Leukemia and Lymphoma, Vol. 6, pp. 239-243
`Reprints available directly from the publisher
`Photocopying permitted by license only
`
`0 1992 Harwood Academic Publishers GmbH
`Printed in the United Kingdom
`
`Priming Therapy with Alpha-Interferon in
`Chemotherapy-Resistant Multiple Myeloma
`
`KARI REMES', ANRI TIENHAARA2, and TARJA-TERTTU PELLINIEMI'
`
`'Departments of Medicine and 'Haematology, Turku University Central Hospital, Turku, Finland.
`
`(Received 26 April 1991; in final form 28 June 1991)
`
`Nine patients with multiple myeloma were treated with alpha-interferon (IFN) priming
`followed by the previous chemotherapy regimen to which the patients had been resistant.
`Natural human leukocyte IFN (8 patients) or recombinant human IFN-2b (1 patient) at a
`dose of 5-6 x lo6 IU S.C. was given for 1-2 weeks before chemotherapy, after which IFN was
`used either cyclically or continuously (3-6 x lo6 IU every other day). Four patients responded;
`three had a good response based on reduction of the paraprotein level, and one patient had
`no further progress of his bone lesions. Two of the patients have had a prolonged response
`lasting 21 and 13 + months, respectively. IFN increased chemotherapy-related myelotoxicity
`considerably, and three patients died of granulocytopenic sepsis. The use of IFN priming may
`possibly offer an alternative for the treatment of some patients with resistant multiple myeloma.
`
`KEY WORDS: Multiple myeloma
`
`interferons
`
`drug resistance.
`
`INTRODUCTION
`
`PATIENTS AND METHODS
`
`Alpha-interferon (IFN) is effective in the treatment of
`multiple myeloma. It increases the response rate when
`combined with primary chemotherapy' and may
`prolong the response duration and survival when used
`as maintenance therapy2. IFN alone has resulted in
`favourable responses in 15-30% of patients with
`resistant myeloma3 and administration of IFN before
`reinstitution of chemotherapy (IFN priming), may
`enhance the effect of cytostatic agents in patients with
`relapsing or resistant myeloma495. The purpose of the
`present study was to clarify if IFN priming could
`to second or
`reduce
`the resistance
`third
`line
`chemotherapy in multiple myeloma. Despite the fact
`that this is only a small series our results suggest that
`IFN priming may have a role in the therapy of
`advanced multiple myeloma.
`
`Address for Correspondence; Dr Kari Remes, Department of
`Medicine, Turku University Central Hospital, Kiinamyllynkatu
`4-8, SF-20520 Turku, Finland.
`
`Data on the patients are presented in Table 1. All the
`patients (N = 9) were resistant to second (N = 3) or
`third line (N = 6) chemotherapy. The mean time
`interval from the beginning of the first chemotherapy
`regimen to IFN priming was 45 months (range: 10 to
`101 months). The primed chemotherapies consisted of
`MOCCA (N = 4), VAD (N = 2), VCAP (N = l), MP
`(N = 1) and C P (N = 1); see Table 1. The respective
`therapies were first used without IFN, and after
`demonstration of chemotherapy resistance (Tables 1
`and 2) the same therapies were continued without
`delay (except in pat 9) with IFN priming.
`Eight patients received natural human leukocyte
`IFN (Finnferon-AlphaR, Finnish Red Cross Blood
`Transfusion Service, Helsinki, Finland) and one
`patient,
`recombinant human
`IFN-2b (IntronaR,
`Schering, New Jersey, USA). IFN, at a daily dose of
`5 to 6 x lo6 IU s.c., was started 1 to 2 weeks before
`reinstituting the initial chemotherapy, to which the
`patient had been unresponsive. Four patients used
`IFN cyclically, i e . , after administration of
`the
`cytostatic regimen IFN was stopped and restarted
`
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`240
`
`K. REMES, A. TIENHAARA AND T.-T. PELLlNlEMl
`
`Table 1 Patient data
`
`Pat
`
`Sex
`
`Age
`
`Myeloma
`
`Previous treatments
`and responses ( + or -)*
`
`Time from 1st treatmeni
`to I F N (months)
`
`I
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`M
`
`M
`
`M
`
`M
`
`M
`
`F
`
`M
`
`F
`
`F
`
`52
`
`74
`
`72
`
`65
`
`50
`
`61
`
`68
`
`50
`
`58
`
`-type
`
`IgG-L
`
`-stage
`
`111 A
`
`IgG-K
`
`II A
`
`B-J
`
`111 A
`
`IgA-K
`
`I I A
`
`IgG-K
`
`II A
`
`IgG-K
`
`I1 A
`
`IgG-L
`
`II A
`
`IgA-L
`
`I11 A
`
`B-J
`
`II B
`
`MP x 6
`-
`MOCCAx4 -
`VAD x 3
`-
`MOCCAx6 -
`VAP x I
`-
`+I-
`CP x 37
`+
`MP x 21
`M P x 3
`-
`MOCCAx5 -
`MOCCAx7 +
`MOCCAx7 +
`-
`MOCCA ~5
`-
`VAD x 6
`-
`MP x 2
`MOCCA x 10 -
`-
`VAP x 12
`MP x I
`-
`+/-
`MP x 12
`+/-
`MOCCA x 5
`+
`V C A P x 5
`V C A P x 6
`-
`-
`M P x 7
`MOCCA x 17 +
`MOCCA x 7 +/-
`-
`M P x 4
`MOCCAx3 -
`-
`VAD x 2
`-
`M P x 6
`MOCCAX I -
`
`16
`
`56
`
`33
`
`43
`
`37
`
`14
`
`101
`
`10
`
`39
`
`* MOCCA: methylprednisolone 1 mdkg p.0. D 1-7; vincristine 0.03 mg/kg, mar 2 mg i.v. D I ; cyclophosphamide 10 mg/kg i.v. D
`1; CCNU 40 mg p.0. D I ; melphalan 0.25 mg/kg p.0. D 1-4; VAD: vincristine 0.4 mg 8-hr in[ D 1-4; doxorubicine 9 mgjm’ I-hr
`inf. D 14; dexamethasone 40 mg p.0. D 1-4, 9-12, 17-20; VCAP: vincristine 1 mg i.v. D I ; cyclophosphamide 100 mg/m’ p.0. D
`14; doxorubicine 25 mg/m2 i.v. D 1; prednisone 60 mg/m* p.0. D 1-4; MP: melphalan 9 mg/mz p.0. D 1-4; prednisone 1 mg/kg
`p.0. D 14; CP: cyclophosphamide 5 mg/kg p.0. D 1 4 ; prednisone 1 mg/kg p.0. D 1 4 .
`
`Table 2 Effect of IFN priming therapy in the responding patients
`
`Pat
`
`Treatment
`therapy without IFN
`-preceding
`-IFN primed therapy
`
`Paraprotein response
`(S.lg:g/l, dU-prot:g)
`
`Bone marrow
`(YO plasma cells)
`
`Bone lesions
`
`Outcome
`
`1
`
`3
`
`4
`
`5
`
`VAD(x3)
`IFN + VAD( x 7)
`
`S-IgG:41.6; dU-prot:12.8
`S-IgG:20.7; dU-prot: 0
`
`90
`90
`
`solitary
`solitary
`
`MOCCA(x5)
`IFN + MOCCA( x 10)
`MOCCA( x 5), VAD( x 6), MP( x 2)
`IFN + MOCCA( x 3)
`MP( x7)
`IFN + MP( x 10)
`
`dU-prot:4.6
`
`dU-prot: <0.1
`S-IgA: 10.3 - 24.6
`
`S-lgA: 5.7
`S-IgG: 16.8
`
`S-IgG: 12.7
`
`30
`
`< 5
`80
`
`80
`10
`
`< 5
`
`numerous,
`in progress
`no progress
`numerous,
`in progress
`progression
`numerous,
`in progress
`no progress
`
`IFN for 7 mo,
`progressive disease,
`exitus in
`neutropenic sepsis
`remission with
`IFN priming
`
`IFN for 4 mo,
`progressive disease
`ad exitus
`cessation of
`progression in
`bone lesions
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`aIFN IN RESISTANT MM
`
`24 1
`
`again, 1 to 2 weeks before the next cycle. Five patients
`were given IFN continuously at a lower dose (3 to
`6 x lo6 IU) every other day. Serum concentration
`and urine excretion of paraprotein, bone marrow
`aspiration and skeletal x-rays were performed to
`assess the effect of the priming therapy. Blood counts
`and hepatic and renal function tests were regularly
`followed. A good response was defined as a decrement
`of 50% or more of the serum paraprotein or 90% or
`more of the urine paraprotein excretion. The patient
`was also regarded as responsive to priming therapy if
`there was a cessation of progression of osteolytic
`lesions associated with otherwise quiescent disease.
`
`RESULTS
`
`Four of the nine patients responded to IFN priming
`therapy (Table 2). Three patients had a good response:
`serum paraprotein level decreased by 50 and 77%
`(patients 1 and 4) or daily proteinuria disappeared
`totally (pat 3). The disease stabilized in one patient
`(pat 5) who had biochemically quiescent myeloma but
`whose bone lesions had progressed during
`the
`preceding two years in spite of MOCCA, VAP and
`MP therapies. With IFN priming therapy there was
`a cessation in progression of the osteolytic lesions.
`Patient 1
`The effect of IFN priming was most evident in
`refractory
`to all
`patient 1. He was primarily
`
`treatments (MP, MOCCA, VAD). During VAD
`therapy alone serum IgG paraprotein was repeatedly
`at least 40 g/l and proteinuria 1&15 g/day. After the
`first IFN primed VAD cycle, urine paraprotein
`became undetectable, and serum paraprotein de-
`creased by 50%. However,
`the bone marrow
`infiltration by myeloma cells remained unchanged at
`90% and later on the disease also progressed as
`assessed by the biochemical profile. The patient died
`of sepsis during cytopenia after the 7th primed VAD
`cycle, 7 months after the initiation of the priming
`courses.
`
`Patient 3
`In patient 3 the remarkable response of urine
`paraprotein excretion to treatment, was associated
`with a normalization of the percentage of bone
`marrow plasma cell infiltration, i.e. he achieved
`remission which was maintained for 3 + months.
`Patient 4
`Patient 4 received recombinant IFN 5 x lo6 IU daily
`combined first with pulses of high-dose corticosteroid.
`During this treatment the serum IgA level decreased
`from 24 to 15 g/l. A further decrease to 5.7 g/l was
`achieved by IFN priming and reinstitution of the
`MOCCA regimen. However, plasma cell infiltration
`of the bone marrow which was massive, did not
`improve, and the patient died of progressive disease
`after 5 months IFN primed chemotherapy.
`
`Table 3 Bone marrow toxicity of IFN priming therapy
`
`Pat
`
`Treatment
`-previous
`-primed
`
`WBC nadir
`( x 10~11)
`
`Pit nadir
`( x 109/r)
`
`Complications
`
`1
`
`2
`
`3
`
`4
`
`5
`6
`7
`
`8
`
`VAD
`IFN + VAD
`CP
`IFN + CP
`MOCCA
`IFN + MOCCA
`MOCCA
`IFN + MOCCA
`MP-/+ IFN
`VCAP -/ + IFN
`MOCCA
`IFN + MOCCA
`VAD
`IFN + VAD
`
`0.6
`0.4
`
`N
`1.4
`1.7
`I .4
`2.7
`1 .o
`N
`N
`1.7
`0. I
`2.1
`1.2
`
`I 1
`13
`
`N
`N
`132
`41
`67
`21
`N
`N
`110
`41
`92
`21
`
`sepsis in 2 of 3 cycles
`sepsis in 3 of 7 cycles;
`septic death
`
`~
`
`-
`
`-
`-
`-
`-
`septic death
`-
`septic death
`
`N = normal.
`Patient no. 9 did not get any IFN primed chemotherapy due to rapid liver toxicity of IFN
`Plt = platelet.
`WBC = leukocytes.
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`242
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`K. REMES. A. TIENHAARA A N D T.-T. PELLlNlEMl
`
`Patient 2
`Patient 2 had a transient 21% decrease in the serum
`paraprotein level (S-IgG from 49.5 to 39.3 g/l) after
`starting the IFN primed C P therapy. However, this
`minor response soon disappeared and serum para-
`protein levelled off at the same level it had been earlier
`for 1.5 years; IFN was stopped after 8 months.
`
`Patients 6, 7, 8, 9
`Patient 6 did not respond to IFN primed VCAP, and
`after 4 months IFN was stopped. Patients 7 and 8
`died of granulocytopenic sepsis soon after the first
`IFN primed chemotherapy cycles (MOCCIA and
`VAD) were given. In patient 9 IFN therapy was
`associated with increasing levels of liver transami-
`nases, and therapy was stopped. Thus, in pa:ients 7,
`8 and 9 the treatment responses could not be
`evaluated appropriately.
`
`The observed responses to IFN priming were
`evident soon after the first primed chemotherapy
`cycle. In patients 1, 2 and 4 the duration of response
`was short, and the disease progressed after one or two
`IFN primed cycles of chemotherapy. Patients 3 and
`5 have retained their response for 13 + and 21 months,
`on continuous IFN. The mean duration of IFN
`primed treatment in all patients was 5.3 months
`(range: 12 days-14+ months).
`
`IFN accentuated chemotherapy-related bone marrow
`toxicity and other side-effects The leukocyte and
`platelet nadirs after the previous chemotherapy cycles
`and the respective IFN primed cycles are shown in
`Table 3. More pronounced cytopenias were recorded
`in all except 2 patients after IFN priming, compared
`to the same chemotherapy given without IFN. In fact,
`the three patients with the lowest leukocyte nadirs
`after IFN primed cytostatics died of sepsis, two of
`them after their first IFN primed chemotherapy cycle.
`The cytopenic effect of IFN priming treatments was
`more marked on leukocytes than platelets.
`Most patients had transient fever and flue-like
`symptoms at the beginning of IFN therapy. The IFN
`dose of patient 5 was reduced from 6 x lo6 IU daily
`to 6 x lo6 IU every other day because of chronic
`fatigue. The IFN therapy had to be stopped because
`of marked side-effects in two patients. Patient 2
`became extremely fatigued, however this symptom
`disappeared after discontinuation of IFN, which had
`been given for 8 months. Patient 9 had marked
`increase in the levels of liver transaminases, with doses
`of both 6 and 3 x lo6
`IU given daily for
`
`1 1 and 5 days, respectively, and IFN had to be
`discontinued.
`
`DISCUSSION
`
`The response rate, obtained by IFN priming therapy
`in patients with resistant myeloma, which includes
`three patients with good biochemical responses and
`one patient with stabilized bone disease, is encour-
`aging. It supports the suggestion made by Costanzi
`and Pollard4, that IFN therapy may be beneficial
`before reinstituting chemotherapy in patients with
`relapsing myeloma. However, they used IFN priming
`in
`relapsing patients without using
`the same
`previously effective chemotherapy alone. Thus, the
`possibility of the responses being due to chemo-
`therapy alone in their series cannot be excluded (6
`responders out of 9 relapsing patients). Two of the 9
`patients with refractory myeloma in that series had a
`minor response when treated with IFN primed
`chemotherapy. In our study we first excluded the
`possible effect of chemotherapy alone and responses
`could thus be attributed to IFN priming. Two patients
`(1 and 9) were primarily refractory, and one of them
`responded to IFN priming.
`Responses with IFN alone may be achieved in
`15-30% of therapy-resistant myeloma patients3. In
`our patients we could assess the effect of IFN without
`chemotherapy in only one (pat 4). Half of the final
`decrease in paraprotein level was observed after initial
`IFN and steroid therapy while the second part of the
`response occurred during the IFN primed chemo-
`therapy.
`Recent in oitro studies have shown that IFN may
`inhibit immunoglobulin synthesis or secretion by
`myeloma cells, and this effect may exceed the
`antiproliferative capacity6*’. In fact, a “paralysis” of
`paraprotein secretion may falsely mimic a
`true
`treatment response. In two patients (1 and 4) this kind
`of transient mimicry was evident, because the bone
`marrow examination and clinical disease evolution
`were not consistent with a true response. However, in
`one patient the decrease in paraprotein level was
`associated with diminished bone marrow plasma cell
`infiltration (pat 3) and in another with cessation of
`progression of osteolytic lesions (pat 5). These
`observations demonstrate that it is possible to control
`progression of disease using IFN primed chemo-
`therapy in some patients with resistant myeloma. This
`concept is shared by other author^^.^**.
`the
`The mechanism by which IFN reverses
`resistance against cytostatics is incompletely under-
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`aIFN IN RESISTANT MM
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`243
`
`stood. In one myeloma patient VAD resistance was
`reversed with verapamil, a possible inhibitor of
`p-glycoprotein'. Multi-drug
`resistance associated
`with overexpression of p-glycoprotein has been found
`in some haematological malignancies'0*' and in
`resistant myeloma, IFN may act by modulating the
`expression of the multi-drug resistance gene.
`It should be noted that IFN priming therapy was
`associated with considerable toxicity. The most severe
`side-effect was the increase in chemotherapy-induced
`myelosuppression, especially leukopenia. Myeloma
`patients with longstanding disease who have received
`many chemotherapy cycles, are especially prone to
`myelosuppression. Caution is consequently needed
`when IFN and cytostatics are combined. Three
`patients in our study, all with rapidly progressive,
`aggressive disease, died of
`sepsis with severe
`granulocytopenia. The two patients who died after the
`first primed chemotherapy cycle had received IFN for
`11 and 12 days before MOCCA and VAD treatments,
`respectively. The third patient was initially cytopenic
`due to heavy bone marrow infiltration and died after
`the 7th primed VAD cycle. Thus, in patients with
`heavy bone marrow plasma cell infiltration, IFN
`should be administered cautiously in order to avoid
`severe neutropenia.
`
`REFERENCES
`
`1. Mellstedt, H. for The Myeloma Group of Central Sweden.
`(1990) M P versus MP/IFN-alpha
`induction
`therapy: a
`randomized trial in multiple myeloma. V. Hannouer Interferon
`Workshop, 21.-23.2. 1990, p. 44.
`
`2. Mandelli, F., Avvisati, G., Amadori, S., Boccadoro, M.,
`Gernone, A,, Lauta, V. M., Marmont, F., Petrucci, M. T.,
`Tribalto, M., Vegna, M. L., Dammacco, F. and Pileri, A. (1990)
`Maintenance treatment with recombinant interferon alfa-2b
`in patients with multiple myeloma responding to conventional
`induction chemotherapy. New England Journal of Medicine,
`322, 143s1434.
`3. Cooper, M. R. (1988) Interferons in the management of multiple
`myeloma. Seminars in Oncology, 15 (Suppl. 5), 21-25.
`4. Costanzi, J. J. and Pollard, R. B. (1987) The use of interferon
`in the treatment of multiple myeloma. Seminars in Oncology,
`14 (Suppl. 2). 2428.
`5. Selbach, J., Purea, H. and Westerhausen, M. (1989) Interferon
`alpha-2B with chemotherapy in advanced or refractory
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`6. McGinnes, K. and Penny, R. (1988) Effects of interferon on the
`in uitro synthesis of paraprotein by plasma cells in myeloma.
`Acta Hematologica, 79, 72-76.
`7. Tanaka, H., Tanabe, O., Iwato, K., Asaoku, H., Ishikawa, H.,
`Nobuyoshi, M., Kawano, M. and Kuramoto, A. (1989) Sensitive
`inhibitory effect of interferon-alpha on M-protein secretion of
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`Damonte, J. C. and Oberling, F. (1988) The combination of
`interferon alpha 2a (Roferon-A) and melphalan for refractory
`multiple myeloma. International Congress on Interferons in
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`9. Durie, B. G. and Dalton W. S. (1988) Reversal of drug-resistance
`in multiple myeloma with verapamil. British Journal of
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`10. Ma, D. D. F., Scurr, R. D., Davey, R. A., Mackertich, S. M.,
`Harman, D. H., Dowden, G., Mister, J. P. and Bell, D. R. (1987)
`Detection of a multidrug
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`11. Kato, S., Nishimura, J., Muta, K., Yufu, Y., Nawata, H. and
`Ideguchi, H. (1990) Overexpression of P-glycoprotein in adult
`T-cell leukaemia. Lancet, i, 573.
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