C o m b i n a t i o n T h e r a p y W i t h T h a l i d o m i d e P l u s D e x a m e t h a s o n e
`f o r N e w l y D i a g n o s e d M y e l o m a
`
`By S. Vincent Rajkumar, Suzanne Hayman, Morie A. Gertz, Angela Dispenzieri, Martha Q. Lacy, Philip R. Greipp, Susan Geyer,
`Nancy Iturria, Rafael Fonseca, John A. Lust, Robert A. Kyle, and Thomas E. Witzig
`
`Purpose: Multiple myeloma is a malignancy of plasma
`cells and is characterized by increased marrow angiogene-
`sis. Thalidomide, an agent with antiangiogenic properties,
`is effective in relapsed myeloma. We report the results of a
`study combining thalidomide and dexamethasone as initial
`therapy for myeloma.
`Patients and Methods: Fifty patients with newly diag-
`nosed myeloma were studied. Thalidomide was given at a
`dose of 200 mg/d orally. Dexamethasone was given at a
`dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17 to 20
`(odd cycles) and 40 mg/d on days 1 to 4 (even cycles),
`repeated monthly.
`Results: Of all 50 patients, a confirmed response was
`seen in 32 patients yielding a response rate of 64% (95%
`confidence interval, 49% to 77%). Thirty-one patients (62%)
`proceeded to stem-cell collection after four cycles of therapy
`including 26 who underwent stem-cell transplantation and
`
`MULTIPLE MYELOMA accounts for 10% of malignant
`
`hematologic neoplasms.1,2 Recent evidence suggests that
`angiogenesis is increased in multiple myeloma and has prognos-
`tic value in this disease.3-5 On the basis of the increased
`angiogenesis observed in myeloma, thalidomide has been stud-
`ied as an antiangiogenic therapy. Although its mechanism of
`action in myeloma is unclear, several trials show that thalido-
`mide is active in 25% to 35% of patients with relapsed,
`refractory myeloma.6,7
`The current standard of care for patients with myeloma who
`are in good performance status is combination chemotherapy
`using non–alkylator-containing regimens such as vincristine,
`doxorubicin, and dexamethasone (VAD) for 4 to 6 months
`followed by high-dose therapy with autologous stem-cell trans-
`plantation. Such an approach has been shown to improve both
`response rates and survival.8-10 The response rate with VAD is
`approximately 55% to 65%.11 The goal of pretransplantation
`chemotherapy with VAD and similar regimens is to reduce
`tumor burden before stem-cell collection and transplantation.12
`VAD is preferred over regimens such as melphalan and pred-
`nisone and other alkylator-based regimens because it is less toxic
`to bone marrow stem cells, which is an important consideration for
`stem-cell transplant. However, VAD has significant toxicity and is
`cumbersome, requiring an indwelling central venous access for
`continuous infusion of chemotherapy that places the patient at risk
`for catheter-related infection, sepsis, and thrombosis.
`Dexamethasone has significant single-agent activity in my-
`eloma in both previously untreated and relapsed disease.13,14
`Recently, Weber et al15 demonstrated a clinical benefit by the
`addition of dexamethasone to patients for whom thalidomide
`alone was unsuccessful. On the basis of these results and the ease
`of administration over infusional VAD and other intravenous
`regimens, we conducted a clinical
`trial of thalidomide and
`dexamethasone in newly diagnosed myeloma. Because autolo-
`
`five who chose stem-cell cryopreservation. Major grade 3 or
`4 toxicities were observed in 16 patients (32%), and the
`most frequent were deep vein thrombosis (six patients),
`constipation (four patients), rash (three patients), and dys-
`pnea (two patients). Three deaths occurred during active
`therapy because of a pancreatitis, pulmonary embolism,
`and infection.
`Conclusion: We conclude that the combination of thalid-
`omide plus dexamethasone is a feasible and active regimen
`in the treatment of multiple myeloma. It merits further study
`as an oral alternative to infusional chemotherapy with
`vincristine, doxorubicin, and dexamethasone and other in-
`travenous regimens currently used as pretransplantation
`induction therapy for myeloma.
`J Clin Oncol 20:4319-4323. © 2002 by American
`Society of Clinical Oncology.
`
`gous stem-cell transplantation has been shown in randomized,
`controlled trials to be superior to conventional dose chemother-
`apy,
`the aim of the study was not
`to determine time to
`progression or survival with this regimen. Rather, our goal was
`to determine whether the combination of thalidomide and dexa-
`methasone would provide an orally administered, less toxic
`alternative to VAD (and other similar regimens) as pretransplan-
`tation induction therapy.
`
`PATIENTS AND METHODS
`
`Eligibility
`
`Patients were eligible to enter onto the study if they had previously
`untreated symptomatic myeloma. Patients were required to have bone
`marrow plasma cells ⱖ 10% and measurable disease defined as serum
`monoclonal (M) protein ⱖ 20 g/L and/or urine M protein ⱖ 400 mg/24
`hours. Patients with hemoglobin less than 70 g/L, platelets less than 25 ⫻
`less than 1,000 ⫻ 106/L, or Eastern
`109/L, absolute neutrophil count
`Cooperative Oncology Group (ECOG) performance score of 4 were ex-
`cluded. Pregnant or nursing women were not eligible. Women of child
`bearing potential who were unwilling to use a dual method of contraception
`and men who were unwilling to use a condom were not eligible for the study.
`All patients gave written informed consent before enrollment onto the study.
`
`From the Division of Hematology, Mayo Clinic and Mayo Foundation,
`Rochester, MN.
`Submitted February 23, 2001; accepted July 19, 2002.
`Supported in part by grant nos. CA85818, CA93842, and CA62242 from
`the National Cancer Institute, Bethesda, MD. S.V.R. is supported by the
`Multiple Myeloma Research Foundation and the Goldman Philanthropic
`Partnerships. S.V.R. and R.F. are also supported by Leukemia and Lym-
`phoma Society translational research awards.
`Address reprint requests to S. Vincent Rajkumar, MD, Division of
`Hematology, Mayo Clinic, 200 First St SW, Rochester, MN 55905; email:
`rajks@mayo.edu.
`
`Journal of Clinical Oncology, Vol 20, No 21 (November 1), 2002: pp 4319-4323
`DOI: 10.1200/JCO.2002.02.116
`
`4319
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`4320
`
`Approval of the study and consent form by the Mayo institutional review
`board was obtained in accordance with federal regulations and the Declara-
`tion of Helsinki. All physicians prescribing the drug and all study partici-
`pants adhered to the requirements of the System for Thalidomide Education
`and Prescribing Safety program. Women of childbearing age were required
`to have a pregnancy test performed every 2 weeks while on the study.
`
`Treatment Schedule
`
`Thalidomide was given orally at a dose of 200 mg/d for 2 weeks and then
`increased as tolerated by 200 mg/d every 2 weeks to a maximum dose of 800
`mg/d. After the first seven patients were enrolled, thalidomide dose escala-
`tion was discontinued because of unexpected skin toxicity in two patients,
`consisting of toxic epidermal necrolysis in one patient and generalized
`erythroderma in one patient.16 The dose of thalidomide was kept constant at
`200 mg/d for all subsequent patients. The thalidomide dose was reduced to
`50 to 100 mg/d if grade 2 or higher toxicity was encountered. Dexametha-
`sone was given at a dose of 40 mg/d orally on days 1 to 4, 9 to 12, and 17
`to 20 (odd cycles) and 40 mg/d days 1 to 4 (even cycles), repeated monthly.
`Patients were evaluated every 4 weeks for response. After four cycles of
`therapy, patients who were candidates for high-dose therapy were allowed to
`terminate study treatment to pursue stem-cell collection and transplantation.
`
`Response and Toxicity Criteria
`
`The primary end point of this trial was a confirmed response on two
`consecutive evaluations at least 4 weeks apart. The response and progression
`criteria used in this study are standard Mayo Clinic and ECOG criteria.
`Response was defined as a reduction of serum and urine M protein by at least
`50% accompanied by a similar reduction of soft tissue plasmacytomas if
`present. If response was assessed solely based on urine M protein, a 90% or
`greater reduction was required. In addition, responses were categorized as a
`complete response if there was complete disappearance of M protein in the
`serum and urine by immunofixation and absence of M plasma cells in the
`bone marrow. Disease progression was defined as a 50% increase in the M
`protein over the lowest response level. Increase in the size of existing lytic
`bony lesions or soft tissue plasmacytomas or the appearance of new lytic
`bony lesions constituted progression. A repeat M protein evaluation was
`required to confirm progression based on serum or urine monoclonal protein
`increase. However, as is standard in other myeloma protocols, if progression
`in M protein was accompanied by any other unequivocal evidence of
`progression, a repeat measurement was not necessary. Disease that does not
`satisfy the criteria for response, complete response, or progression was
`categorized as stable disease. The National Cancer Institute common toxicity
`criteria (version 2) were used to grade adverse effects.
`
`Statistical Analysis
`
`This trial was originally designed to accrue 30 patients to assess the
`response rate and toxicity of thalidomide and dexamethasone in the setting of
`newly diagnosed multiple myeloma. On the basis of promising activity noted
`at interim analysis, 20 additional patients were accrued to better define
`toxicity and response rate.
`Ninety-five percent confidence intervals (CIs) for the confirmed response
`probability were calculated using exact binomial 95% CIs. Toxicity inci-
`dence was estimated and summarized using frequency and descriptive
`techniques to assess any patterns. The Fisher’s exact test was used to
`compare differences in nominal variables.
`
`RESULTS
`
`Patient characteristics are listed in Table 1. The median age
`was 61 years (range, 33 to 78 years). The median serum M
`protein level before therapy was 3.8 g/dL (range, 0.0 to 7.6
`g/dL). The bone marrow plasma cell percentage before therapy
`ranged from 10% to 97% (median, 41%).
`Among the first seven patients treated, two had grade 3 or 4
`skin toxicity including one patient with toxic epidermal necroly-
`sis.16 One other patient had grade 2 exfoliation. Therefore, the
`protocol therapy was amended to stop the dose escalation of
`thalidomide and to keep the thalidomide dose constant at 200 mg
`for the subsequent 43 patients studied. Of the first seven patients,
`
`Table 1. Patient Characteristics
`
`RAJKUMAR ET AL
`
`All Patients
`
`Characteristic
`
`Sex
`Male
`Female
`Immunoglobulin heavy chain type
`IgG
`IgA
`Biclonal IgG and IgA
`Light-chain only (Bence Jones protein)
`Beta 2-microglobulin ⬎ 2.7 ␮g/mL
`Plasma cell labeling index ⱖ 1%
`Lactate dehydrogenase ⬎ 250 U/L
`Bone marrow plasma cell % ⬎ 40%
`
`No.
`
`31
`19
`
`33
`10
`1
`6
`31
`18
`5
`26
`
`%
`
`62
`38
`
`66
`20
`2
`12
`62
`36
`10
`52
`
`one patient did not receive dose escalation beyond 200 mg. The
`remaining six patients received a maximum thalidomide dose of
`400 mg. However, only two of these patients received this dose
`level for more than one cycle (one patient received 400 mg for
`six cycles and another for two cycles).
`
`Response to Therapy
`
`Thirty-two of the 50 patients (64%) had a response to therapy
`(95% CI, 49% to 77%). An additional 14 patients were catego-
`rized as stable disease and all had more than a 25% reduction in
`serum and urine M protein and can be considered as minor
`responses. If these minor responses are included, the overall
`response rate increases to 92%. The level of M protein reduction
`and bone marrow plasma cell reduction is listed in Table 2.
`When response was assessed by baseline M immunoglobulin
`(Ig) subtype, the confirmed response rates for IgG, IgA, and
`light-chain only were similar at 62%, 64%, and 60%, respec-
`tively. Four patients were taken off the study because of
`progressive disease after initial response.
`Response to therapy was accompanied by hematologic recov-
`ery and improvement in symptoms. Forty-seven patients had
`anemia at baseline (grade 1 in 29 patients, grade 2 in 16 patients,
`and grade 3 in two patients). Of these, 38% (18 of 47) patients
`had an increase in hemoglobin by at least 20 g/L or higher,
`
`Table 2.
`
`Extent of Monoclonal Protein and Bone Marrow Response
`
`Response Level
`
`No. of Patients
`
`Level of monoclonal protein reduction from baseline*
`90% or greater
`75%-90%
`50%-75%
`25%-50%
`No response or progression
`Level of bone marrow response from baseline†
`90% or greater
`75%-90%
`50%-75%
`25%-50%
`10%-25%
`No response or progression
`
`15
`11
`8
`12
`4
`
`10
`12
`6
`4
`4
`6
`
`%
`
`30
`22
`16
`24
`8
`
`24
`29
`14
`10
`10
`14
`
`*Urine monoclonal protein level was used when serum monoclonal protein level
`was less than 1 g/dL; two patients who achieved ⬎ 50% reduction in monoclonal
`protein levels in this Table were not considered responders because they did not meet
`all criteria for response and were classified as stable disease.
`†Of 42 patients in whom a repeat bone marrow biopsy was performed after
`protocol therapy.
`
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`THALIDOMIDE IN MYELOMA
`
`Table 3. Major (grade 3 and 4) Toxicities
`
`Type
`
`Treatment-related deaths
`Thrombosis
`Constipation
`Rash
`Dyspnea
`Depression
`Sedation
`Arrhythmia
`Rash
`Edema
`Inner ear
`Neuropathy
`Syncope
`
`No. of
`Patients
`
`3
`6
`4
`3
`2
`1
`1
`1
`1
`1
`1
`1
`1
`
`%
`
`6
`12
`8
`6
`4
`2
`2
`2
`2
`2
`2
`2
`2
`
`including both patients with grade 3 anemia and 11 of 16 patients
`with grade 2 anemia. One of the patients with improvement in
`anemia received erythropoietin support. Seven patients had
`baseline grade 1 or 2 leukopenia, which resolved with therapy in
`five patients. Eleven patients had baseline thrombocytopenia
`(grade 1 in nine patients, grade 2 in one patient, and grade 3 in
`one patient). Six of the nine patients with grade 1 thrombocyto-
`penia had an increase in platelet count by at least 50 ⫻ 109/L
`after therapy.
`Of the 50 patients treated, 31 proceeded to stem-cell collection
`after four cycles of therapy including 26 who underwent stem-
`cell transplantation and five who chose stem-cell cryopreserva-
`tion and are back on thalidomide plus dexamethasone. No
`problems were encountered with stem-cell collection. The re-
`maining 19 patients did not undergo stem-cell collection for
`varying reasons; this includes eight patients not considered to be
`transplant candidates because of age or patient refusal and were
`continued on thalidomide/dexamethasone therapy, four who
`proceeded to other therapy because of disease progression, four
`who pursued other therapy because of lack of adequate response
`or toxicity, and three patients who died while receiving therapy.
`
`Toxicity
`Therapy was generally well tolerated except for unexpected
`grade 3 or 4 skin toxicity in two of the first seven patients who
`had thalidomide dose escalation. There were three deaths that
`occurred during study treatment. One patient died with acute
`pancreatitis within 1 week of initiating therapy, which was
`attributed to either gallstones or dexamethasone therapy. One
`patient died within days of initiating therapy with a clinical
`diagnosis of pulmonary embolism, and one other patient died of
`infectious complications also in the first month of therapy. Grade
`3 or higher nonhematologic toxicity was seen in 17 patients
`(34%), and the most frequent were venous thrombosis in six
`patients (12%), constipation in four patients (8%), rash in
`three patients (6%), and dyspnea in two patients (4%). Table
`3 summarizes the grade 3 and 4 toxicities seen in the trial. The
`most common grade 1 and 2 toxicities were constipation
`(72%), neuropathy (58%), fatigue (50%), sedation (46%),
`rash (38%), tremor (30%), edema (28%), and elevated alka-
`line phosphatase (22%).
`
`DISCUSSION
`Thalidomide was first introduced in clinical practice as a
`sedative in the late 1950s and was subsequently withdrawn from
`
`4321
`
`the market in 1962 because of its severe teratogenicity. The
`mechanism of its teratogenicity is still unclear but may be related
`to its antiangiogenic properties or inhibition of tumor necrosis
`factor alpha (TNF ␣) production.17 Free radical mediated oxi-
`dative damage to DNA has also been postulated as a mechanism
`for the teratogenic effects.18 Despite its tragic past, thalidomide
`has re-entered clinical practice because of its immunomodula-
`tory and antiangiogenic properties. It was found to be effective
`in the treatment of erythema nodosum leprosum in the mid-
`1960s.19 In the last 10 years, thalidomide has been studied and
`found to be useful in the treatment of AIDS-related cachexia,
`aphthous ulcers in patients with Behc¸et’s disease, and in the
`treatment of chronic graft versus host disease.
`Clinical trials with thalidomide in myeloma were initiated
`because of its antiangiogenic properties and based on evidence
`indicating a role for increased angiogenesis in the pathogenesis
`and progression of myeloma.3,20 Researchers at the University of
`Arkansas conducted a landmark trial investigating the activity of
`thalidomide in relapsed myeloma.6 For most patients (90%) in
`this study, stem-cell transplantation had failed. Treatment con-
`sisted of thalidomide given at a dose of 200 mg/d orally for 2
`weeks and then increased by 200 mg/d every 2 weeks up to a
`maximum daily dose of 800 mg/d depending on toxicity. They
`observed an overall response rate of 32% with a median time to
`response of 1 month. M protein responses were accompanied by
`improvements in anemia and disease-related symptoms. The
`median duration of response was not reached after 14.5 months
`of follow-up. Considering that for 90% of the patients transplan-
`tation had failed, these results were impressive. An update to this
`study on 169 patients confirmed these results, demonstrating a
`2-year overall and event-free rates of 48% and 20%, respective-
`ly.21 Several groups including ours have since confirmed the
`activity of thalidomide in relapsed, refractory myeloma.7,22,23 A
`recent Mayo Clinic trial demonstrated a 38% response rate with
`the use of thalidomide in patients with previously untreated
`indolent or smoldering myeloma, indicating that thalidomide
`may have a role in early-stage disease as well.24
`The present study enrolled patients with newly diagnosed
`active myeloma, and most patients had high-risk disease. Sixty
`percent of those studied had high ␤2M levels, and 36% had a
`high plasma cell labeling index, which are two known adverse
`prognostic factors in myeloma. Only patients with marked
`cytopenias (hemoglobin ⬍ 70 g/L, platelet count ⬍ 25 ⫻ 109/L,
`or absolute neutrophil count ⬍ 1,000 ⫻ 106/L) were excluded
`from this study. The restrictions on cytopenias were placed
`because of safety concerns and concern that thalidomide may
`cause neutropenia. Further, when the study was designed, the
`combination had not been tested in newly diagnosed myeloma,
`and these restrictions excluded only a small minority of patients
`with myeloma. The study demonstrates significant activity (64%
`partial response rate) for the combination of thalidomide and
`dexamethasone in these patients. In addition, both the original
`Arkansas study in relapsed myeloma6 and the recent Mayo
`Clinic study in smoldering myeloma24 used less stringent criteria
`for measuring response (⬎ 25% reduction in serum and urine M
`protein) and observed response rates of 32% and 69%, respec-
`tively, with single-agent thalidomide. When this definition of
`response is used in the present study, the response rate with
`thalidomide plus dexamethasone increases to 92%. Thus, this
`combination merits further study as a simple oral alternative to
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`4322
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`VAD as induction therapy in preparation for stem-cell transplan-
`tation. The toxicity seems lower, and the response rate is as good
`or better than that obtained using complex combination chemo-
`therapy regimens.11,12 None of the known prognostic markers in
`myeloma predicted response to therapy. More research is needed
`to determine which factors predict response to thalidomide
`therapy.
`This trial allowed patients to go off the study at 4 months to
`pursue stem-cell collection and transplantation. We believe that
`the current standard of therapy for multiple myeloma includes
`autologous stem-cell transplantation after three to four cycles of
`induction therapy with VAD or dexamethasone or a similar
`regimen. Randomized trials have shown this approach to be
`superior to conventional chemotherapy in terms of overall
`survival.25 In the United States, Medicare now covers autologous
`transplantation for newly diagnosed myeloma up to the age of
`78. The effect of prolonged thalidomide therapy on the collection
`of stem cells is unknown. For these reasons, we felt it was
`unethical to deny patients the option of stem-cell collection and
`transplantation. Thus, the study did not attempt to answer the
`question of time to progression with thalidomide and dexameth-
`asone therapy. The main goal of this study was to develop an
`alternative pretransplantation induction regimen for VAD that
`would be easier to use and possibly less toxic. However, a study
`comparing long-term thalidomide plus dexamethasone versus
`transplantation would be of interest in the future.
`The appropriate dose of thalidomide in myeloma is still
`unknown and is the subject of much debate. This trial was the
`first to combine thalidomide with dexamethasone for newly
`diagnosed myeloma. At the time this trial was designed, shortly
`after reports of the efficacy of thalidomide in relapsed myeloma,
`200 mg was felt to be the appropriate starting dose. During this
`study we learned that thalidomide doses more than 200 mg in
`combination with high-dose dexamethasone might be toxic.
`Doses less than 200 mg are being studied by other investigators
`in an attempt to minimize toxicity. In fact, grade 3 and 4
`neuropathy, constipation, and fatigue were infrequently seen in
`this study probably as a result of the relatively short duration of
`therapy for most patients, as well as the lower dose of thalido-
`mide compared with earlier studies in relapsed myeloma. Other
`studies have also found that toxicities are much lower with the
`200 mg dose of thalidomide compared with higher doses.6
`However, there is no data at present on whether there is any
`accompanying loss of efficacy.
`Most side effects can be managed by decreasing the dose of
`thalidomide to 50 to 100 mg/d. Because of our experience
`with skin toxicity at higher doses,16 we do not recommend
`escalating the dose of thalidomide beyond 200 mg when
`combining with dexamethasone. The increased skin toxicity
`seen with this combination is felt to be the result of potenti-
`ation of thalidomide toxicity by dexamethasone, the mecha-
`nisms for which are unclear.16 We also recommend that
`physicians exercise caution when combining thalidomide with
`other drugs known to cause skin toxicity, such as tri-
`methoprim-sulfamethoxazole and allopurinol.
`Twelve percent of patients had deep vein thrombosis (DVT) in
`this study. However, it is known that up to 10% to 20% of
`patients with newly diagnosed myeloma develop DVT in the first
`6 months of therapy.12 There is evidence that the combination of
`thalidomide with doxorubicin containing multiagent chemother-
`
`RAJKUMAR ET AL
`
`apy may increase the incidence of DVT.26,27 The incidence of
`DVT with single-agent thalidomide is less than 5%.21 It is not
`clear if the risk of DVT with thalidomide therapy is increased in
`the absence of doxorubicin and other cytotoxic agents.
`Most patients (52%) in this study will proceed to stem-cell
`collection and transplantation after four cycles of thalidomide
`and dexamethasone. In addition, some patients (10%) have
`elected to resume thalidomide and dexamethasone after stem-
`cell mobilization has been completed, opting to delay transplan-
`tation until disease progression. In this case, their stem cells are
`cryopreserved for future use. We currently mobilize stem cells
`after four cycles of therapy because the effects of prolonged
`thalidomide therapy on stem-cell yield is not known. Only eight
`patients not considered candidates for transplantation because of
`advanced age or poor performance status are continuing long-
`term thalidomide/dexamethasone therapy.
`The high response rate seen suggests a synergy between
`thalidomide and dexamethasone. There are in vitro data that lend
`support to this hypothesis.28 The mechanisms of the synergy are
`likely complex because both drugs have a wide variety of
`preclinical and clinical effects. One hypothesis is that dexameth-
`asone has a preferentially greater effect on the myeloma cells
`directly, and thalidomide effects are indirect, mediated through
`its effect on the microenvironment. It is also hypothesized that
`thalidomide helps in overcoming dexamethasone-induced resis-
`tance by its effects on adhesion molecules, tumor cell growth,
`and survival.28 In addition, both agents probably inhibit angio-
`genesis through different pathways.29,30 Preliminary results from
`Weber et al15 demonstrate responses with combined thalidomide
`and dexamethasone among patients with relapsed myeloma for
`whom previous treatment with the same agents given individu-
`ally had failed. The increased toxicity seen in this trial at higher
`doses of thalidomide in the first seven patients also supports a
`potentiation of thalidomide effects by dexamethasone.
`The mechanism of action of thalidomide in myeloma is
`unclear. Laboratory studies using the rabbit cornea micropocket
`assay have shown that thalidomide has potent antiangiogenic
`properties.30,31 Animal studies show that it can decrease vascular
`density in granulation tissue.32 In the Arkansas study, there were
`no statistically significant differences in posttreatment microves-
`sel density change between responders and nonresponders.6
`However, these findings do not fully exclude an antiangiogenic
`mechanism. In addition to its antiangiogenic effects, thalidomide
`also has several immunomodulatory properties. It inhibits the
`production of TNF␣ by enhancing the degradation of TNF␣
`mRNA.33 Thalidomide stimulates cytotoxic T-cell proliferation
`and induces the secretion of interferon gamma and interleukin-2
`by these cells.34 It may also modulate the expression of several
`cell surface adhesion molecules.35 Another potentially signifi-
`cant mechanism of action of thalidomide may be through
`inhibition of the transcription factor nuclear factor-kappaB.36,37
`The response rate seen in this study is higher than historical
`data with dexamethasone alone (43%) or thalidomide alone
`(38%) for previously untreated myeloma. Nevertheless,
`the
`results of this trial do not establish that thalidomide plus
`dexamethasone has superior response rate to dexamethasone
`alone. The response criteria used in this trial differ from the
`response criteria used in clinical
`trials using single-agent
`dexamethasone and other induction regimens used before
`tandem transplantation at the University of Arkansas. We
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`THALIDOMIDE IN MYELOMA
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`4323
`
`believe that a randomized clinical trial comparing the two
`regimens is needed. Such a trial,
`led by ECOG,
`is now
`ongoing in the United States.
`We conclude that the response rate to induction therapy with
`the combination of thalidomide plus dexamethasone is similar to
`
`that expected with VAD and dexamethasone. Further studies are
`needed to document the effect on long-term outcomes posttrans-
`plantation with this regimen. Another strategy that needs study is
`to initiate induction therapy with dexamethasone alone and add
`thalidomide to patients who fail to respond.
`
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`Identification of prognostic factors in a phase 2 study of 169 patients. Blood
`1. Greenlee RT, Murray T, Bolden S, et al: Cancer statistics, 2000. CA
`98:492-494, 2001
`Cancer J Clin 50:7-33, 2000
`22. Kneller A, Raanani P, Hardan I, et al: Therapy with thalidomide in
`2. Bataille R, Harousseau JL: Multiple myeloma. N Engl J Med 336:
`refractory multiple myeloma: The revival of an old drug. Br J Haematol
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