British Journal of Haematology 2000, 109, 89–96
`
`Frequent good partial remissions from thalidomide including
`best response ever in patients with advanced refractory and
`relapsed myeloma
`
`G U N NA R J U L I U S S O N, 1 F R E D R I K C E L S I N G, 2 I N GE M AR T U R E S S O N, 3 S T I G L E NH O F F, 4 M AG N US A D R I A N S S O N
`A ND
`1 1Department of Haematology, University Hospital, Linko¨ping, 2Department of Haematology,
`C L A E S M A L M
`Karolinska Hospital, Stockholm, 3Department of Haematology, University Hospital MAS, Malmo¨,
`4Department of Haematology, University Hospital Lund, and 5Department of Medicine, County Hospital, Kalmar, Sweden
`
`5
`
`Received 16 November 1999; accepted for publication 30 December 1999
`
`Summary. Twenty-three patients with advanced and heavily
`pretreated myeloma were treated with thalidomide. Starting
`dose was 200 mg/d, and 20 patients had dose escalations up
`to 400 (n (cid:136) 5), 600 (n (cid:136) 12) or 800 mg/d (n (cid:136) 3), usually in
`divided doses. Nineteen patients were refractory to recent
`chemotherapy, and four had untreated relapse after prior
`intensive therapy. Ten out of 23 patients (43%) achieved
`partial response (PR; nine with refractory and one with
`relapsed disease), six patients had minor response or
`stabilization of the disease and four had disease progression.
`Another three patients died early from advanced myeloma at
`less than 3 weeks of thalidomide therapy. Of the 10 patients
`with PR, seven had a better response than after any prior
`therapy, despite vincristine–doxorubicin–dexamethasone
`(VAD)-based treatment
`in all but one and high-dose
`melphalan with autologous stem cell support in four. Time
`to achieve PR was rapid in patients receiving thalidomide in
`divided doses
`(median 31 d). Responses also included
`
`reduced bone marrow plasma cell infiltration and improved
`general status. Normalized polyclonal gammaglobulin levels
`were seen in four cases. Six out of 10 patients with PR
`remained in remission with a median time on treatment of
`23 weeks (range 15–50 weeks). Sedation was common but
`usually tolerable, and some patients continued full- or part-
`time work. Four patients had skin problems, three patients
`had pneumonia, one hypothyrosis, one sinus bradycardia
`and one minor sensory neuropathy. Thalidomide may induce
`good partial remissions in advanced refractory myeloma
`with tolerable toxicity, and should be evaluated in other
`settings for myeloma patients. Divided thalidomide doses
`seem to reduce time to achieve remission and may improve
`response rate.
`
`Keywords: myeloma,
`response.
`
`thalidomide,
`
`therapy,
`
`refractory,
`
`Few drug types with documented effect as treatment for
`myeloma are currently available. Steroids and alkylating
`agents, mainly melphalan and cyclophosphamide, have
`significant and dose-related anti-tumour effects. In contrast,
`clinical benefit of anthracyclins have not been documented,
`but still they are frequently incorporated into combination
`chemotherapies (Barlogie et al, 1984). High-dose dexa-
`methasone pulse-based therapy (Barlogie et al, 1984)
`followed by high-dose melphalan with autologous stem cell
`support (Barlogie et al, 1999) leads to a prolonged disease
`control with significant improvement in survival (Attal et al,
`
`Correspondence: Dr Gunnar Juliusson, Department of Haematology,
`University Hospital, SE-581 85 Linko¨ping, Sweden. E-mail: gun-
`nar.juliusson@lio.se.
`
`q 2000 Blackwell Science Ltd
`
`1996; Barlogie et al, 1997; Lenhoff et al, 2000). Still, the
`complete response rate is well below 50%, cure has not
`been documented, as progression-free survival
`is limited
`to a few years, and there is no plateau in the survival
`curves. However, recent studies suggest that allogeneic stem
`cell transplantation may improve response duration and
`outcome.
`Thalidomide (a-(N-phthalimido)glutarimide; C13H10N2O4)
`is a drug that was used as a sedative in the 1960s, but that
`was withdrawn because of severe birth defects. It has a slow
`absorption after oral administration, a plasma half-life of
`about 6 h, and is degraded by non-enzymatic hydrolysis. It
`has immunomodulatory effects with a down-regulation of
`tumour necrosis factor a (Shannon et al, 1997; Haslett et al,
`1998); up-regulation of adhesion molecules (Geitz et al,
`
`89
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`

`90
`
`G. Juliusson et al
`
`Fig 1. Serum IgG M protein levels for patients
`1–3 (A–C respectively) before and during
`thalidomide treatment. Time points for
`previous therapies are indicated by arrows.
`MP, melphalan 0·25 mg/kg and prednisone
`2 mg/kg for 4 d every 6-weeks; VAD and
`HyperCVAD, given according to Barlogie et al
`(1984) and Dimopoulos et al (1996)
`respectively; SC, autologous stem cell support;
`Cy, cyclophosphamide 2 g/m2; Z (cid:135) TBI (cid:135) M,
`high-dose idarubicin (42 mg/m2), total body
`irradiation (12 Gy) and melphalan 140 mg/
`m2; M iv, melphalan 30–70 mg intravenously;
`M70, melphalan 70 mg/m2; M200, melphalan
`200 mg/m2.
`
`1996) and also antiangiogenetic properties (Bauer et al,
`1998; Or et al, 1998; Berenson et al, 1999; Gasparini, 1999).
`It has been used as therapy for erythema nodosum in leprosy,
`for Behcet’s disease, for HIV-related cachexia and recurrent
`aphthous stomatitis (Jacobsen et al, 1997) and also for
`
`graft-versus-host disease after allogeneic bone marrow
`transplantation (Vogelsang et al, 1992).
`Myeloma is commonly accompanied by an increased
`microvessel density of the bone marrow, which is considered
`to be an adverse prognostic factor (Vacca et al, 1994;
`
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`
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`

`

`Berenson et al, 1999). Such an increased vascularization
`may persist after high-dose therapy (Rajkumar et al, 1999)
`and contribute to relapse.
`Recently, positive treatment results with thalidomide given
`to 84 patients with advanced myeloma were reported as 21
`patients (25%) achieved at
`least partial response from
`thalidomide in doses ranging from 200 to 800 mg per day,
`always given as a single dose in the evening (Singhal et al,
`1999).
`We report here the Swedish experience from advanced
`myeloma treated with thalidomide mostly given in divided
`daily doses.
`
`MATERIALS AND METHODS
`
`Patients. Twenty-three patients with previously treated
`advanced myeloma from five Swedish centres are reported.
`There were 16 men and seven women, and the median age
`was 61·1 years (range 44–78). Myeloma subtype was IgG in
`14 cases, IgA in five and only Bence-Jones proteinuria in
`four. Light chains were kappa in nine, lambda in two and
`data were unavailable in 12. All but one (patient 2; Fig 1)
`had had multiple prior therapies,
`including vincristine–
`doxorubicin–dexamethasone (VAD)-like therapies (Barlogie
`et al, 1984), and 10 had undergone high-dose melphalan
`with autologous stem cell support. The disease duration from
`start of initial treatment was 44 months (range 7–137). At
`inclusion, 19 patients had disease refractory to ongoing
`treatment, whereas four had untested relapse after prior
`intensive therapy. The median plasma cell infiltration in the
`bone marrow was 38% (n (cid:136) 16, range 6–90%), and serum
`beta-2-microglobulin 4·1 mg/l (n (cid:136) 11, range 1·7–5·8). The
`median M-protein level for IgG patients was 49 g/l (range
`21–72 g/l) and for IgA patients it was 24 g/l (range 13–
`44 g/l).
`Drug therapy. Thalidomide tablets (Gru¨ nenthal, Aachen,
`Germany) were given orally, following individual approval
`from the Swedish Medical Drug Agency. The starting dose
`was initially 200 mg twice daily, but as some patients
`became very sedated from the first dose subsequent patients
`started on 100 mg twice daily. Dose escalation to 200 mg
`twice daily was performed within 1 week, and subsequently,
`according to tolerance, to 300 or 400 mg twice daily. Seven
`patients in one centre had one daily dose of up to 800 mg
`thalidomide given in the evening. The dose escalation
`
`Thalidomide in Refractory or Relapsing Myeloma
`
`91
`
`strategy resulted in a maximum thalidomide dose of
`800 mg/d in three patients, 600 mg/d in 12 patients and
`400 mg/d in five; three patients in poor condition who had
`an early death did not have dose escalation. Therapy was
`continued in individual dosing according to response and
`tolerance until prohibitive toxicity, progression, death or
`allogeneic stem cell transplantation. Response was evaluated
`according to the EBMT/IBMTR/ABMTR guidelines (Blade´
`et al, 1998).
`
`RESULTS
`
`Patients with partial response
`Ten patients (43%) had partial response (PR) (Blade´ et al,
`1998) (Tables I and II), two of them had maximum doses of
`800 mg thalidomide/d, seven had 600 mg/d and two had
`400 mg/d. Seven of these patients had a better response to
`thalidomide than to any previous therapy, including high-
`dose melphalan with stem cell support in four and VAD-like
`treatment in all but one (patient 2). PR was achieved in 8/16
`(50%) patients having thalidomide in divided doses, com-
`pared with 2/7 (29%) of those who had single daily doses
`(including patients with early deaths). The clinical courses
`for three of these patients (1–3) are illustrated in Fig 1. One
`patient, who did not tolerate higher doses of thalidomide
`because of somnolence and dizziness, seemed to have a direct
`correlation between thalidomide dose and M-protein level
`(patient 4; Fig 2). Another patient (9) with side-effects due to
`thalidomide had a rapid disease progression after cessation of
`thalidomide. One patient with PR had progression on
`600 mg/d thalidomide after 31 weeks (patient 8), whereas
`other patients have had continuing paraprotein response to
`date or until allogeneic transplantation or death (Table I).
`Time to achieve partial response was rapid; among eight
`patients who had PR to thalidomide in divided doses, the
`median time to PR was 31 d (range 28–81 d), whereas for
`two patients who had PR to single-dose daily therapy
`(patients 7 and 8) the time to PR was 70 d in one and 116 d
`in the other patient. Responding patients rapidly showed
`evidence of responsiveness through declining paraprotein
`levels after only 1 week of therapy (Fig 1). The serum M-
`protein levels before and during thalidomide therapy for all
`individual patients (except for those with early death) are
`shown in Fig 3. Improvements of anaemia and skeletal pain
`was usually slower, although responding patients had a
`
`Table I. Response to thalidomide according to thalidomide dosing (number of patients).
`
`Refractory
`
`Relapsed
`
`Divided/single dose
`
`Divided/single dose
`
`Total
`
`Partial response
`Stable disease/minor response
`Progression
`Early death
`Total
`
`7/2
`1/2
`3/1
`2/1
`13/6
`
`1/0
`2/1
`0/0
`0/0
`3/1
`
`10
`6
`4
`3
`23
`
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`

`92
`
`G. Juliusson et al
`
`Table II. Characteristics of patients with partial response to thalidomide.
`
`Patient no.
`(age/sex)
`
`Ig isotype/
`stage
`
`Disease duration
`(months)
`
`Therapy prior to
`thalidomide
`
`Refractory/ relapse
`to prior therapy
`
`Highest dose of
`thalidomide
`
`Thalidomide response
`duration (weeks)
`
`Outcome
`
`1 (57/M)
`
`IgG-kappa/IIIA
`
`10
`
`2 (72/M)
`
`IgG-lambda/IIIA
`
`137
`
`3 (52/M)
`
`IgG/IIIA
`
`4 (56/M)
`
`IgA-kappa/IIIA
`
`5 (54/M)
`
`IgG-kappa/IIIA
`
`6 (44/F)
`7 (54/F)
`8 (64/F)
`
`BJ-kappa/IIIA
`IgG/IIIB
`IgG/IIIA
`
`9 (68/M)
`
`IgG-kappa/IIIA
`
`10 (68/F)
`
`IgA/IIIA
`
`55
`
`51
`
`70
`
`28
`45
`71
`
`34
`
`17
`
`VAD · 3, HyperCVAD · 2,
`M70 (cid:135) SC · 2, M200 (cid:135) SC
`MP · 18
`
`VAD · 3, M200 (cid:135) SC, IFN
`VAD · 2, HDCy, HyperCVAD
`ZTBIM (cid:135) SC, M iv · 5
`VAD · 3, M200 (cid:135) SC, IFN
`VAD · 5, VBAP, VAD · 4, Dex
`VAD · 3, M200 (cid:135) SC
`IFN, VADx2, RT
`VAD · 3, M200 (cid:135) SC, IFN
`VAD · 3, VACP · 5
`CyD (cid:135) IFN · 3, VACP · 24
`
`MP · 5, Z · 3, VAD · 5
`
`CyD · 3, M200 (cid:135) SC
`IFN, RT, MP · 2
`
`Refractory
`
`Refractory
`
`Refractory
`
`Refractory
`
`Refractory
`
`Relapse
`Refractory
`Refractory
`
`Refractory
`
`Refractory
`
`400 mg · 2
`
`200 mg · 2
`
`300 mg · 2
`
`200 mg · 2
`
`300 mg · 2
`
`200 mg · 3
`600 mg · 1
`600 mg · 1
`
`400 mg · 2
`
`300 mg · 2
`
`48
`
`20
`
`32
`
`35
`
`24
`
`20
`50
`31
`
`15
`
`16
`
`Continuing response
`
`Dead, obstructive
`lung disease
`Continuing response
`
`Dose-related
`response
`Allotransplant
`
`Allotransplant
`Continuing response
`Progression on
`treatment
`Progression off
`treatment
`Dead, bone
`marrow failure
`
`IFN, interferon alpha; RT, radiotherapy, CyD, cyclophosphamide (cid:135) dexamethasone; VBAP, vinblastine, BCNU, doxorubicin, prednisone; VACP, etoposide, doxorubicin, cyclophosphamide,
`prednisone; Z, idarubicin orally. For further abbreviations, see legend to Fig 1.
`
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`Thalidomide in Refractory or Relapsing Myeloma
`
`93
`
`Fig 2. Serum IgA M-protein level and Bence-
`Jones kappa proteinuria excreted per 24 h in
`relation to thalidomide dose in patient 4, who
`experienced dose-related dizziness and vertigo.
`
`significant subsequent improvement of blood counts, symp-
`toms and performance status. Significant improvement of
`cytopenia was seen in patients with minor response.
`Haemoglobin levels and platelet counts from start of
`thalidomide therapy for selected patients with PR or minor
`response are shown in Fig 4.
`Responding patients had a decrease in bone marrow
`plasma cell infiltration to usually below 10%, and serum
`beta-2-microglobulin levels also improved in all five patients
`with follow-up samples available.
`their
`Four responding patients had improvement of
`polyclonal gammaglobulin levels (patients 2, 5, 6 and 10).
`Polyclonal IgG levels were normalized in one patient with
`IgG myeloma (from less than 1 up to 6 g/l; patient 5), one
`with IgA myeloma (4·9 up to 9·8 g/l; patient 10) and one
`with Bence-Jones myeloma (5·2 up to 9·2 g/l; patient 6), and
`one patient with IgG myeloma improved his IgA level from
`0·13 g/l up to 0·93 g/l (patient 2).
`One patient (10), who had a prompt and early reduction of
`her IgA paraprotein during the first month of thalidomide,
`developed a progressive paraparesis due to spinal plasmacy-
`toma that was diagnosed by magnetic resonance tomogra-
`phy and treated with surgery followed by radiotherapy,
`leading to a partial clinical response. She subsequently
`
`developed bone marrow failure 3 months after the start of
`thalidomide and died.
`There was no clear-cut correlation between myeloma
`isotype and response. Patients achieving PR were younger
`(median age 56·5 years vs. 63 years for others), possibly
`reflecting a better ability to accept thalidomide toxicity.
`Nine of 16 (56%) patients refractory to ongoing treatment
`had partial response compared with one of four patients
`given thalidomide as a result of progression off therapy
`(Table I).
`
`Patients with less than partial response
`Among three patients with relapse, minor responses were
`achieved from thalidomide in two, and a significant
`stabilization of the disease in one case. Two of them, both
`with prior autotransplantation, subsequently received oral
`melphalan and prednisone, and had a minor reduction of
`their M-protein levels at the cost of deteriorating blood
`counts. Three patients refractory to previous therapy had
`minor responses, and another had a short clinical improve-
`ment followed by disease progression and death. Three
`patients had continuing myeloma progression,
`in one
`of them thalidomide was discontinued early because of
`skin toxicity.
`
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`
`Fig 3. Serum M-protein before and during
`thalidomide treatment for patients with IgG
`and IgA myelomas.
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`

`94
`
`G. Juliusson et al
`
`Fig 4. Haemoglobin (g/dl) and platelet counts
`(· 109/l) during the first 3 months after the
`start of thalidomide for seven patients with PR
`(thick lines and patient numbers as in Table II)
`and for three patients with minor myeloma
`response (thin lines). Patient 3 received blood
`transfusions during the first month.
`
`Three patients with very advanced disease, one aged 66,
`one aged 68 and one aged 76 years, died within 3 weeks
`from start of
`thalidomide therapy because of disease
`progression without evidence of thalidomide-related toxicity.
`One of them had amyloidosis of the heart.
`
`Toxicity
`All patients became sedated from thalidomide, most sig-
`nificantly within several hours of drug intake. However,
`three of the younger patients managed to continue full-time
`or part-time work. Four patients had to reduce the dose
`because of sedation, vertigo and mood changes. One patient
`did not tolerate thalidomide because of skin toxicity, which
`was reversible but which reappeared on repeated drug
`challenge. Three other patients reported skin problems.
`Three patients had leg oedemas responding to diuretics.
`Moderate obstipation was also observed. One young patient
`had sinus bradycardia with no significant symptoms. One
`elderly patient (2) developed hypothyrosis, which in combi-
`nation with prior chronic obstructive lung disease con-
`tributed to death in good clinical remission from myeloma.
`Two patients with previous recurrent airway infections had
`pneumonia during the first month of thalidomide, and
`another (patient 1) had hypoxia and lung infiltrates with
`cytomegalovirus and Candida albicans diagnosed by bronch-
`eoalveolar lavage. Both patients recovered with treatment
`and had no sequelae. Another patient had pneumonia
`during end-stage disease. One heavily pretreated patient (3;
`Fig 1) had moderate sensory ulnar peripheral neuropathy,
`
`which did not progress during continuing thalidomide
`therapy.
`
`DISCUSSION
`
`We report here the Swedish data on thalidomide therapy for
`advanced myeloma, indicating a high response rate in highly
`refractory disease that was achieved with a low level of
`severe toxicity, although some patients required withdrawal
`or dose reduction because of dose-related toxicities. More
`than half of the patients who were refractory to ongoing
`therapy had partial remission, excluding patients with early
`death due to advanced disease. Of major interest is that many
`of these patients had a better response from thalidomide than
`from any prior therapy,
`including VAD-containing total
`therapy and including high-dose melphalan with autologous
`stem cell support. It is thus clear that thalidomide is an agent
`with major anti-tumour activity against myeloma, and that
`this activity is not cross-reactive to other currently available
`antimyeloma therapies. In fact, in our study, response to
`thalidomide was greater for patients progressing on recent
`chemotherapy than for those with untreated relapse.
`Most of our patients were given a twice daily schedule of
`thalidomide because the plasma half-life of the drug is short
`(< 6 h). This is in contrast to the study by Singhal et al
`(1999),
`in which thalidomide was given once daily. Of
`interest is that in our cohort of patients receiving thalido-
`mide in a single daily dose the time to achieve PR and the
`response rate were similar to that reported by Singhal et al
`(1999), whereas the time to response in those who received
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`

`thalidomide in divided doses seemed to be improved (Table I).
`The optimal dose and schedule of thalidomide remains to be
`determined.
`Thalidomide has several modes of action, of which the
`antiangiogenetic activity has been suggested to be important
`in myeloma (Bauer et al, 1998; Or et al, 1998; Berenson et al,
`1999; Gasparini, 1999). Increased bone marrow vessel
`density is described and related to response to therapy in
`myeloma (Vacca et al, 1994; Berenson et al, 1999; Rajkumar
`et al, 1999). However, the effect of thalidomide on the
`cytokine network (Jacobsen et al, 1997) might also be
`contributing to the anti-myeloma activity. Both these modes
`of action are less likely for alkylating agents. However, the
`rapid paraprotein response in several of our myeloma
`patients might suggest additional mechanisms, as would
`the rapid progression after withdrawal of thalidomide in two
`others.
`One patient (10) had a rapid major response of her IgA
`paraprotein level, but simultaneously with continuing
`paraprotein improvement she had progressive paraparesis
`due to spinal plasmacytoma. One could speculate whether
`there are differences in the microvessels of the bone marrow
`compartment
`compared with those
`in extraosseous
`tumours, leading to a different response to thalidomide in
`different tissues.
`Although the decline of paraprotein levels was the first
`evidence of response, patients could subsequently benefit
`from improved blood counts and bone marrow findings, but
`most importantly from an improved performance status.
`However, most patients encountered sedation and drowsi-
`ness. In some, these problems enforced withdrawal, but most
`patients tolerated therapy well and some were able to
`continue full- or part-time work. In addition, some patients
`had skin problems that were major in one case and minor in
`others. One patient developed advanced hypothyrosis, which
`might indicate that routine check-ups of thyroid-stimulating
`hormone should be performed. One patient had asympto-
`matic sinus bradycardia, which has been previously reported
`with thalidomide. One patient had moderate peripheral
`neuropathy, which is known to be a significant risk with
`long-term thalidomide therapy. Our case (patient 3) had a
`major general improvement with thalidomide therapy, and
`he had no progression of the neuropathy during continuing
`thalidomide therapy. Of specific interest is that thalidomide
`did not seem to induce bone marrow suppression. Significant
`cytopenia was not seen in this cohort of heavily pretreated
`patients, except for two patients who developed pancytope-
`nia presumed to be myeloma-related during end-stage
`disease. In addition, two younger patients also tolerated
`thalidomide shortly after allogeneic transplantation without
`impairment of their blood counts (patients 5 and 6). On the
`other hand, recovery from cytopenia induced by myeloma or
`by previous treatment was sometimes slow. As regards
`infectious complications, four patients had pneumonia, one
`of which was associated with severe hypoxia and was
`presumably caused by cytomegalovirus and Candida, as
`judged from bronchoalveolar lavage specimens (patient 1).
`All recovered with therapy without sequelae. Thalidomide is
`known to increase HIV virus load in AIDS patients (Jacobsen
`
`Thalidomide in Refractory or Relapsing Myeloma
`
`95
`
`et al, 1997), and it might be considered whether the
`reactivation of cytomegalovirus in our patient was related
`to an immunosuppressive effect of thalidomide. Birth defects
`are rarely if ever a problem in myeloma patients.
`In summary, thalidomide is an old drug with a recently
`identified significant anti-tumour activity in heavily pre-
`treated myeloma patients. Data suggest
`that
`it might
`synergize with conventional chemotherapy, and it does not
`seem to induce bone marrow suppression. Its sedative effects
`are common, but mostly tolerable, and severe side-effects are
`less common and usually reversible. Thus, thalidomide is
`likely to be a major auxiliary drug in myeloma and should be
`evaluated in other settings, such as in combination with
`chemotherapy and in less advanced myeloma.
`
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