Multiple Myeloma: A Review of 92 Cases at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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1 Multiple Myeloma: A Review of 92 Cases at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Salem H. Khalil, MB, BS; M. Andrew Padmos, BA(Hons), MD, FRCP(C); Peter Ernst MD, PhD; Hugh M. Clink, MB, BS, FRCPath From the Departments of Pathology and Laboratory Medicine (Dr. Khalil) and Oncology (Drs. Padmos, Ernst, Clink), King Faisal Specialist Hospital and Research Centre, Riyadh. Address reprint requests and correspondence to Dr. Khalil: Department of Pathology, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Accepted for publication 12 December A review of 92 cases of multiple myeloma (66 males and 26 females) seen at the King Faisal Specialist Hospital and Research Centre from October 1975 through December 1987 revealed the age for affected patients ranged from 23 to 90 years (mean, 56 years). Six percent of the patients were less than 40 years old at the time of diagnosis. Bone pain was the most common presenting symptom in our patients (80%), most frequently involving the back. Anemia was the initial finding in 74%, followed by plasmacytoma (22.8%), hypercalcemia (19.6%), and renal insufficicency (18.5%). Skeletal survey abnormalities were seen in 92.4% of the cases, with osteolytic lesions as the predominant finding. Serum protein electrophoresis showed a monoclonal paraprotein in 78% of the cases, of which 55.5% were the IgG class. Free light chains were detected in the urine of 20 patients. The median survival time for all patients was 68 months. Twenty patients died of renal failure and/or infection. The combination of melphalan and prednisone was used for treatment in 37 patients, while 31 patients received the M2 protocol and 19 patients received different therapy such as VCEP (vindesine, cyclophosphamide, VP 16 and prednisone), MPV (melphalan, prednisone, and vincristine) or high-dose melphalan. Five patients either refused treatment or died before treatment could be started. SH Khalil, MA Padmos, P Ernst, HM Clink, Multiple Myeloma: A Review of 92 Cases at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 1991; 11(6): Multiple myeloma is a systemic malignant neoplasm arising from plasma cells, usually in the bone marrow but occasionally in extramedullary sites. It is usually generalized, causing widespread skeletal destruction, bone marrow failure, renal dysfunction, and problems related to quantitatively abnormal serum or urine protein concentrations or both, such as the hyperviscosity syndrome and infection. Multiple myeloma accounts for about 1% of all types of malignant diseases and slightly more than 10% of hematological malignancies [1]. It is more common in males than in females, and in the USA is twice as common in blacks in whom it represents 7.2% of malignancies [2]. The incidence in Saudi Arabia is still unknown and the only report, which concerned 15 patients seen at Dhahran Health Center, appeared in the Annals of Saudi Medicine three years ago [3]. At the King Faisal Specialist Hospital and Research Centre, which is the largest cancer referral facility in the

2 Kingdom of Saudi Arabia, opened in 1975, a total of 122 myeloma patients and its variants have been seen. Ninetytwo cases of multiple myeloma seen between 1975 and 1987 are reviewed in this study. Twenty-seven cases of solitary localized plasmacytoma and three cases of plasma cell leukemia have been excluded. Patients and Methods The records of all patients with a diagnosis of multiple myeloma who were treated at the King Faisal Specialist Hospital and Research Centre from October 1975 through December 1987 were reviewed. Patients were included in the study if two of the following were present: (1) increased numbers (more than 10% of all nucleated cells) of abnormal, atypical, or immature plasma cells in the bone marrow; (2) the presence of a monoclonal protein in the serum or urine; and (3) skeletal roentgenographic findings consistent with those of myeloma. All patients were treated with chemotherapy ab initio, and radiotherapy for specific indications (pain, fracture, or local lesions). Thirty-seven patients received only melphalan and prednisone. The dosages were 9 mg/m2 p.o. for 5 days and 20 mg/m2 p.o. for five days, respectively. This was repeated at 4- to 6-week intervals, depending on the hematological status of the patient (hemoglobin, > 100 gm/l; WBC, > L; and platelets, > /L). Therapy was continued for two years, or until a stable paraprotein plateau had been reached. Thirty-one patients received the M2 protocol, which consisted of: vincristine, 2 mg IV, Day 1; BCNU, 0.5 mg/kg IV, Day 1; cyclophosphamide, 10 mg/kg IV, Day 1; prednisone, 100 mg p.o. daily, Days 1-4; and melphalan, 0.25 mg/kg p.o. daily, Days 1-4. Treatment was continued at 5- to 6-week intervals up to two years. The remaining 19 patients did not receive a continuous standard therapy as in the first two groups. These treatments were as follows: Eleven patients with nonresponsive disease were controlled with VCEP: vindesine, 6 mg/m2 IV, Day 1; cyclophosphamide, 100 mg p.o. bid, Days 1-5; VP 16,100 mg p.o. bid, Days 1-5; and prednisone, 100 mg daily, Days 1-5. Four patients were treated with vincristine in addition to melphalan and prednisone, while high-dose melphalan (140 mg/m2) was used in two patients and high-dose cyclophosphamide (5 gm/ M2) was used in another two patients. Toward the end of the study period, alpha interferon became available and was used in two patients, both with end-stage, resistant disease. The data were analyzed using a Tandon Plus Personal Computer using R-base and then transferred into a Statgraph package for statistical analysis. The BMDPIL package was also used for survival analysis. Results There were 66 (72%) male patients and 26 (28%) female patients. Patient age ranged from 23 to 90 years (mean, 56 years). The age distribution is shown in Table 1. Major clinical presentations consisted of bone pain, anemia, renal insufficiency, and hypercalcemia. Bone pain was the most common initial presentation, seen in 74 patients (80%), with the lower back and chest wall the most frequent sites. Anemia with a hemoglobin of less than 120 gm/l was found at the time of diagnosis in 68 (74%) of our patients. In 14 (5.2%) patients, the hemoglobin value was less than 80 gm/l. Hypercalcemia with an initial serum calcium concentration greater than 2.80 mmol/l was present in 18 (19.6%) of the patients. Renal insufficiency with a serum creatinine level greater than 140 μηιοι/l was found in 17 (18.5%) of the patients. Age range Table 1. Age distribution. Number of Patients < 40 years years years years years 15 > 80 years 3 Total 92 Patients with plasmacytoma (tumor masses) accounted for 22.8% (N = 21). Extramedullary involvement was noted in three patients, two of whom had involvement of the thyroid gland and one, the eye (Table 2). A skeletal survey was performed in all patients and was abnormal in 85 (92.4%). The most frequent radiological

3 abnormalities and sites are summarized in Table 3. Osteolytic lesions were seen in 89.4%. Generalized osteoporosis was seen in 22 (25.9%), pathological fractures in 15 (17.6%), and vertebral compression in 26 (30.6%). All patients had the following laboratory tests done: full blood count and bone marrow examination (Table 4), serum and urine protein electrophoresis, and Immunoelectrophoresis (Table 5), 24-hour urine protein quantitation, immunoglobulin quantitation, Bence-Jones protein (Bradshaw test), and plasma viscosity (Table 6). Cytogenetic studies were carried out in 28 patients. Two demonstrated nonspecific initial chromosome abnormalities at diagnosis and two others demonstrated specific findings consistent with secondary myelodysplastic changes, 3- to 5- years after treatment with chemotherapy (Table 7). The remainder were normal. The median survival time for the whole group was 68 months. Following the staging system devised by Durie and Salmon [4], 75 (82%) of our patients were in Stage II at the time of diagnosis, seven (8%) were in Stage III, and only nine (10%) were in Stage I. Among the patients with Stage I disease, only two were dead by the end of the study. One died at 19 months with renal failure and the other at 75 months with disease resistant to chemotherapy and cerebral hemorrhage. All patients with Stage III disease either died within the first ten months or were discharged to their original primary hospital for terminal care. Discussion It is not known if the behavior of multiple myeloma in Saudi Arabia is different from that observed for other parts of the world. In our group of patients, no significant difference from other studies was noted in terms of age, sex distribution, clinical presentation, radiological changes, monoclonal protein class, nor hematological and cytogenetic findings [5]. Table 2. Frequency of major clinical presentations and laboratory findings at presentation. Features Frequency (%) Bone pain 80 Anemia (Hgb < 120 gm/l) 74 Tumor mass 22.8 Hypercalcemia 19.6 Weakness and fatigue 19.6 Renal insufficiency 18.5 Weight loss 17.4 Table 3. Summary of skeletal survey findings positive in 85 patients. Finding Frequency (%) Osteolytic lesions 89.4 Skull 60.5 Chest wall 59.2 Spine 48.7 Pelvis 47.4 Femur 39.5 Humerus 22.4 Others 23.7 Vertebral compression 30.6 Osteoporosis 25.9 Pathological fractures 17.6

4 Table 4. Peripheral blood and bone marrow findings in 92 patients. Hgb = hemoglobin; WBC = white blood cell. Finding Percentage Peripheral blood Hgb <120 gm/l 74 Hgb < 80 mg/l 15.2 WBC < 4 109/L 8.7 WBC > /L 10.9 Platelets < /L 6.5 Platelets > /L 10.9 Bone marrow Diagnostic 89.1 Nondiagnostic 10.9 In this review, all but one of our patients received chemotherapy as soon as the initial investigations had been completed, since all were symptomatic. No periods of observation were possible because most were in Stage II or III. Onder [3], in a report of a small group of cases with multiple myeloma from the Eastern Province of Saudi Arabia, also found that his patients presented at a relatively advanced stage. Chemotherapy is the preferred initial treatment for overt, symptomatic multiple myeloma, and in all our patients, cytotoxic therapy was the treatment of choice, with or without palliative irradiation for local pain control, soft tissue swelling, and pathological fractures. Table 5. Monoclonal protein analysis. Immunoglobulin Frequency (%) IgG 55.5 Kappa 46.7 Lambda 8.8 IgA 22.8 Kappa 9.8 Lambda 13 Free light chain 21.7 Kappa 15.2 Lambda 6.5 Table 6. Miscellaneous laboratory investigations. Test 24-hour urine protein quantitation > 0.2gm/d % Positive 50.9 Plasma viscosity > Quantitative IgG > 18 gm/l 51.2 < 7 gm/l 16.3 Quantitative IgA > 6 gm/l 17.4 < 0.5 gm/l 30.2 Quantitative IgM > 5 gm/l 00.0 < 0.3 gm/l 53.5 Bence Jones protein (Bradshaw test) 35.7

5 Table 7. Cytogenetic findings. CHROMOSOMAL ABNORMALITIES AT DIAGNOSIS 1. One cell showed multiple extra and missing chromosomes. 2. Two cells showed -4, -8, -13, +3, +5, +9, +15, +18, + 19, +21, 20q +, 22q-, Xp-, +M2. CHROMOSOME ABNORMALITIES POST THERAPY 1. 46, XX,-7, +M, t(18q;?) // 45, XX, -7, t( 18q;?) 2. 44, X, -Y -5, -7, -17, del 5 del 17, 16q-, 21q+ One cell 45, XY, -18, 20q Melphalan and prednisone have for many years been the standard regimen in most clinical trials for multiple myeloma. These drugs are known to yield a 50% response rate with a medial survival of about 30 months [6]. An approach to treatment, similar to that used in acute leukemia with multidrug therapy, has also been tested with variable results, but there is no definite evidence showing its superiority. One study by Harley et al [7] showed improved survival for one subgroup of patients with a poor prognosis, using a three-drug combination plus prednisone (cyclophosphamide, melphalan, and BCNU). Low-risk patients (Stage I) appeared to do better on melphalan and prednisone therapy, but by definition have a lower disease burden and slower tempo of progression. Vincristine may have a beneficial role, as evaluated by the South West Oncology Group [8], but this has not been fully confirmed [9,10]. In a multi-drug study [9], using vincristine, melphalan, cyclophosphamide, and prednisone, alternating with a combination of vincristine, cyclophosphamide, adriamycin, and prednisone, or vincristine, BCNU, adriamycin, and prednisone, there was a 75% tumor mass regression in 53% of the patients with a median survival time of 40 months. A response rate of 32% and median survival of 24 months was observed when melphalan and prednisone were used alone. Figure 1. Survival time for the entire group of 92 patients with multiple myeloma. Despite the need for early treatment in our group of patients, the median survival time of the whole group is 68 months, which compares very favorably with other studies. The majority were, however, in Stage II at diagnosis. Approximately 9% of our patients were lost to follow-up within 1- to 2- years. This is a recurring problem in

6 Saudi Arabia, together with a significant degree of noncompliance. With the recent enormous advances in medical services available in Saudi Arabia, the referral pattern and follow-up should improve. The pattern of response versus the treatment received will be the subject of a second communication. Acknowledgment We would like to thank Professor Peter B. Herdson for his critical review of this manuscript and also to thank Mr. Salah Algain, Dr. Edward B. DeVol, and Mr. Mashnouf Al-Rowaily from the Department of Biomedical Statistics and Scientific Computing for their constructive comments on statistical analysis. The authors would like to extend their thanks to Dr. David Spence and Dr. George Roberts for their comments on the clinical data. References 1. Kyle RA. Multiple myeloma: a review of 869 cases. Mayo Clin Proc 1975;50: Oken MN. Multiple myeloma. Med Clin North Am 1984;68(3): Onder O. Multiple myeloma: Dhahran Health Center experience. Ann Saudi Med 1987;7(l): Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Cancer 1975;36: Ahmed MH, Motawy MS. Multiple myeloma in Kuwait: clinical features as a prognostic index. J Kuwait Med Assoc 1981;15: Bergsagel PE. Controversies in treatment of plasma cell myeloma. Postgrad Med J 1985;61: Harley JB, Pajak TF, McIntyre OR, et al. Improved survival of increased-risk myeloma patients on combined triple-alkylating agent therapy: a study of CALGB. Blood 1979;54: Alexanian R, Salmon S, Bonnet J, et al. Combination chemotherapy for multiple myeloma. Cancer 1977;40: Cornwell GG, Pajak TF, Kochwa S, et al. Comparison of oral melphalan, CCNU, and BCNU with and without vincristine and prednisone in the treatment of multiple myeloma. Cancer 1982;50: Salmon SE, Haut A, Bonnet JD, et al. Alternative combination chemotherapy and levamisole improves survival on multiple myeloma: a Southwest oncology group study. J Clin Oncol 1983;1: