`
`Chimaeric anti-interleukin 6 monoclonal antibodies
`in the treatment of advanced multiple myeloma:
`a phase I dose-escalating study
`
`H. C. T. VAN ZAANEN,1 H. M. LOKHORST,2 L. A. AARDEN,3 H. J. A. M. RENSINK,3 S. O. WARNAAR,4
`1
`1 1Department of Haematology, Academic Medical Centre, Amsterdam,
`J. VAN DER LELIE
`AND M. H. J. VAN OERS
`2Department of Haematology, Academic Hospital Utrecht, 3Central Laboratory of the Netherlands Red Cross
`Blood Transfusion Service, Amsterdam, and 4Centocor, Leiden, The Netherlands
`
`Received 18 February 1998; accepted for publication 11 May 1998
`
`Summary. Interleukin 6 plays a key role in the pathogenesis
`of multiple myeloma (MM). Therefore we conducted a phase I
`dose-escalating study with chimaeric monoclonal anti-IL6
`antibodies (cMab) in MM patients resistant to second-line
`chemotherapy. The cMab (CLB IL6/8; Kd 6·25 · 10¹12
`M)
`was given in two cycles of 14 daily infusions, starting on day
`1 and day 28, repectively, with a daily dose of 5 mg in
`patients 1–3, 10 mg in patients 4–6, 20 mg in patients 7–9
`and 40 mg in patients 10–12 (total dose 140 mg, 280 mg,
`560 mg and 1120 mg of anti-IL6, respectively). 11/12
`patients had elevated pretreatment IL6 levels.
`Except for transient thrombocytopenia in two patients
`there was no toxicity. There were no changes in haemoglobin
`levels, granulocyte count, liver enzymes or renal function.
`
`No human anti-chimaeric antibodies were induced. This was
`also reflected in a long half-life time of the cMab (median
`17·8 d), resulting in accumulation of the anti-IL6 cMab and
`high levels of circulating IL6. However, this was in the form
`of biologically inactive IL6/cMab complexes and did not
`result in acceleration of the disease. Although C-reactive
`protein (CRP) levels were decreased to below detection level
`in 11/12 patients, indicating effective IL6 blocking, none of
`the patients achieved a response according to the standard
`criteria. We conclude that this chimaeric anti-IL6 Mab has a
`low toxicity, low immunogenicity and a long T1/2. A dose of
`40 mg/d for 14 d can safely be used in future phase II studies.
`
`Keywords: chimaeric, anti-interleukin 6, multiple myeloma.
`
`Interleukin-6 (IL6) is a cytokine with multiple biological
`activities. It has been shown to be involved in such diverse
`processes as T-cell activation,
`induction of acute-phase
`proteins, and stimulation of haemopoietic precursor cell
`growth and differentiation (Heinrich et al, 1990; Kishimoto,
`1989). In the last decade in vitro and in vivo observations
`have suggested a major role of IL6 in the pathogenesis of
`multiple myeloma (MM) (Anderson et al, 1989; Hilbert et al,
`1995; Kawano et al, 1988; Klein et al, 1989; Lokhorst et al,
`1994; Nordan et al, 1987; van Oers et al, 1993; Zhang et
`al, 1989). Especially in patients with active and/or terminal
`disease, serum IL6 levels have been found to be elevated
`(Bataille et al, 1989; Klein et al, 1990).
`Murine anti-IL6 Mab have been used (in rather hetero-
`genous schedules) in the treatment of myeloma patients
`(Bataille et al, 1995; Klein et al, 1991). No major side-effects
`
`Correspondence: Dr H. C. T. van Zaanen, Sint Franciscus Gasthuis,
`Kleiweg 500, 3045 PM Rotterdam, The Netherlands.
`
`䉷 1998 Blackwell Science Ltd
`
`have been observed, but antibodies to mouse immuno-
`globulin (HAMA) were frequently detected about 2 weeks
`after starting the treatment. This resulted in rapid Mab
`clearance and diminished efficacy of this treatment. These
`HAMAs are frequently directed against the Fc part of the
`mouse immunoglobulin (Hoffman, 1990), and may also
`induce anaphylactic reactions.
`In order to reduce the risk of induction of HAMAs and thus
`to increase efficacy of
`the treatment, we produced a
`chimaeric anti-IL6 antibody (cMab). With this cMab we
`performed a phase I dose-escalating study in MM patients
`who were resistant to second-line chemotherapy. Here we
`report the results of this phase I study.
`
`PATIENTS AND METHODS
`
`All patients had MM according to the criteria of Durie &
`Salmon (1975), and had relapsed after, or were resistant to,
`second-line chemotherapy (VAD (vincristine, adriamycin
`
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`784 H. C. T. van Zaanen et al
`Table I. Patients’ characteristics.
`
`Pt
`
`M/F
`
`Age (yr)
`
`M-protein
`
`Stage
`
`CRP
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`Median
`
`M
`F
`F
`F
`F
`F
`F
`F
`F
`F
`M
`F
`
`53
`70
`58
`71
`74
`63
`60
`58
`54
`53
`69
`64
`61·5
`
`IgG(cid:107)
`(cid:108)
`IgG(cid:107)
`IgG(cid:107)
`IgA(cid:107)
`IgG(cid:107)
`IgA(cid:108)
`IgG(cid:107)
`IgG(cid:107)
`IgG(cid:108)
`IgA(cid:107)
`*
`
`IIIa
`IIIa
`IIIa
`IIIa
`IIIa
`IIIa
`IIIa
`IIa
`IIIa
`IIIa
`IIIa
`IIIa
`
`8
`<3
`3
`12
`6
`4
`6
`<3
`4
`<3
`6
`76
`5
`
`IL6
`
`50
`3
`7
`22
`17
`13
`10
`41
`7
`5
`33
`9
`11·5
`
`(cid:98)2M
`
`1·9
`4·2
`4·4
`7·7
`5·4
`1·5
`3·3
`2·4
`4·0
`2·9
`2·8
`10·2
`3·7
`
`CRP, C-reactive protein (normal value <5 mg/l); IL6, interleukin-6 (normal value <3 pg/ml);
`(cid:98)2M, beta-2 microglobulin (normal value 1·1–2·4 mg/l).
`* Non-secretor.
`
`and dexamethasone) or VAD-like regimens, intermediate to
`high doses of melphalan; 70–140 mg/m2 with or without
`autologous bone marrow or peripheral stem cell support).
`Exclusion criteria were; age <18 or >75 years,
`life
`expectancy <3 months, Karnofsky score <60, diabetes
`mellitus, hypercalcaemia requiring treatment, recent allo-
`geneic bone marrow transplantation, creatinine level
`> 150 (cid:109)mol/l, co-existing malignancies and active infection.
`Pretreatment characteristics of these 12 patients are
`shown in Table I.
`Chimaeric monoclonal anti-IL6 antibody. A murine-human
`chimaeric anti-IL6 monoclonal antibody (chimaeric CLB
`IL6/8) was developed, containing the antigen-binding
`variable region of the murine anti-IL6 antibody (CLB IL6/
`8) (Brakenhoff et al, 1990) and the constant region of a
`human IgG1 kappa immunoglobulin. The neutralizing Mab
`CLB IL6/8 blocks binding of IL6 to the IL6 receptor (CD 126)
`(Ehlers et al, 1994) and has a high affinity for recombinant
`as well as native IL6 (Kd ¼ 6·25 · 10¹12
`M) (Brakenhoff et al,
`1990; van Zaanen et al, 1996). The chimaeric Mab was
`manufactured by Centocor, Leiden, The Netherlands.
`Treatment schedule. After obtaining written informed
`consent according to the guidelines of the participating
`institutes, each patient received two cycles of treatment with
`cMab. Both cycles (starting at day 1 and 28 respectively)
`consisted of 14 daily 2 h i.v. infusions of the cMab (see Fig 1).
`This schedule was chosen to study the possible occurrence
`and response to re-treatment of a rebound phenomenon (i.e.
`acceleration of disease activity following cessation of the
`antibody administration) as has been described in patients
`treated with murine anti-IL6 Mab at the moment therapy
`was stopped (Klein et al, 1991). Before each cycle a test dose
`(10 (cid:109)g) was given by slow i.v. push over 5 min. As none of the
`12 patients developed an immediate hypersensitivity reac-
`tion, in all cases treatment was started 15 min later. The first
`three patients received a daily dose of 5 mg of the cMab (total
`
`dose 140 mg), the next three patients received 10 mg/d (total
`dose 280 mg), patients 7–9 received 20 mg/d (total dose
`560 mg) and the last three patients received 40 mg/d (total
`dose 1120 mg).
`Levels of IL6 and anti-IL6 antibodies. During treatment with
`the chimaeric CLB IL6/8 almost all the IL6 in the plasma
`circulated as a complex with the antibody (van Zaanen et al,
`1996). IL6 levels were determined with the B9 bioassay as
`described before (Aarden et al, 1987; van Zaanen et al,
`1996). One unit of B9-stimulating activity was defined as the
`amount
`inducing half-maximal proliferation and corre-
`sponded to 1 pg of IL6. To determine the total IL6 level (i.e.
`free IL6 plus IL6 complexed to cMab), an excess (10 (cid:109)g/ml) of
`CLB IL6/14 was added to each well in order to displace IL6
`from its binding to the in vivo administered neutralizing
`chimaeric CLB IL6/8. CLB IL6/14 and CLB IL6/8 Mab
`recognize partly overlapping sites of IL6. However, CLB
`IL6/14 is not capable of inhibiting IL6 activity in the B9
`bioassay (Aarden, 1991). During treatment with the cMab
`actual
`free IL6 levels cannot be measured, because the
`dilution of the samples necessary for testing in the B9
`bioassay or ELISA immediately influences the equilibrium
`between IL6–cMab complex,
`free IL6 and free cMab.
`Therefore free IL6 levels were calculated using the
`Henderson-Hasselbalch equation, with the Kd, the daily
`serum cMab levels and the total IL6 levels as known
`parameters.
`Levels of the chimaeric CLB IL6/8 monoclonal antibody
`were determined using a radioimmunoassay as described in
`detail before (van Zaanen et al, 1996). The threshold of this
`assay is 0·5 ng/ml of antibody.
`Human anti-chimaeric antibody (HACA) levels were deter-
`mined using an ELISA. Briefly, the cMab (CLB IL6/8, IgG1-
`kappa) was coated overnight at room temperature (2 (cid:109)g/ml
`in 100 (cid:109)l well) on flat-bottomed microtitre plates. The plates
`were washed four times with PBS/Tween solution. Patients
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`Chimaeric Anti-IL6 in Advanced Multiple Myeloma
`
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`Fig 1. Mean serum levels of chimaeric anti-IL6
`Mab in the different dosage groups. Patients
`1–3 (a) ¼ 5 mg/d; patients 4–6 (b) ¼ 10 mg/d;
`patients 7–9 (c) ¼ 20 mg/d; patients 10–12
`(d) ¼ 40 mg/d. Patient 12 received treatment
`on days 1–4 and 16–29. Day 65: n ¼ 9,
`day 100: n ¼ 5.
`
`Patient 5 had fever and an urinary tract infection when
`admitted for the second treatment cycle on day 28. In patient
`9 anti-IL6 was stopped at day 34 because of pneumonia and
`septicaemia. In patient 12 (receiving anti-IL6 until day 5)
`treatment was interrupted because of fever. With antibiotic
`treatment her clinical condition improved and anti-IL6 was
`given from day 16 to day 29 (one treatment cycle of 14 d).
`A second cycle was not given at the patient’s request.
`Pretreatment values of IL6, CRP and B2M are shown in
`Table I. In all but one patient pretreatment IL6 levels were
`elevated. 6/12 patients had elevated CRP levels. There was
`no correlation between CRP and IL6 levels (r ¼ ¹0·13) in
`these patients. Serum (cid:98)2M was increased in nine patients.
`Patient 12 had a non-secreting myeloma, with large
`plasmacytomas on the chest wall and the right upper arm.
`The plasmacytoma on the chest wall was measured
`bidimensionally, before and daily during anti-IL6 treatment.
`Before treatment it had a diameter of 14 · 16 cm and a
`growth rate of 1·5 cm/week in two perpendicular directions.
`
`Levels of cMab and IL6
`Data regarding the pharmacokinetics have been published
`previously (van Zaanen et al, 1996). The median half-life
`time of this cMab was 17·8 d (range 7·8–39·7), with a
`median distribution volume of 6·0 litres (range 3·0–9·7).
`Peak serum levels of the cMab ranged between 6·7 (cid:109)g/ml
`(patient 1) and 288 (cid:109)g/ml (patient 11). No HACAs were
`found in any of the patients during the study period of 100 d.
`During treatment, accumulation of the cMab occurred due
`to its long half-life time (Fig 1). This resulted in high total
`serum IL6 levels, complexed with the cMab (van Zaanen et
`al, 1996). Calculated free IL6 levels decreased to <0·5 pg/ml
`during treatment in all patients (Fig 2).
`
`Toxicity
`During and after administration of the cMab, no changes in
`
`sera were added in different dilutions (1/50 up to 1/800) in
`HPE-buffer (CLB, Biotechnology, Amsterdam, The Nether-
`lands) and incubated for 2 h at room temperature. After
`washing, the plates were incubated with HRP-conjugated
`monoclonal mouse anti-human lambda light chain (KH29,
`CLB, Amsterdam, The Netherlands) in 100 (cid:109)l HPE buffer for
`1 h at room temperature. Subsequently, after washing, the
`bound peroxidase was detected at 450 nm in a Titertek
`Multiskan.
`C-reactive protein (CRP) was determined by nephelometry
`(Behring, Germany); detection level 3 mg/l; normal value
`<5 mg/l.
`Beta-2 microglobulin ((cid:98)2M) was determined by a micro-
`particle enzyme immunoassay (Abbott Laboratories, U.S.A.);
`normal value 1·1–2·4 mg/l.
`levels were determined once
`Paraprotein (M-protein)
`weekly by immunonephalometry (Behring Nephalometer
`100 Analyzer; Behring Diagnostics, Amsterdam, The
`Netherlands).
`Levels of IL6 and the cMab were determined daily from day
`0 until day 14 and day 28 until day 41 (samples were drawn
`before starting infusion of anti-IL6), and on days 17, 21, 44,
`48, 56 and 100.
`Response to treatment was defined as a decrease in M-
`protein level of >50% or a decrease in plasmacytoma size in
`patient 12.
`
`RESULTS
`
`Dosage of chimaeric anti-IL6
`Twelve patients (three in each dosage group) completed at
`least one treatment cycle of 14 d. Eight of
`them also
`completed a second 14 d treatment cycle. In the other four
`patients anti-IL6 treatment was stopped because they
`fulfilled a predefined stopping criterion: patient 1 required
`radiotherapy for neurological complications at day 30.
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`Fig 2. Free IL6 levels. (A) The eight patients who received two
`complete treatment cycles. Free IL6 levels <0·3 pg/ml during
`treatment in all patients. (B) The three patients who completed
`one treatment cycle of 14 d (see Results). Patient 1: anti-IL6 until
`day 30; patient 5: anti-IL6 until day 14; patient 9: anti-IL6 until day
`34. (C) Patient 12 received anti-IL6 on days 1–4 and 16–29.
`Because of
`fever of unknown origin, anti-IL6 treatment was
`interrupted at day 5.
`
`blood pressure, pulse rate or temperature were observed.
`These parameters were measured every 15 min for 2 h
`immediately after the administration of anti-IL6. No changes
`in liver function were found. Creatinine levels fluctuated in
`
`patients 2, 5, 10 and 12 but remained <150 (cid:109)mol/l; in the
`other eight patients no changes in renal
`function were
`found. Haemoglobin levels remained stable, while minor
`changes occurred in platelet and leucocyte counts.
`In
`patients 2 and 5 we observed a transient thrombocytopenia
`with a nadir of 24 and 58 · 109/l respectively (on days 56
`and 14,
`respectively). Before anti-IL6 treatment both
`patients had hypocellular bone marrow aspirate and
`biopsy (with a decreased number of megakaryocytes). In 6/
`12 patients (patients 2, 4, 7, 8, 9 and 11) a mild transient
`granulocytopenia was documented after one dose of anti-
`IL6. The median decrease in the number of granulocytes was
`32·5% (range 20–46%), with a median time to nadir of 1 d.
`The granulocytes returned to base-line levels within 2 d. No
`alterations in lymphocyte subsets were found.
`Three patients developed infectious complications; patient
`5 (with known recurrent urinary tract infections) had fever
`with low blood pressure due to a urinary tract infection with
`Escherichia coli on the day she was admitted for the second
`treatment cycle. Patient 9 died because of pneumonia and
`septicaemia with Staphylococcus aureus. Patient 12 developed
`fever of unknown origin on day 5. She was treated with
`antibiotics; all cultures remained negative.
`
`Clinical effects
`In all but one patient the M-protein level did not change
`during both cycles of anti-IL6 treatment. In eight patients
`(patients 1, 3, 4, 7–11) this indicated an unaffected disease
`course because they had similar M-protein levels at 2
`months before anti-IL6 treatment (Figs 3A and 3B). In
`patient 2 disease activity remained progressive during the
`first treatment cycle; this was reflected by a rise of M-protein
`and (cid:98)2M levels (77% and 145% increase in relation to day 0,
`respectively). However, during the second treatment cycle,
`M-protein and (cid:98)2M levels remained stable (Fig 3B). After day
`60 she received 70 mg/m2 melphalan intravenously, result-
`ing in a temporary decrease of M-protein level. In two
`patients (patients 5 and 6) a marked stabilization of the M-
`protein occurred during therapy (Fig 3B). This was also true
`for the growth rate of the plasmacytoma of patient 12. In
`two patients (patients 1 and 7) we observed a possible
`acceleration in the increase of the M-protein levels after
`stopping anti-IL6 (Fig 3B). Likewise, after the anti-IL6
`treatment was stopped in patient 12, the growth rate of
`the plasmacytoma was increased when compared to the
`growth rate before therapy (1·5 cm/week versus 2 cm/
`week).
`Immediately after starting the anti-IL6 treatment the CRP
`levels decreased to below detection level in all patients except
`for patient 12 in which CRP decreased from 76 to 10 mg/l.
`Other acute-phase proteins tested, pre-albumin, alpha-1
`antitrypsin and alpha-1 acid glycoprotein, remained stable
`and within normal ranges.
`
`Survival
`Six patients were still alive 9 months after treatment with
`anti-IL6. Three patients died within the study period of 100 d
`(patients 5, 9 and 12). Patient 5 went off study because of
`an urinary tract infection on day 28. After appropriate
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`Chimaeric Anti-IL6 in Advanced Multiple Myeloma
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`Fig 3. Percentage of M-protein levels before,
`during and after anti-IL6 treatment in relation
`to day 0 (day 0 ¼ 100%). Anti-IL6 cMab was
`given in two cycles of 14 d (two boxes below
`abscissa). (A) Patients 3, 4, 8, 9, 10 and 11; (B)
`patients 1, 2, 5, 6 and 7. At day 60, patient 2
`received melphalan i.v. (70 mg/m2).
`
`treatment she was discharged and died several weeks later at
`home from progressive disease. Patient 9 died on day 35 due
`to an irreversible septic shock. Although radiotherapy was a
`treatment option for the large plasmacytomas in patient 12,
`no further treatment was given according to the wish of the
`patient. She died shortly afterwards because of progressive
`disease with pleural effusion. Three patients died after day
`100 because of refractory multiple myeloma.
`
`DISCUSSION
`
`From this phase I dose-escalating study with chimaeric anti-
`IL6 Mab in patients with advanced MM, two important
`conclusions can be drawn. First, the use of this cMab is
`safe. Despite high levels of circulating cMab, no toxicity
`was observed and no HACAs were induced. Second,
`
`accumulation of the high-affinity cMab resulted in high
`levels of circulating IL6. However, this was in the form of
`biologically inactive complexes and did not
`result
`in
`acceleration of the disease during anti-IL6 treatment.
`
`Toxicity
`Although IL6 is a multi-functional cytokine, blocking its
`biological activity by chimaeric anti-IL6 Mabs did not result
`in serious side-effects. Only a transient thrombocytopenia
`occurred in two patients who had hypocellular bone marrow
`before starting anti-IL6 treatment. The mechanism of this
`thrombocytopenia during anti-IL6 treatment is not com-
`pletely understood. Although from studies in primates and
`humans it has become evident that IL6 is able to induce
`megakaryocyte maturation and thrombocytopoiesis (Asano
`et al, 1990; Stahl et al, 1991; Wickenhauser et al, 1995;
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`788 H. C. T. van Zaanen et al
`Stouthard et al, 1996), its role in steady-state thrombo-
`cytopoiesis
`is not clear because IL6 knock-out mice
`have normal platelet counts. Thrombopoietin (TPO) levels
`did not change during anti-IL6 treatment (unpublished
`observations).
`Three patients developed infectious complications during
`therapy. Although a relationship with anti-IL6 cannot be
`totally excluded, it is not likely because infectious complica-
`tions are common in end-stage multiple myeloma and are a
`major cause of death (Foerster, 1993). Moreover, in IL6
`knock-out mice the outcome of TNF-induced shock was not
`different from IL6 wild-type mice (Libert et al, 1994). The
`three patients involved (patients 5, 9 and 12) were still able
`to respond to the infection with an increase of
`their
`endogenous IL6 production, resulting in increased free IL6
`serum levels, fever and increased CRP levels.
`
`High levels of circulating IL6
`In agreement with other studies (Heremans et al, 1992;
`Martens et al, 1993; May et al, 1993, 1994; Mihara et al,
`1991), we found that the use of anti-IL6 Mab led to
`accumulation of circulating IL6 in the form of
`immune
`complexes. An important question is whether this complexed
`IL6 has biological activity. If so, treatment with anti-IL6
`might result in disease progression and/or clinical deteriora-
`tion. Several observations make this possibility unlikely.
`First, during anti-IL6 treatment the CRP level (which is
`completely IL6 dependent; Heinrich et al, 1990) decreased to
`below detection level in 11/12 patients. In the remaining
`patient CRP decreased by 87% compared to the pretreatment
`value. Second, we did not observe an accelerated disease
`course during anti-IL6 treatment. However, after anti-IL6
`was stopped, in three patients a possible rebound phenom-
`enon was seen, resulting in increased M-protein levels in two
`patients and an accelerated plasmacytoma growth in
`one patient. A possible explanation might be that when free
`cMab levels decrease some time after stopping administration
`of cMab,
`IL6 gradually dissociates from the cMab/IL6
`complex. The free IL6 level will increase according to the
`Henderson-Hasselbalch equation: Kd ¼ [IL6free] [cMabfree] /
`[complex].
`It has been suggested that the rebound phenomenon
`might be prevented by the formation of multivalent IL6/Mab
`complexes which are rapidly cleared from the circulation.
`Indeed in mice it has been found that simultaneous
`treatment with three anti-IL6 Mab (binding to three distinct
`epitopes of IL6) induced a rapid uptake of these complexes by
`the liver, leading to enhanced elimination of IL6 from the
`circulation (Montero-Julian et al, 1995).
`
`whereas mature myeloma cells display a low proliferative
`activity with higher secretion of M-protein (Kawano et al,
`1993). Joshua et al (1996) found that the in vivo labelling
`index was almost entirely determined by a subpopulation of
`‘primitive’ (¼immature) plasma cells. It is possible that
`myeloma cell proliferation and CRP production are blocked
`by anti-IL6 cMab, whereas M-protein production by mature
`myeloma cells is less affected. This assumption is supported
`by the observation by Sonneveld et al (1991) that in vitro Ig-
`synthesis and proliferation of MM cells are stimulated by
`different cytokines and that anti-IL6 can block plasma cell
`proliferation, but not Ig-synthesis. Indeed,
`for the three
`patients in whom we were able to analyse the plasma cell
`labelling index before and after anti-IL6 treatment we found
`a strong decrease in LI (data not shown).
`The existence of IL6-independent myeloma cells in these
`end-stage patients might be another explanation for the
`minor
`clinical
`responses during anti-IL6 treatment.
`Decreased IL6 dependence of myeloma cells in the course
`of the disease has been described (Asaoku et al, 1988). On
`the other hand, Zhang et al (1992) have shown that in the
`terminal phase of MM and plasma cell leukaemia, in vitro
`tumour growth was totally dependent on IL6. Moreover,
`from the pleural effusion of patient 12 we were able to obtain
`an IL6-producing myeloma cell line. IL6 production and
`growth of this cell
`line can totally be blocked by anti-
`IL6 cMab (unpublished observation). Likewise, in the two
`patients (patients 2 and 3) in whom we were able to test it,
`the myeloma cells were still IL6-dependent in vitro.
`In vitro studies showed that IL6 (which is overproduced in
`MM) reversed the growth arrest of dexamethasone on all
`myeloma cell lines tested (Juge-Morinea et al, 1995). Thus,
`neutralization of IL6 by anti-IL6 Mab might improve the
`response of MM patients to dexamethasone. Therefore in
`future studies it would be relevant to combine this chimaeric
`anti-IL6 Mab with, for example, dexamethasone or VAD. An
`additional theoretical advantage of the use of anti-IL6
`antibodies could be the beneficial effects on myeloma-
`associated bone disease. Several data suggest that IL6,
`probably in synergy with IL-1 beta and TNF, also plays an
`important role in the pathogenesis of this aspect of the
`disease (Kurihara et al, 1990; Bataille et al, 1992; Roodman,
`1995; Barille et al, 1995).
`In conclusion, this phase I dose-escalating study indicated
`that treatment of end-stage MM patients with chimaeric
`anti-IL6 Mabs had a very low toxicity. A dose of 40 mg/d for
`14 d can safely be used in future phase II studies.
`
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