INSTITUTE OF ONCOLOGY, LJUBLJANA
TREATMENT OF REFRACTORY MYELOMA WITH HUMAN LEUKOCYTE INTERFERON ALPHA IN COMBINATION WITH HALF BODY IRRADIATION AND MELPHALAN - A
CASE PRESENTATION
Plesnicar A, Petric G, Zwitter M, Jereb B
Abstract — A female patient with refractory myeloma progressing during third line chemotherapy, was treated with human leukocyte interferon in combination with half body irradiation and melphalan. After an objective response the disease has stabilized during 18 months from the start of the treatment. The combination of human leukocyte interferon and half body irradiation, together with chemotherapeutic agents, seems to be an encouraging approach to treatment of advanced refractory myeloma.
UDC: 616-006.448-08
Key words: myeloma-therapy, interferon type 1, radiotherapy, melphalan Case report
Radiol lugosl 1989; 23: 279-81
lntroduction — Survival of patients with multiple myeloma has improved with the introduction of alkylating agents (usually melphalan or cyclophosphamide) and better supportive care. It has improved from a median of 7 months in the 1950 s to about 30 months at present (1). Nevertheless, in about 30% to 50% of patients we do not achieve a response with first treatment, and all of those who initially respond to standard treatment finally experience relapse. Reinduction therapy usually is of no effect (2, 3).
Options for patients with advanced and/ or refractory myeloma include treatment with interferon or with systemic radiotherapy. Results of interferon therapy published in the late 1970 s and in the early 1980s showed response rates between 8% and 33%. No clear difference in response rate was observed in patients with previously treated or untreated myeloma. The duration of response varied, from 1 to 25+ months (2, 4, 5). Whole body irradiation (WBI) and half body irradiation (HBI) have been used in the treatment of refractory myeloma since 1942. Relief of pain was reported in nearly all and objective responses in approximatelly one third of patients. The median survival of patients treated with WBI was 13 months and it was 11 months in patients treated with HBI (2, 6).
We report here on a female patient with multiple myeloma with progression of the disease during third line chemotherapy. She was then successfuly treated with a combination of human leukocyte interferon alpha (HLl-alpha), HBI and melphalan.
Methods — To identify the M-component in serum and in concentrated urine immune fixation after agarose electrophoresis was used. Serum albumin, alpha 1, alpha 2, beta and gamma globulin concentrations were determined by protein electrophoresis on celogel. Serum immunoglobulin (lgG, lgA, lgM) concentrations were determined immunochemically with laser nephelometry or with radial immunodiffusion. Bone marrow specimens were obtained by aspiration biopsies, plasma cells were determined according to the method described by Rohr (7).
The patient's disease was staged according to the system proposed by Durie and Salmon (8), clinical response was defined according to the criteria proposed by the Committee of the Chronic Leukemia Myeloma Task Force. For an »objective response« to therapy at least one of the following criteria has to be fulfilled: (a) >50% reduction in serum M-protein concentrations; (b) > 50% reduction in urinary M-protein excre-
Received: April 21, 1989 — Accepted: May 9, 1989
279
Plesnicar A et al. Treatment of refractory myeloma with human leukocyte interferon alpha in combination with half body irradiation and melphalan.
tion; (c) 50 % decrease in cross-sectional area of a plasmacytoma; or (d) recalcification of bone lesions without development of new lesions.
HLl-alpha was supplied by lmmunological Institute, Zagreb, Yugoslavia. It was given by intramuscular injection diluted in 5 milliliter distilled water. HBls were delivered from a Cobalt source (Theratron 80, AECL), no shielding was used.
Case history — In September 1984 a 55 years old female was admitted to the Institute of Oncology, Ljubljana, Yugoslavia, because of 2 months long severe back pain, fever and weight loss. The results of the laboratory tests made at the time of admmission are shown in Table 1. lgG kappa was identified as serum M-protein, no
Tests	Results	Normal values	
E.S.R. (mm/h)	80	0-1	5
Hb (g/L) q	104	120-	-140
White cells (X 109/L) Thrombocytes (X 10S/L)	5.4	4.0-	10.0
	250	140-	-340
Serum albumin (g/L)	30.5	35-	50
Serum alpha 1 glubulin (g/L)	5.9	1.6-	3.4
Serum alpha 2 globulin (g/L)	5.4	4.5-	-8.5
Serum beta globulin (g/L)	11.4	5.4-	10.0
Serum gamma globulin (g/L)	30.9	9.1-	17.0
Serum lgG (g/L)	38.53	7.6-	20.0
Serum lgA (g/L)	1.22	1.15	-4.0
Serum lgM (g/L)	0.51	0.8-	2.5
Serum creatinine (micromol/L)	68	71-	-106
Serum calcium (mmol/L)	2.5	2.1-	2.6
Abbreviations:
E.S.R.: Erythrocyte sedimentation rate Hb: Hemoglobin
Table 1 — Laboratory findings at the time of the first admission
Bence-Jones protein was found in urine. Bone marrow aspirate examination showed 113 plasma cells and 37 erythroblasts. Skeletal X-rays revealed osteolytic lesions in the skull, ribs, pelvis and spine. Her disease was staged as III A.
Primary treatment consisted of systemic chemotherapy with melphalan and corticosteroids, irradiation of painful sites and HBI of 500 cGy to the upper and 300 cGy to the lower half of the body after 6 weeks interval. There was no objective response. In July 1986, 7 months after primary treatment, progression of the disease was observed. After treatment with cyclophosphamide, vincristine and corticosteroids, and then with third line chemotherapy consisting of vincristine, BCNU, adriamycin and corticosteroids (VBAP) the disease progressed continuously. After the third cycle of VBAP in July 1987 the patient was bedridden, with debilitating pain in the back and in both hips. Her performance status was 30 % according to Karnofsky scale. The treatment with intramuscular injections of 2,8 X 106 IU of HLl-alpha three times weekly was started. In the first and in the second week of treatment with HLl-alpha, the patient was additionally treated with HBI of the lower half of the body, each time with 250 cGy. No immediate side effects were noticed and pain relief occurred. In november 1987, after 3 months of continuous treatment with HLl-alpha toxic side effects were observed: Nausea, diarrheas, insomnia and fever. Therefore, HLl-alpha was given intermittently and combined with melphalan. Every 4 to 6 weeks the patient receives 2 X 106 IU of HLl-al-pha for three days and then continues with melphalan in standard doses for four days.
Tests
Months after the start of the treatment with HLl-alpha, HBI and M
	0	1	3	4	6	8	10	12	14	16	18
E.S.R.	36	_	65	65	77	65	57	44	53	33	48
Hb	115	126	101	115	109	108	112	121	121	133	140
White cells	4.6	4.4	2.6	3.1	2.6	4.3	3.7	3.2	2.3	2.8	3.1
Thrombocytes	287	257	242	232	177	176	193	234	225	257	299
Serum albumin	38.2	36.2	34.5	—	40.0	43.8	—	47.18	-	—	—
Serum lgG	22.62	—	25.84	—	24.31	25.42	21.64	-	25.68	—	—
Serum lgA	0.8	—	1.41	—	1.17	1.38	1.18	—	1.51	—	—
Serum lgM	0.36	—	0.66	—	0.78	0.69	0.65	—	0.79	—	—
Serum creatinine	92	77	104	—	—	92	104	106	—	-—	—
Serum calcium	2.4	—	2.1	—	2.6	2.3	2.4	—	2.3	—	—
Myelogram											
Erythroblasts (cells/100L)	10	—	46	—	—	—	51.5	—	—	—	—
Plasma cells (cells/100L)	9	—	8	—	—	—	13	—	—	—	—
Abbreviations:	HLl-alpha: Human leukocyte interferon alpha
E.S.R.: Erythrocyte sedimentation rate	HBI: Half body irradiation
Hb: Hemoglobin	M: Melphalan
L: Leukopoietic cells
Table 2 — Laboratory findings after the start of the treatment with HLl-alpha and HBI (first three months) and later with HLl-alpha and M. For units and normal values see Table 1
280	Radiol lugosl 1989; 23: 279-81
Plesnicar A et al. Treatment of refractory myeloma with human leukocyte interferon alpha in combination with half body irradiation and melphalan
In 18 months since the start of treatment with HLl-alpha in combination with HBI and melphalan objective response has been achieved. Remineralisation of the bone lesions in the pelvis was noticed in may 1988 and has continued untii present. Both lgA and lgM have reached nearly normal levels and the results of other tests have improved (Table 2). Performance status has improved to 60 %. The patient now walks with sticks and is hospitalized only during the applications of HLl-alpha and melphalan.
Discussion — After unsuccessful treatment with three different combinations of chemotherapy clinical response and stabilisation of multiple myeloma were achieved in our patient with HLl-alpha, HBI and melphalan. This remission is at present stable tor 18 months, and the patient is alive 54 months from diagnosis. The results of treatment of refractory multiple myeloma with sequential HBI alone or HLl-alpha alone reported earlier, have not been very encouraging, the response rates were low and the durations of remissions short (2, 4, 5, 6). In our patient, in whom remission was achieved, the duration of the stable condition is longer than in similar patients treated with interferon or sequential HBI alone (10, 11). Even a change from progression to a static state has been considered a result (12). There is evidence tor interferon to enhance the effect of irradiation as well as the effect of different chemotherapeutic agents (13, 14). It is therefore possible that treatment with combination of HLl-alpha, sequential HBI and melphalan in a larger group of patients with multiple myeloma would result in better remission rates and longer duration of remissions.
Povzetek
ZDRAVLJENJE REFRAKTARNEGA MIELOMA S HUMANIM LEVKOCITNIM INTERFERONOM ALFA V KOMBINACIJI Z OBSEVANJEM POLOVICE CELEGA
TELESA IN MELFALANOM — PRIKAZ PRIMERA
Pri bolnici z refraktarnim mielomom je bolezen napredovala med zdravljenjem s sistemsko kemoterapijo tretjega reda. Zdravili smo jo s humanim levkocitnim interferonom alfa v kombinaciji z obsevanjem polovice celega telesa in melfalanom. Po objektivnem odgovoru je v 18 mesecih od začetka zdravljenja nastopila stabilizacija bolezni. Kombinacija humanega levkocitnega
interferona z obsevanjem polovice telesa in melfalanom najverjetneje predstavlja nov možen način zdravljenja napredovalega refraktarnega mieloma.
References
1.	Bergsagel DE. Use a gentle approach for refractory myeloma patients. J Ciin Oncol 1988; 6: 757—8.
2.	Buzaid AC, Durie BGM. Management of refractory myeloma: A review. J Clin Oncol 1988; 6: 889—905.
3.	Zaniboni A, Simoncini E, Marpicati P, Montini E, Rossi G, Marini G. Peptichemio, teniposide and highdose dexamethasone: A new active combination for relapsing and refractory multiple myeloma. A pilot study. Anticancer Res 1988; 8: 125—8.
4.	Mellstedt H, Ahre A, Bjorkholm M, Holm G, Johansson B, Strander H. Interferon therapy in myelomatosis. Lancet 1979; 1: 245—7.
5.	Ohno R. Interferon in the treatment of multiple myeloma. lnt J Cancer 1987; Suppl 1: 14—20.
6.	Rostom AY. A review of the place of radiotherapy in myeloma with emphasis on whole body irradiation. Hematol Oncol 1988; 6: 193-8.
7.	Rohr K. Das menschliche Knochenmark. Stuttgart: Georg Thieme Verlag, 1960.
8.	Durie BGM, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 1975; 36: 842-54.
9.	Chronic Leukemia and Myeloma Task Force. Proposed guidelines for clinical studies. Cancer Chemother Rep 1973; 4: 145-58.
10.	Ahre A, Bjorkholm M, Mellstedt H, Brenning G, Engstedt L, Gahrton G, Gyllenhammar H, Holm G, Johansson B, Jarnmark M, Karnstrom L, Killander A, Lerner R, Lockner D, Lonnqvist B, Nilsson B, Simonsson B, Stalfelt AM, Strander H, Svedmyr E, Wadman B, Wedelin C. Human leukocyte interferon and intermittent high-dose melphalan-prednisone administration in the treatment of multiple myeloma: A randomized clinical trial from the Myeloma Group of Central Sweden. Cancer Treat Rep 1984; 68: 1331—8.
11.	Jacobs P, le Roux 1, King HS. Sequential half-body irradiation as salvage therapy in chemotherapy resistant multiple myeloma. Am J Ciin Oncol 1988; 2: 104—9.
12.	Waldenstrom J. Some reflections on myeloma. Scand J Haematol 1985; 35: 4—9.
13.	Torrisi J, Berg C, Bonnem E, Dritschilo A, The combined use of interferon and radiotherapy in cancer management. Semin Oncol 1986; 13 (Suppl 2): 78—83.
14.	Cooper MR, Fefer A, Thompson J, Case DC, Kempf R, Sacher R, Neefe J, Bickers J, Scarffe JH, Spiegel R, Bonnem E. Alpha-2- interferon/melphalan/-prednisone in previously untreated patients with multiple myeloma: A phase 1—11 trial. Cancer Treat Rep 1986; 70: 473—6.
Author's adress: Plesničar A, MD, The Institute of Oncology, 61000 Ljubljana, Zaloška c. 2.
Radiol lugosl 1989; 23: 279—81
281