Thalidomide in multiple myeloma

doi:10.1016/S0753-3322(02)00168-3

Biomedicine & Pharmacotherapy

Volume 56, Issue 3, May 2002, Pages 115-128

https://doi.org/10.1016/S0753-3322(02)00168-3 Get rights and content

Abstract

Thalidomide – removed from widespread clinical use by 1962 because of severe teratogenicity – has anti-angiogenic and immunomodulatory effects, including the inhibition of TNF alpha. It has returned to practice as an effective oral agent in the management of various disease states including erythema nodosum leprosum, for which it was FDA-approved in 1998, and more recently certain malignancies, including multiple myeloma. Whilst the mechanism of action of thalidomide remains incompletely understood, considerable insight has been generated by extensive preclinical studies in multiple myeloma. Moreover, clinical trials both as a single agent and in combination have confirmed benefit in relapsed and refractory disease. Thalidomide’s role in treating newly diagnosed patients is currently under study and it is now established as an important therapeutic option in the treatment of multiple myeloma.

Section snippets

Pharmacology

Thalidomide is a derivative of glutamic acid and is pharmacologically classified as an immunomodulatory agent 〚84〛. Structurally, thalidomide contains 2 amide rings and a single chiral center (see figure 1), and its full chemical name is alpha-N{phthalimido}glutarimide 〚C 13 O4 N2 H9〛 with a gram molecular weight of 258.2 〚84〛.

The currently available formulation is a non-polar racemic mixture present as the optically active S and R isomers at physiologic pH, which can effectively cross cell

Preclinical studies of thalidomide and its analogs in multiple myeloma

Although thalidomide was initially used to treat multiple myeloma based upon its anti-angiogenic effects, the mechanism of its anti-myeloma activity appears to be more complex. Preclinical studies of thalidomide and its potent analogs (also known as immunomodulatory drugs, IMiDs) suggest that these drugs act against myeloma in several ways. First, there appears to be a direct effect on the myeloma cell and/or bone marrow (BM) stromal cell which inhibits tumor growth and survival. Second,

Clinical studies in multiple myeloma

Despite recent advances in treatments, including transplant, myeloma remains incurable and more effective therapies are clearly needed 2, 78. The development of resistance to chemotherapy and radiation is a characteristic of myeloma, and this has spurred research in new biologically derived treatment strategies. One such approach involves anti-angiogenesis, a strategy based on observations that hematologic malignancies, such as multiple myeloma, are associated with intense neo-vascularization

Conclusion

It is evident that new approaches are needed to target the biological processes associated with disease progression in multiple myeloma. Current data suggest that thalidomide, which has anti-angiogenic as well as immunomodulatory properties, has major activity in patients with multiple myeloma. The emergence of orally active thalidomide derivatives with considerable promise for improved efficacy and less toxicity also provide an exciting platform for the future treatment of this otherwise

Acknowledgements

The authors gratefully acknowledge the contribution of Keith Doucet in the preparation of this manuscript.

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As a result of this serendipitous repositioning, sildenafil citrate has grossed over $15 billion in revenue since its release in 1998 [16]. Another notable example is thalidomide (2), a sedative that received much notoriety in the early 1960s due to its severe teratogenic effects [17]. Despite its infamy, thalidomide was repositioned to treat erythema nodosum leprosum and was approved for the treatment of this form of leprosy by the Food and Drug Administration (FDA) in 1998 (Thalomid®) with the caveat of its teratogenic effects [18].
This chapter summarizes some of the novel methods used to accelerate the discovery of old drugs that could potentially treat new indications, either by the established mechanism of action or by the identification of new ones. Representative case studies of the approaches to therapeutic discoveries are also highlighted. Researchers have previously identified repositioned drugs by serendipity, novel insights, or target searching. The innovative strategies directed toward drug repositioning discussed in this chapter are phenotypic, high throughput, and in silico screening of commercial, public, and pharmaceutical compound libraries, the prospective mining of drug/activity databases, the exchange of compound information in collaborative networks, and data collection from the Internet and social networks. The term “drug repositioning” has been used interchangeably with “drug repurposing” or “drug reprofiling,” which is a promising field in drug discovery that identifies new therapeutic opportunities for existing drugs.
The neutropenia induced by the thalidomide analogue CC-4047 in patients with multiple myeloma is associated with an increased percentage of neutrophils bearing CD64
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A major limitation to the treatment of multiple myeloma by the thalidomide analogue CC-4047 (Actimid™) is the development of a severe neutropenia. We investigated the hypothesis that this effect may have been due to CC-4047 enhancing the removal of neutrophils from the circulation by altering the expression of surface adhesion molecules required for endothelial binding, by binding to platelets, or by enhancing apoptosis. Flow cytometric analysis was used to examine the expression of neutrophil surface molecules, platelet binding and apoptosis in whole blood samples from 19 patients with multiple myeloma who were assigned to receive either 1, 2, 5 or 10 mg of CC-4047 every other day (e.o.d.) for 28 days. CC-4047 induced dose-related decreases in neutrophil numbers and increases in the percentage of CD64-positive neutrophils, but had little, or no effect on the expression of CD11b, CD62L or CD162, neutrophil-platelet binding, or apoptosis. Relative decreases in the neutrophil count were inversely associated with relative increases in the intensity of CD64 expression on neutrophils (r = − 0.307; p = 0.028). Although seven patients developed severe neutropenia, none suffered severe or recurrent bacterial infections. The percentage of CD64-positive neutrophils was still increased in eight patients who continued receiving 1–5 mg CC-4047 e.o.d. for several months afterwards, but neutrophil counts were similar to pre-treatment values.
Thalidomide inhibits growth of tumors through COX-2 degradation independent of antiangiogenesis
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Thalidomide is an antiangiogenic drug and is clinically useful in a number of cancers. However, the molecular mechanism by which thalidomide exerts its antitumor effects is poorly understood. This study was designed to clarify the relationship between antiangiogenesis and antitumor effects of thalidomide and to explore the molecular mechanism for its antitumor activity. We evaluated the effects of thalidomide on the growth of human tumor cells expressing (MCF-7 and HL-60) or not expressing (HeLa and K562) COX-2 in vitro. We also studied the effects of thalidomide on COX-1, COX-2 or bcl-2 expression, TNFα, VEGF, GSH and cytochrome c in these cells. Thalidomide could inhibit tumor growth in a concentration-dependent manner in MCF-7 and HL-60; its IC₅₀s for them were 18.36 ± 2.34 and 22.14 ± 2.15 μM, respectively, while this effect was not observed in HeLa and K562. Thalidomide reduced COX-2 expression accompanied by a decrease of bcl-2 protein, TNFα, VEGF, GSH and an increased cytochrome c, but had no effect on that of COX-1, in MCF-7 and HL-60. Moreover, cells not expressing COX-2 were insensitive to the growth-inhibitory and effects on cytokines of thalidomide. In our mouse xenograft model of OVCAR-3 and HCT-8, we found that thalidomide could decrease intratumoral microvessel density in both tumors; it exerted antitumor effects only on OVCAR-3 expressing COX-2 but did not on HCT-8 not expressing COX-2. Effect of thalidomide on COX-1 and COX-2 in vivo was consistent with that of in vitro. These results demonstrated that thalidomide might inhibit growth of tumors through COX-2 degradation independent of antiangiogenesis.
Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: Results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity
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In murine models of human MM, lenalidomide decreases tumor cell growth and prolongs host survival.8,9 Our phase 1 study of lenalidomide showed remarkable anti-MM activity without the adverse effects of somnolence, constipation, or neuropathy associated with thalidomide, and preliminary results of our phase 2 trial have shown stabilization of disease or response in 84% of evaluable patients with relapsed and refractory MM, including some complete responses.18–20 In both phase 1 and phase 2 trials, most patients’ disease was refractory to thalidomide, highlighting the ability of lenalidomide to overcome drug and even thalidomide resistance.
To determine the progression-free survival at 12 weeks, to evaluate the toxic effects, and to analyze the biological activity of thalidomide in patients with relapsed multiple myeloma (MM) after high-dose chemotherapy and stem cell transplantation.
From 1999 to 2001, we performed a multicenter prospective phase 2 study in patients with MM that relapsed after high-dose chemotherapy and stem cell transplantation to evaluate the efficacy of oral thalidomide, with dose escalation from 200 to 600 mg/d over 12 weeks and a subsequent maintenance phase of 200 mg/d for up to 1 year. Outcome was correlated with serum and plasma levels of vascular endothelial growth factor and serum levels of tumor necrosis factor α, soluble intercellular adhesion molecule 1, interferon γ, interleukin (IL) 2, and IL-6 during treatment.
Thirty patients were treated (19 men and 11 women; median age, 58 years). The median number of prior therapies was 5, and the median duration from diagnosis of MM to study enrollment was 4.3 years. The 12-week progression-free survival rate was 67% (95% confidence interval [CI], 48%-86%). The observed response rate (partial response plus minor response) was 43% (95% CI, 28%-60%) with a median duration of 6 months. Attributable toxicities included constipation, fatigue, rash, and neuropathy, which was dose limiting in 8 patients (27%). Dose escalation from 200 to 600 mg/d was achieved in 50% of patients. Although responses were observed with lower doses, possibly eliminating the need to escalate the dose, responses were also seen in patients who completed the dose escalation. Some patients had disease progression while receiving the maintenance dose of 200 mg/d. Analysis of biomarker assays did not identify any biomarker associated with greater response, but a significant increase in levels of soluble intercellular adhesion molecule 1, IL-2, and interferon γ was seen with thalidomide therapy.
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Dossier : MyelomaThalidomide in multiple myeloma

Abstract

Section snippets

Pharmacology

Preclinical studies of thalidomide and its analogs in multiple myeloma

Clinical studies in multiple myeloma

Conclusion

Acknowledgements

Semin Hematol

Blood

Biochem Pharmacol

J Biol Chem

Blood

Blood

Blood

J Pharm Sci

Immunopharmacology

Blood

Blood

J Biol Chem

Exp Eye Res

Surgery

Life Sci

Blood

Mayo Clin Proc

Immunopharmacology

Immunopharmacology

Sem in Hematol

J Am Acad Dermatol

Blood

Blood

Blood

Clin Ther

Management of multiple myeloma today

Semin Hematol

Thalidomide-induced peripheral neuropathy. Effect of serum factor on nerve cultures

Arch Dermatol

Single course D.T. PACE anti-angiochemotherapy effects CR in plasma cell leukemia and fulminant multiple myeloma (MM)

Blood

Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies

Cancer Res

Thalidomide in dermatology. New indications for an old drug

Int J Dermatol

Plasma pharmacokinetics and urinary excretion of thalidomide after oral dosing in healthy male volunteers

Drug Metab Dispos

Thalidomide neurotoxicity

Arch Dermatol

Non-myeloppressive therapy with BLT-DC (Biaxin, Low-dose thalidomide and dexamethasone) is highly active in Waldenstrom's macroglobunemia and myeloma

Blood

Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF- alpha

J Immunol

Thalidomide is an inhibitor of angiogenesis

Proc Natl Acad Sci U S A

Effects of thalidomide on neutrophil respiratory burst, chemotaxis, and transmigration of cytokine- and endotoxin-activated endothelium

Naunyn Schmiedebergs Arch Pharmacol

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer

Br J Cancer

Anti-angiogenic treatment of metastatic melanoma, renal cell, ovarian and breast cancers with thalidomide: a phase II study

Proc Am Soc Clin Oncol

Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide

Chirality

The metabolism of thalidomide: some biological effects of thalidomide and its metabolites

Br J Pharmacol

The metabolic fate of thalidomide

Experientia

Does thalidomide affect IL-2 response and production?

Exp Hematol

Randomized, phase II study of thalidomide in androgen-independent prostate cancer (AIPC)

Proc Am Soc Clin Oncol

A phase II trial of the anti-angiogenic agent, thalidomide, in patients with recurrent high-grade gliomas

Proc Am Soc Clin Oncol

Thalidomide neuropathy: a clinical electrophysiological, and histological follow-up study

J Neurol Neurosurg Psychiatry

Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: Therapeutic applications

Leukemia

Dossier : Myeloma
Thalidomide in multiple myeloma