`
`The Official Journal of the American Society of Clinical Oncology
`
`Vol 19, No 16
`
`August 15, 2001
`
`EDITORIAL
`T h a l i d o m i d e i n t h e T r e a t m e n t o f P l a s m a C e l l M a l i g n a n c i e s
`
`THALIDOMIDE, REMOVED from clinical use because
`
`of severe teratogenicity, is back.1 In a comeback that
`has proceeded with remarkable speed, the drug that ad-
`versely affected more than 10,000 infants just over four
`decades ago now seems to be a lifesaver for patients with
`advanced plasma cell malignancies.
`In a sense, thalidomide never really went away. Shortly
`after reports of teratogenicity forced the drug off the market,
`it was found to be effective in the treatment of erythema
`nodosum leprosum.2 The drug has since been available in a
`limited manner to leprosy patients in many countries. In
`1998, the Food and Drug Administration approved the drug
`for use in erythema nodosum leprosum, with substantial
`precautions. Over
`the last 10 years, other uses have
`emerged, including AIDS-related cachexia and oral ulcers,3
`aphthous ulcers in Behcet’s disease,4 and chronic graft-
`versus-host disease.5
`Thalidomide was first studied as an anticancer agent by
`astute investigators intrigued by its potent teratogenic po-
`tential. In 1962, only 4 months after the initial reports of
`teratogenicity, Woodyatt6 treated a woman with malignant
`mixed mesodermal tumor of the uterus. The interest in
`studying thalidomide as an anticancer agent led to at least
`three clinical trials in the early 1960s, including a study by
`the Eastern Cooperative Oncology Group.7,8 These trials did
`not show any significant activity, and interest in thalidomide
`as an anticancer agent diminished greatly.
`The recent studies of thalidomide in plasma cell disorders
`were prompted by the growing interest in studying tumor
`angiogenesis as a novel therapeutic target. Given its com-
`passionate use availability and its anti-angiogenic proper-
`ties,9 Barlogie et al initiated clinical studies with thalido-
`mide in refractory multiple myeloma. Their
`results,
`published in 1999 by Singhal et al,1 demonstrated an overall
`response rate of 32% in 84 patients with relapsed, refractory
`myeloma. Considering that 90% of patients in this study had
`failed autologous stem-cell
`transplantation,
`these results
`
`were impressive. The activity of thalidomide in relapsed
`myeloma with response rates in the range of 25% to 45%
`has since been confirmed by numerous studies world-
`wide.10-12 These studies indicate a median response duration
`of 9 months to 1 year. Approximately 10% to 20% of
`patients are free of progression at 2 years. Based on these
`results, thalidomide is now considered as part of standard
`therapy for relapsed myeloma, but Food and Drug Admin-
`istration approval for this indication is pending.
`In this issue of the Journal of Clinical Oncology, Dimo-
`poulos et al13 report activity of thalidomide in Walden-
`stro¨m’s macroglobulinemia, a closely related plasma cell
`malignancy. The study of thalidomide in this disease is
`certainly warranted given the striking activity seen in
`advanced myeloma. The authors report a response rate of
`25% in an unselected group of patients with Waldenstro¨m’s
`macroglobulinemia. Responses seem durable and were as-
`sociated with improvement in marrow infiltration, hemoglo-
`bin concentration, and uninvolved immunoglobulin levels.
`The study demonstrates proof of principle that thalidomide
`has activity in this disease. Although the sample size is too
`small to make definite conclusions, it is worth noting that all
`responders had received less than 24 months of prior
`therapy, and none of the patients with refractory relapse
`responded to therapy.
`Two findings made by the authors resonate well with
`observations made in myeloma trials. First, doses higher
`than 200 mg to 400 mg are associated with significantly
`higher toxicity and may not necessarily yield better re-
`sponse rates. Second, the effect of thalidomide is rapid.
`Patients who do not achieve at least a 25% reduction in
`monoclonal protein levels in 1 to 2 months are unlikely to
`respond with continued therapy.
`How can we explain the efficacy of thalidomide in
`plasma cell malignancies? Given its unstable nature (upon
`absorption it spontaneously and nonenzymatically cleaves
`into over 20 metabolites),
`the mechanism of action of
`
`Journal of Clinical Oncology, Vol 19, No 16 (August 15), 2001: pp 3593-3595
`
`3593
`
`Downloaded from jco.ascopubs.org on May 31, 2016. For personal use only. No other uses without permission.
`Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
`
`ALVOGEN, Exh. 1011, p. 0001
`
`
`
`3594
`
`thalidomide has not been easy to elucidate.14 It has
`complex effects on tumor angiogenesis,
`the immune
`system, and various cytokines and adhesion molecules.
`Using the rabbit cornea micropocket assay, D’Amato et
`al9 determined that thalidomide had potent anti-angio-
`genic properties, probably by blocking the action of
`angiogenic cytokines such as basic fibroblast growth
`factor and vascular endothelial growth factor. In the
`myeloma trials, no statistically significant differences
`have been observed in posttreatment microvessel density
`(MVD) change between responders and nonresponders,
`and pretreatment MVD is not a predictor of
`re-
`sponse.1,15,16 Because MVD is a crude measure of bone
`marrow angiogenesis, the lack of a consistent decrease in
`bone marrow MVD after thalidomide therapy does not
`fully exclude an anti-angiogenic mechanism of action for
`this agent. However, it is clear that other properties of
`thalidomide may play a role in its anticancer activity.10,17
`Recently, Parman et al18 demonstrated that thalidomide-
`induced birth defects in rabbits can be abolished by
`pretreatment with the free radical spin-trapping agent
`alpha-phenyl-N-t-butylnitrone, suggesting free radical–
`mediated DNA damage as a mechanism of action. Other
`studies show that
`thalidomide inhibits tumor necrosis
`factor alpha (TNFa) activity by promoting the degrada-
`tion of TNFa mRNA19 and enhancing the effect of
`a1-acid glycoproteins that possess intrinsic anti-TNFa
`effects.14,20 In addition, it stimulates the proliferation and
`secretion of interferon gamma and interleukin-2 by cy-
`totoxic T cells21 and may modulate the expression of cell
`surface adhesion molecules that allow myeloma cells to
`interact with the bone marrow microenvironment.22 We
`are convinced that elucidation of the mechanism of action
`of thalidomide in plasma cell malignancies will provide
`significant insights into tumor biology and will open the
`door to the development of other novel therapies.
`Where do we go from here? At present, there is a need
`to test thalidomide in early-stage plasma cell disorders.
`Two recent studies with thalidomide in untreated patients
`with indolent or smoldering myeloma indicate a response
`rate of approximately 35% to 40%.16,23 Because the
`standard approach to these patients is observation with-
`out therapy, randomized trials are needed to determine
`whether thalidomide at low doses can delay progression
`to active symptomatic disease. Another critical question
`is the benefit of combining thalidomide with other active
`agents. Weber et al24 have observed responses in 24
`(52%) of 47 patients with resistant myeloma using a
`combination of thalidomide and dexamethasone. Many
`patients (46%) in this trial had previously failed dexa-
`
`RAJKUMAR AND KYLE
`
`methasone and thalidomide as single agents, suggesting a
`synergistic effect when the two agents are combined.
`Preliminary results from a Mayo Clinic study using this
`combination as initial therapy for previously untreated
`myeloma indicate promising activity with a response rate
`of over 75%.16 Laboratory studies also support
`the
`presence of synergistic interactions between thalidomide
`and dexamethasone.25 The efficacy of thalidomide ad-
`ministered in combination with other chemotherapeutic
`agents is being addressed by ongoing randomized clinical
`trials at the University of Arkansas for Medical Sciences.
`Although results with thalidomide in combination with
`other active agents in early-stage disease seem promis-
`ing, we recommend caution until further safety and
`efficacy data are available. This is important, considering
`the risk of irreversible neuropathy with long-term thalid-
`omide therapy and the observation of unexpected added
`toxicity in studies combining the drug with dexametha-
`sone26 or doxorubicin-based chemotherapy27 for newly
`diagnosed myeloma.
`The main limitations of thalidomide are the risk of
`teratogenicity and side effects such as drowsiness, fatigue,
`constipation, rash, and neuropathy. Although adverse ef-
`fects are usually mild, they can be troublesome and severe
`in a small proportion of patients. To overcome this, analogs
`of thalidomide (immunomodulatory drugs) are being devel-
`oped and tested in clinical trials. These analogs have the
`promise of improved efficacy with fewer side effects. One
`such analog, CC-5013, has significantly more potent effects
`against human myeloma cells and less adverse effects than
`thalidomide. Based on promising preclinical data, two phase
`I studies with CC-5013 have been initiated in relapsed
`myeloma, and a larger multi-institutional phase II trial is
`expected to open early next year.
`Thalidomide has emerged as an effective agent in the
`treatment of relapsed myeloma. It seems to have activity in
`Waldenstro¨m’s macroglobulinemia and merits
`further
`study. As an anticancer agent, thalidomide may prove useful
`in the treatment of other cancers. Preliminary data suggest
`activity in myelodysplastic syndrome, myelofibrosis, glio-
`mas, and renal cell cancer. Further studies should focus on
`its mechanism of action, ideal dosing schedule, duration of
`therapy, and role in maintenance therapy. Finally, patients
`and physicians must continue to exercise caution when
`using thalidomide to avoid teratogenic complications.
`
`S. Vincent Rajkumar
`Robert A. Kyle
`Mayo Clinic and Mayo Foundation
`Rochester, MN
`
`Downloaded from jco.ascopubs.org on May 31, 2016. For personal use only. No other uses without permission.
`Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
`
`ALVOGEN, Exh. 1011, p. 0002
`
`
`
`EDITORIAL
`
`3595
`
`REFERENCES
`1. Singhal S, Mehta J, Desikan R, et al: Antitumor activity of
`(MM) with laboratory correlative studies. Blood 96:168a, 2000
`thalidomide in refractory multiple myeloma. N Engl J Med 341:1565-
`(abstr 723)
`1571, 1999
`16. Rajkumar SV, Hayman S, Fonseca R, et al: Thalidomide plus
`2. Sheskin J: Thalidomide in the treatment of lepra reactions. Clin
`dexamethasone (Thal/Dex) and thalidomide alone (Thal) as first line
`Pharmacol Ther 6:303-306, 1965
`therapy for newly diagnosed myeloma (MM). Blood 96:168a, 2000
`3. Jacobson JM, Greenspan JS, Spritzler J, et al: Thalidomide for the
`(abstr 722)
`treatment of oral aphthous ulcers in patients with human immunodefi-
`17. Raje N, Anderson K: Thalidomide: A revival story. N Engl
`ciency virus infection: National Institute of Allergy and Infectious Dis-
`J Med 341:1606-1607, 1999
`eases AIDS Clinical Trials Group. N Engl J Med 336:1487-1493, 1997
`18. Parman T, Wiley MJ, Wells PG: Free radical-mediated oxidative
`4. Hamuryudan V, Mat C, Saip S, et al: Thalidomide in the
`DNA damage in the mechanism of thalidomide teratogenicity. Nature
`treatment of the mucocutaneous lesions of the Behcet syndrome: A
`Med 5:582-585, 1999
`randomized, double-blind, placebo-controlled trial. Ann Intern Med
`19. Moreira AL, Sampaio EP, Zmuidzinas A, et al: Thalidomide
`128:443-450, 1998
`exerts its inhibitory action on tumor necrosis factor alpha by enhancing
`5. Parker PM, Chao N, Nademanee A, et al: Thalidomide as salvage
`mRNA degradation. J Exp Med 177:1675-1680, 1993
`therapy for chronic graft-versus-host disease. Blood 86:3604-3609, 1995
`20. Turk BE, Jiang H, Liu JO: Binding of
`thalidomide to
`6. Woodyatt PB: Thalidomide. Lancet 1:750, 1962
`alpha1-acid glycoprotein may be involved in its inhibition of tumor
`7. Olson KB, Hall TC, Horton J, et al: Thalidomide (N-phthaloyl-
`necrosis factor alpha production. Proc Natl Acad Sci USA 93:7552-
`glutamimide) in the treatment of advanced cancer. Clin Pharmacol Ther
`7556, 1996
`6:292-297, 1965
`21. Haslett PA, Corral LG, Albert M, et al: Thalidomide costimu-
`8. Grabstad H, Golbey R: Clinical experience with thalidomide in
`lates primary human T lymphocytes, preferentially inducing prolifera-
`tion, cytokine production, and cytotoxic responses in the CD81 subset.
`patients with cancer. Clin Pharmacol Therap 6:298-302, 1965
`9. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is an
`J Exp Med 187:1885-1892, 1998
`inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1994
`22. Geitz H, Handt S, Zwingenberger K: Thalidomide selectively
`10. Rajkumar SV, Witzig TE: A review of angiogenesis and
`modulates the density of cell surface molecules involved in the
`anti-angiogenic therapy with thalidomide in multiple myeloma. Cancer
`adhesion cascade. Immunopharmacol 31:213-221, 1996
`Treat Rev 26:351-362, 2000
`23. Weber DM, Rankin K, Gavino M, et al: Angiogenesis factors
`11. Rajkumar SV, Fonseca R, Dispenzieri A, et al: Thalidomide in
`and sensitivity to thalidomide in previously untreated multiple my-
`the treatment of relapsed multiple myeloma. Mayo Clin Proc 75:897-
`eloma (MM). Blood 96:168a, 2000 (abstr 724)
`902, 2000
`24. Weber DM, Rankin K, Gavino M, et al: Thalidomide with
`12. Juliusson G, Celsing F, Turesson I, et al: Frequent good partial
`dexamethasone for resistant multiple myeloma. Blood 96:167a, 2000
`remissions from thalidomide including best response ever in patients
`(abstr 719)
`with advanced refractory and relapsed myeloma. Br J Haematol
`25. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its
`109:89-96, 2000
`analogs overcome drug resistance of multiple myeloma cells to
`13. Dimopoulos MA, Zomas A, Viniou NA, et al: Treatment of
`conventional therapy. Blood 96:2943-2950, 2000
`Waldenstrom’s macroglobulinemia with thalidomide. J Clin Oncol
`26. Rajkumar SV, Gertz MA, Witzig TE: Life-threatening toxic
`19:3956-3601, 2001
`epidermal necrolysis with thalidomide therapy for myeloma. N Engl
`14. Stirling DI: Pharmacology of thalidomide. Semin Hematol
`J Med 343:972-973, 2000
`37:5-14, 2000
`27. Osman K, Comenzo R, Rajkumar SV: Deep vein thrombosis and
`15. Rajkumar SV, Fonseca R, Dispenzieri A, et al: A phase II
`thalidomide therapy for multiple myeloma. N Engl J Med 344:1951-
`trial of thalidomide in the treatment of relapsed multiple myeloma
`1952, 2001
`
`Downloaded from jco.ascopubs.org on May 31, 2016. For personal use only. No other uses without permission.
`Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
`
`ALVOGEN, Exh. 1011, p. 0003
`
`