Thalidomide in the treament of relapsed multiple myeloma
`Mayo Clinic Proceedings; Sep 2000; 75, 9; ProQuest Centralpg. 897
`
`Original Article
`
`Thalidomide in the Treatment of Relapsed Multiple Myeloma
`
`s. VINCENT RAJKUMAR, MD; RAFAEL FONSECA, MD; ANGELA DISPENZIERI, MD; MARTHA Q. LACY, MD;
`JOHN A. LusT, MD, PHD; THOMAS E. WITZIG, MD; ROBERT A. KYLE, MD; MORIE A. GERTZ, MD;
`AND PHILIP R. GREIPP, MD
`
`• Objective: To describe the efficacy of therapy with
`thalidomide, a drug that has antiangiogenic properties, in
`patients with relapsed multiple myeloma.
`• Patients and Methods: We studied 16 patients (median
`age, 64 years) who received thalidomide for relapsed
`myeloma at the Mayo Clinic in Rochester, Minn, between
`November 1998 and August 1999. Treatment consisted of
`thalidomide given orally at a dose of 200 mg/d for 2 weeks,
`then increased by 200 mg/d every 2 weeks, up to a maximal
`dose of 800 mg/d.
`• Results: The stage of myeloma at treatment was
`Durie-Salmon IIIA in 9 patients (56%) and IIIB in 7
`( 44 % ). The median time from myeloma diagnosis to initia(cid:173)
`tion of thalidomide therapy was 32 months. In 4 patients
`(25%) prior stem cell transplantation had failed, and 14
`(88 % ) had received 2 or more prior chemotherapeutic
`
`regimens before institution of thalidomide. All patients
`were evaluable for response. Four (25%) achieved a par(cid:173)
`tial response to therapy, with a greater than 50% reduc(cid:173)
`tion in the serum or urine· M protein level. Responses
`lasted 2, 4+, 8, and 10+ months. Major adverse effects
`included constipation, sedation, rash, and peripheral
`neuropathy.
`• Conclusion: Thalidomide is an active agent in the
`treatment of patients with advanced myeloma.
`Mayo Clin Proc. 2000;75:897-901
`
`bFGF = basic fibroblast growth factor; IL = interleukin;
`PCLI = plasma cell labeling index; STEPS = System for Tha(cid:173)
`lidomide Education and Prescribing Safety; VEGF = vascular
`endothelial growth factor
`
`M ultiple myeloma accounts for more than 11,000
`
`deaths each year in the United States. 1 The median
`survival with conventional chemotherapy is about 3 years.
`Survival is improved with autologous stem cell transplan(cid:173)
`tation in selected patients.24 However, almost all patients
`eventually have a relapse, and therapy for relapse is disap(cid:173)
`pointing. Typically, patients who have a relapse are treated
`with chemotherapeutic regimens such as VAD (vincristine,
`doxorubicin [Adriamycin], and dexamethasone), VBMCP
`(vincristine, bleomycin, melphalan, cyclophosphamide,
`prednisone ), or dexamethasone. With such treatment, re(cid:173)
`missions are usually brief.
`Angiogenesis, the formation of new blood vessels,
`normally occurs during embryonal growth and wound
`healing, as well as in the female genital system during the
`menstrual cycle. Angiogenesis is also important for the
`
`From the Division of Hematology and Internal Medicine, Mayo Clinic,
`Rochester, Minn.
`
`This study was supported in part by grants CA85818 and CA62242
`from the National Cancer Institute, Bethesda, Md. Dr Rajkumar and
`Dr Fonseca are Leukemia and Lymphoma Society of America Trans(cid:173)
`lational Research Awardees. Dr Rajkumar is also supported by the
`Judith and George Goldman Foundation.
`
`Address reprint requests and correspondence to S. Vincent
`Rajkumar, MD, Division of Hematology, Mayo Clinic, 200 First St
`SW, Rochester, MN 55905.
`
`proliferation and metastases of most malignant neoplasms. 5
`In the absence of angiogenesis, tumors cannot grow be(cid:173)
`yond 1 to 2 mm. 5 Increased angiogenesis has been found
`to be an adverse prognostic factor in several solid tumors. 6
`7
`•
`Although many initial studies were done on solid tumors,
`angiogenesis seems important in hematologic malignan(cid:173)
`
`cies as well. 8·9 There is evidence that increased bone mar(cid:173)
`row angiogenesis occurs in myeloma and is correlated with
`the plasma cell labeling index (PCLI) ( a measure of plasma
`cell proliferative activity) and the stage of disease. 10
`Thalidomide, previously withdrawn from clinical use
`because of its severe teratogenicity, has been reintroduced
`because of its immunomodulating and antiangiogenic
`properties. The aim of this study was to analyze the effect
`of thalidomide in the treatment of patients with relapsed
`multiple myeloma.
`
`PATIENTS AND METHODS
`Patients and Data Collection
`Our study population comprised 16 patients (median
`age, 64 years) who received thalidomide for relapsed
`myeloma at the Mayo Clinic in Rochester, Minn, between
`November 1998 and August 1999. Treatment consisted of
`thalidomide given orally at a dose of 200 mg/d for 2 weeks,
`then increased by 200 mg/d every 2 weeks, up to a maximal
`dose of 800 mg/d depending on toxicity.
`
`Mayo Clin Proc. 2000;75:897-901
`
`897
`
`© 2000 Mayo Foundation for Medical Education and Research
`
`Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
`
`DR. REDDY’S LABS., INC. EX. 1048 PAGE 1
`
`Rajkumar, S Vincent;Fonseca, Rafael;Dispenieri, Angela;Lacy, Martha Q;et al
`

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`898
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`Thalidomide in Myeloma
`
`Mayo Clin Proc, September 2000, Vol 75
`
`Table 1. Patient Characteristics
`
`Characteristic
`
`Sex
`Male
`Female
`Durie-Salmon stage
`IIlA
`IIlB
`No. of prior chemotherapeutic regimens
`~2
`~4
`Prior transplantation
`
`No.(%)
`of patients
`(N=l6)
`
`11 (69)
`5 (31)
`
`9 (56)
`7 (44)
`
`14 (88)
`4 (25)
`4 (25)
`
`All patients gave written informed consent on the Sys(cid:173)
`tem for Thalidomide Education and Prescribing Safety
`(STEPS) consent form before receiving treatment. Ap(cid:173)
`proval of the study by the Mayo Institutional Review Board
`was obtained in accordance with federal regulations and
`the Declaration of Helsinki. All physicians prescribing the
`drug and all study participants adhered to the requirements
`of the STEPS program.
`
`Definition of Response
`Complete response was defined as lack of detectable
`monoclonal (M) protein in the serum and urine by immu(cid:173)
`noelectrophoresis and immunofixation. Partial response
`was defined as reduction of M protein in the serum or urine
`by at least 50% accompanied by a similar reduction of soft
`tissue plasmacytomas if present. Disease progression was
`defined as a 50% increase in the M protein over the lowest
`remission level. An increase in the size of existing lytic
`bony lesions or soft tissue plasmacytomas or appearance of
`new lytic bony lesions constituted progression. Disease that
`did not satisfy the criteria for complete response, partial
`response, or progression was categorized as stable disease.
`
`Statlstlcal Analysis
`Overall survival was calculated from the date of initia(cid:173)
`tion of therapy to the date of death or date of last follow-up.
`Survival analysis was done by using the method described
`by Kaplan and Meier. 11
`
`RESULTS
`Patient characteristics are summarized in Table 1. Among
`the 16 patients, the median age was 64 years (range, 48-85
`years). The median serum M protein spike was 25 g/L, and
`the median time from myeloma diagnosis to initiation of
`thalidomide therapy was 32 months.
`In 4 patients (25%), prior stem cell transplantation had
`failed, and 14 patients (88%) had received 2 or more previ-
`
`ous chemotherapeutic regimens before thalidomide had
`been instituted, including 4 patients (25%) in whom 4 or
`more regimens had failed. Patients had progressive disease
`at the time of initiation of thalidomide therapy. No patient
`was in plateau phase at the time thalidomide therapy was
`initiated, and no patient was lost to follow-up.
`
`Response and Survival
`All patients were evaluable for response. No complete
`responses were observed. Four patients (25%) achieved a
`partial response to therapy. All responders had pronounced
`improvement in symptoms, associated with recovery of
`cytopenias. In 2 of these patients, response duration was 2
`months and 8 months. The other 2 patients continue to
`respond, after 4 months and 10 months of follow-up. Six
`other patients had stable disease for a median duration of 5
`months (range, 2-9 months), including l who had a minor
`response (48% reduction in M protein). Two of the patients
`with stable disease had improvements in hemoglobin con(cid:173)
`centration and platelet counts, but none had improvement
`in renal function.
`The PCLI was high (> l % ) in 3 of 4 patients who
`achieved a partial response, as well as in 5 of 12 non(cid:173)
`responders, indicating that drug effects were not restricted
`to the hypoproliferative category. Deletions of chromo(cid:173)
`some 13 were noted in 1 of 4 responders and in 5 of 12
`nonresponders.
`Nine patients have died, and the median survival after
`thalidomide therapy was 5 months (Figure 1, left); pro(cid:173)
`gression-free survival was 3 months (Figure 1, right).
`Cause of death was progressive myeloma in 8 patients and
`stroke in 1 patient. The median survival from the initial
`diagnosis of myeloma was 56 months.
`
`Illustrative Case
`A 69-year-old woman in whom 2 prior chemothera(cid:173)
`peutic regimens and radiation therapy for myeloma had
`failed was referred for treatment. She had advanced dis(cid:173)
`ease, poor performance status, gingival bleeding, and ex(cid:173)
`tensive ecchymoses. Her hemoglobin concentration was
`9.9 g/dL, and her leukocyte count was 14.8 x 109/L with
`20% circulating plasma cells on the differential test. She
`had pronounced thrombocytopenia with a platelet count
`of 3 x 109/L. A bone marrow examination revealed
`greater than 90% involvement with myeloma, and the se(cid:173)
`rum M protein level was 66 g/L (lgAic). Within 2 months of
`initiation of thalidomide therapy, she had a dramatic re(cid:173)
`sponse, with substantial improvement in symptoms and
`laboratory test results. Her hemoglobin concentration im(cid:173)
`proved to 12.2 g/dL, leukocyte count was 3.6 x 109/L with
`no plasma cells on the differential test, and platelet count
`was 202 x 109/L. The serum M protein level decreased to
`
`Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
`
`DR. REDDY’S LABS., INC. EX. 1048 PAGE 2
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`Mayo Clio Proc, September 2000, Vol 75
`
`Thalidomide in Myeloma
`
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`
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`
`Figure 1. Kaplan-Meier estimation of (left) overall survival and (right) progression-free survival after thalidomide therapy for relapsed
`myeloma.
`
`less than IO g/L. She is still in remission after 4 months of
`follow-up.
`
`Thalldomlde Dosage and Toxicity
`The median tolerated dose of thalidomide was 400 mg/
`d. For each patient, the dosage of thalidomide varied con(cid:173)
`siderably, from I 00 to 800 mg/d. The dose of thalidomide
`was reduced according to toxicity. If a grade 2 or higher
`toxicity (grade 3 or higher for sedation and constipation)
`occurred at a dosage of 400 mg/d or greater, the dose was
`withheld until toxicity subsided and then decreased to 200
`mg/d. If such toxicity was seen with a dosage of 200 mg/d,
`the dose was withheld until toxicity subsided and then
`reinitiated at 50 to 100 mg/d. All responses occurred with
`doses ranging from 200 to 400 mg/d and could be sustained
`with doses as low as 100 mg/d. However, 2 of the respond(cid:173)
`ing patients required doses of up to 400 mg/d to sustain a
`response.
`Major adverse effects included constipation (25%), ex(cid:173)
`cessive sedation (25%), fatigue (25%), and rash (19%).
`These toxicities were grade 1 to 2 (on a scale of 1 to 4),
`except in 2 patients who had grade 3 sedation and constipa(cid:173)
`tion. One patient each discontinued treatment because of
`peripheral neuropathy and cardiac arrhythmia (grade 3
`toxicity).
`
`DISCUSSION
`Earlier we reported that angiogenesis is increased in mye(cid:173)
`loma and persists even after a complete response. 8 We also
`determined that angiogenesis is a powerful prognostic fac(cid:173)
`tor in newly diagnosed myeloma. 12 Data from Munshi et
`al1 3 lend additional support to these findings.
`Antiangiogenic therapy represents a novel and possibly
`less toxic approach to treat malignancies. 14 Researchers at
`the University of Arkansas recently reported on the activity
`
`of thalidomide in a group of heavily pretreated patients
`with myeloma. 15 In most of the patients in that study, stem
`cell transplantation had failed. Treatment consisted of tha(cid:173)
`lidomide given orally at a dose of 200 mg/d for 2 weeks,
`then increased by 200 mg/d every 2 weeks, up to a maximal
`dose of 800 mg/d depending on toxicity. The overall re(cid:173)
`sponse rate was 32%. The median time to response was 1
`month. Eight patients ( 10%) had a greater than 90% reduc(cid:173)
`tion in paraprotein levels. Paraprotein responses were
`accompanied by improvements in anemia and other symp(cid:173)
`toms. Among the 48 patients who had repeated bone
`marrow analysis after thalidomide therapy, 81 % had con(cid:173)
`firmation of paraprotein responses. The best predictor of a
`response was a PCLI lower than 0.2. The median duration
`of response had not been reached after 14.5 months of
`follow-up.
`Our study demonstrates a 25% response rate with tha(cid:173)
`lidomide in patients with relapsed myeloma. In addition,
`some patients had clinically meaningful stabilization of
`their disease, including 1 who achieved a 48% reduction in
`the monoclonal protein level but did not meet criteria for a
`partial response. Since almost all available therapy for
`relapse had failed in most of these patients, the responses
`observed are impressive. Thalidomide is also the first drug
`to demonstrate clinically important single-agent activity in
`relapsed refractory myeloma in more than 2 decades.
`Based on the available evidence, thalidomide can be
`considered for patients with relapsed multiple myeloma
`after stem cell transplantation or conventional chemo(cid:173)
`therapy. Until ongoing studies are completed, thalidomide
`is not recommended as initial therapy for patients with
`newly diagnosed myeloma. The usual starting dose is 200
`mg/d taken orally as a single dose at bedtime. In the ab(cid:173)
`sence of adverse effects, the dose is increased by 200 mg
`every 2 weeks, to a maximal dose of 800 mg/d. Most
`
`Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
`
`DR. REDDY’S LABS., INC. EX. 1048 PAGE 3
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`900
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`Thalidomide in Myeloma
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`Mayo Clin Proc, September 2000, Vol 75
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`proliferation and induces the secretion of interferon y and
`interleukin (IL) 2 by these cells. 22 Thalidomide also in(cid:173)
`duces helper T cell type 2 cytokine production in human
`peripheral blood mononuclear cell cultures while concomi(cid:173)
`tantly inhibiting helper T cell type l cytokine production. 23
`Finally, it modulates the expression of cell surface adhe(cid:173)
`sion molecules.24 The responses seen in myeloma may be
`due to a combination of these immunologic effects of tha(cid:173)
`lidomide with its antiangiogenic effects.
`The association of angiogenesis with PCLI, its prognos(cid:173)
`tic value, and the responses observed with thalidomide
`support a role for angiogenesis in the pathogenesis and
`progression of myeloma. There are also data that myeloma
`cells express VEGF and bFGF. 25
`26 Stimulation of myeloma
`•
`cell lines with IL-6 leads to an increase in VEGF secre(cid:173)
`tion.27 Moreover, stimulation of human microvascular en(cid:173)
`dothelial cells and bone marrow stromal cells with VEGF
`induces an increase in IL-6 secretion in a dose-dependent
`manner.
`We conclude that thalidomide is an active agent in the
`treatment of patients with advanced myeloma. A prospec(cid:173)
`tive trial to confirm these findings is ongoing at the Mayo
`Clinic in Rochester, Minn, and includes correlative studies
`to assess the effect of thalidomide on bone marrow
`angiogenesis, as well as the expression of VEGF, bFGF,
`and their receptors. We are also studying patients with
`newly diagnosed, untreated asymptomatic myeloma with
`single-agent thalidomide. Moreover, studies of chronic
`lymphocytic leukemia, myelodysplastic syndrome, and
`myelofibrosis are being developed.
`
`patients are unable to tolerate doses greater than 400 to 600
`mg/d. Preliminary data from Munshi et al 16 suggest that
`thalidomide can be effectively combined with chemo(cid:173)
`therapy. However, because of concerns of toxicity, we do
`not recommend the use of thalidomide in combination with
`dexamethasone or other chemotherapeutic agents except as
`part of a clinical trial.
`Because of the risk of severe teratogenicity, the use of
`thalidomide in pregnant women is absolutely contra(cid:173)
`indicated. There are restrictions on the prescribing and
`dispensing of the drug. Both the prescribing physician and
`the dispensing pharmacy are required to register with the
`STEPS program. Women in the childbearing age group
`must undergo pregnancy testing before therapy can be
`instituted and every 2 to 4 weeks during treatment. They
`must abstain from sexual intercourse or use 2 highly effec(cid:173)
`tive contraceptive methods during treatment. Men must
`abstain from sexual intercourse or use a condom while
`receiving treatment even if they have undergone a success(cid:173)
`ful vasectomy. All patients must continue these measures
`for at least l month after the last dose of the drug. Breast(cid:173)
`feeding is contraindicated.
`The most common adverse effects of thalidomide are
`sedation, fatigue, constipation, and rash. Most patients
`are unable to tolerate doses greater than 400 mg/d be(cid:173)
`cause of excessive sedation and fatigue. Laxatives have
`been prescribed prophylactically. Peripheral neuropathy
`can occur, usually with treatment durations of 6 months or
`longer.
`The mechanism of action of thalidomide in myeloma is
`unknown. Laboratory studies using the rabbit cornea
`micropocket assay have shown that thalidomide has potent
`antiangiogenic properties, probably by blocking the action
`of potent angiogenic factors such as basic fibroblast growth
`factor (bFGF) and vascular endothelial growth factor
`(VEGF). 17•18 Animal studies indicate that thalidomide treat(cid:173)
`ment can decrease vascular density in granulation tissue. 19
`In studies of murine Lewis lung tumors, thalidomide re(cid:173)
`duced the development of metastases and increased sensi(cid:173)
`tivity to chemoradiotherapy.20 Since angiogenesis is in(cid:173)
`creased in myeloma, the efficacy of thalidomide may be
`related to its antiangiogenic properties. However, in the
`Arkansas study, 15 there were no statistically significant
`differences in bone marrow angiogenesis after thalidomide
`therapy, suggesting that other mechanisms may also be
`involved. The rapidity of response seen with thalidomide
`therapy also argues against antiangiogenesis as the sole
`mode of action. Thalidomide has potent immunomodula(cid:173)
`tory effects, which may be responsible for its activity in
`myeloma. It is a potent inhibitor of tumor necrosis factor a,
`enhancing the degradation of tumor necrosis factor a mes(cid:173)
`senger RNA. 21 Thalidomide stimulates cytotoxic T-cell
`
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