrees of azotemia before treatment is often associated with a significantly worse prognosis [l]. The presence of pleural effusion due to plasma cell invasion is also considered to indicate a poor prognosis [2]. Moreover, the prognosis is usually found to be poorer in patients who respond rapidly to therapy than in those showing a slow response [3]. We herein report on a patient with IgA myeloma who has no evidence of residual disease except persistent osteolytic lesions after 11 years of follow-up, despite the initial presence of features usually associated with a poor prognosis-severe anemia, malignant pleural effusion, and a rapid response to chemotherapy. To our knowledge, this is the first patient with IgA myeloma who has survived for longer than 10 years without evidence of disease. In March 1978, a 43-year-old woman was admitted because of bilateral exophthalmos, diplopia, and dyspnea. Physical examination disclosed three tumors of the anterior chest wall and dullness in the left lower lung field. Laboratory study showed the following values: hemoglobin 8.4 g/dL, serum creatinine 1.7 mg/dL, and serum calcium 11.2 mg/dL. Serum protein electrophoresis showed a monoclonal spike of 4.3 g/dL in the /3 region. Subsequent immunoelectrophoresis revealed an IgA X monoclonal protein. The 24-hour urinary excretion of protein was 10.2 g. Bone marrow aspiration showed 58% abnormal plasma cells. Bone radiographs demonstrated multiple lytic lesions in the skull and ribs. Chest roentgenograms disclosed a left-sided massive pleural effusion, and pleurocentesis was performed. The aspirated pleural fluid was found to contain many abnormal plasma cells (Figure 1). The patient underwent chemotherapy with 500 mg of cyclophosphamide given as a one-hour intravenous infusion every two to three weeks, plus 40 mg of prednisolone daily for two weeks. Dyspnea, diplopia, subcutaneous tumors, and the pleural effusion had virtually disappeared by the end of May 1978. No protein was detectable in a 24-hour urine specimen collected on June 24,1978, and no spike was
BRIEF CLINICAL OBSERVATIONS
Figure 1. Atypical plasma cells in the pleural effusion (Wright-Giemsa stain; original magnification X400, reduced by 10%).
visible on serum protein electrophoresis. Long-term follow-up of the patient was subsequently performed on an outpatient basis. Cyclophosphamide was continued orally, at a dosage ranging from 50 to 100 mg daily, until January 1, 1985. She has currently survived 11 years since the diagnosis of myeloma and four years since discontinuing her medication, and has no evidence of disease. Protein electrophoresis, immunoelectrophoresis, and immunofixation of the serum and urine have shown normal results, the most recent series of tests being in January 1989. Repeated bone marrow aspirations have revealed no evidence of multiple myeloma. The bone surveys remain unchanged, with minimal evidence of recalcification of the lytic lesion. A few patients with symptomatic multiple myeloma have survived for 10 years or longer, Kyle [4] reported that 19 (2.2%) of a series of 870 patients with overt multiple myeloma survived for longer than 10 years. In a series of 305 patients, Alexanian [5] reported 13 (4.3%) who survived longer than 10 years. Most patients with overt myeloma who survive 10 years or longer have persistent symptoms requiring chemotherapy, and only occasionally do patients with multiple myeloma become asymptomatic after they respond to chemotherapy. However, even these patients still tend to have evidence of residual myeloma after many years. Only two patients with symptomatic multiple myeloma (one with IgG
myeloma, the other with IgD myeloma) have ever been reported who showed a complete response to treatment with alkylating agents and had no evidence of multiple myeloma more than 10 years after diagnosis [6,7]. Although patients with multiple myeloma usually survive only two to three years, it is important for physicians to realize that some patients can show an impressive response to chemotherapy, resulting in long survival and even cure. However, the following problems remain to be solved before this fact becomes clinically significant: (1) Are there any characteristics common to patients in whom longterm, disease-free survival is possible with the appropriate therapy? (2) Can the prognosis of the subgroup of patients defined by these characteristics be improved by the use of aggressive treatment? HIROSHI KAMESAKI, M.D. HIROYUKI AMANO,M.D. SHI~EMI TOYODA, Ph.D. YOHICHIRO OHNO, M.D. TAKANOBU IMANAKA, M.D. YUTAKA TAKAHASHI, M.D. Tenri Hospital Mishima 200 Tenri, Nara, Japan 1. Alexanian R, Balcerzak S, Bonnet JD, et a/; Prognosticfactors In multiple myeloma. Cancer 1975: 36: 1192-1201. 2. Hughes JC, Votaw ML: Pleural effusion in multiple myeloma. Cancer 1979; 44: 1150-1154. 3. Hansen OP, Jessen B, Videbaek A: Prognosis of myelomatosis on treatment wtth prednisone and cytostatics. Stand J Haematol 1973; 10: 282-290. 4. Kyle RA: Long-term survival in multiple myeloma. N Engl J Med 1983: 308: 314-316. 5. Alexanian R: Ten-year survival in multlple myeloma. Arch Intern Med 1985; 145: 2073-2074. 6. Dutcher JP, Wiernik PH: Long-term survival of a
February
1990
patient with multiple myeloma-a cure? Cancer 1984; 53: 2069-2072. 7. Kyle RA: IgD multiple myeloma: a cure at 21 years. Am J Hematol 1988; 29: 41-43. Submitted
July 13. 1989, and accepted in revised form September 7, 1989
CHRONIC MYELOGENOUS LEUKEMIA COMPLICATED BY fJJ;;MUNE HEMOLYTIC Autoimmune hemolysis is a frequent complication of certain diseases with abnormal immunologic reactivity. Systemic lupus erythematosus and malignant lymphoproliferative disorders are the most common entities associated with autoimmune hemolysis. Autoimmune hemolytic anemia is a rare feature of chronic myelogenous leukemia and is even denied by some authors [l]. However, a few cases have been reported [2,3], and we herein report another one. The patient was a 55-year-old black man who in January 1985 sought medical attention because of heartburn after spicy foods. His white blood cell count was 109,000/ mm3 and he had an enlarged spleen. The leukocyte alkaline phosphatase score was 5 (normal, 16 to 120), and the result of a bone marrow examination was compatible with the diagnosis of chronic myelogenous leukemia. The patient was treated with busulfan intermittently. The patient was first seen in our Hematology Unit in September 1985. The white blood cell count was 85,000/mm3, and busulfan
The American
Journal
of Medicine
Volume
88
197