Thalidomide in Multiple Myeloma

ABSTRACT: Recent evidence suggests that angiogenesis is increased in multiple myeloma andhas prognostic value in the disease. Based on the increased angiogenesisobserved in myeloma, thalidomide (Thalomid) has been studied as antiangiogenictherapy. Although its mechanism of action in myeloma is unclear, several trialsshow that thalidomide is active in 25% to 35% of patients with relapsed myeloma.Since many patients who respond have failed other active regimens, includingtransplantation, these results are impressive. Major toxicities includeconstipation, sedation, skin rash, fatigue, and peripheral neuropathy. Studiesare ongoing to determine its role as initial treatment for myeloma. Trials arealso underway combining thalidomide with other active agents. This articlesummarizes the current status of thalidomide therapy in myeloma. [ONCOLOGY14(Suppl 13):11-16, 2000]

Introduction

Multiple myeloma accounts for 10% of malignant hematologicneoplasms.[1,2] In 2000, approximately 13,800 new cases of myeloma will bediagnosed in the United States and over 11,000 patients will die of thedisease.[1] Recently, it has been found that thalidomide (Thalomid) can induceimpressive responses in relapsed myeloma. The current status of thalidomidetherapy in myeloma is summarized in this article.

Plasma-Cell Proliferative Disorders

Multiple myeloma is a clonal plasma-cell disordercharacterized by the presence of a monoclonal (M) protein in the serum or urine,osteolytic bone lesions, increased plasma cells in the bone marrow, anemia,renal failure, and hypercalcemia.[2] Not all patients with evidence of a clonalplasma-cell proliferative disorder have multiple myeloma. Patients with a serumM protein < 3 g/dL, bone marrow plasma cells < 10%, and no evidence ofanemia, hypercalcemia, renal failure, and bone lesions are considered to havemonoclonal gammopathy of undetermined significance. These patients do notrequire any therapy. However, they need indefinite follow-up as approximately20% to 25% will eventually transform to overt myeloma, amyloidosis, or anon-Hodgkin’s lymphoma at a rate of 1% per year.[3] The serum M protein isrechecked at 6 months, and if it remains stable, yearly thereafter.

Some patients have a serum M protein that is ³3 g/dL and/or ³ 10% plasma cells in the bone marrowwithout anemia, bone lesions, hypercalcemia, or renal insufficiency, and areconsidered to have smoldering multiple myeloma.[4] These patients have a higherrisk of transformation to myeloma than those with monoclonal gammopathy ofundetermined significance. However, many smoldering multiple myeloma patientscan be observed without therapy for months to years. Close follow-up once every4 months is recommended.

Patients who present with a single plasmacytoma, with noevidence of other bone or extramedullary lesions, are considered to have asolitary plasmacytoma. The usual treatment consists of radiation therapy to theinvolved area followed by close observation. These patients are also at risk foreventual progression to overt multiple myeloma, particularly if they have aresidual monoclonal gammopathy of undetermined significance after radiationtherapy.

Current Therapy for Multiple Myeloma

The standard therapy for multiple myeloma consists ofmelphalan (Alkeran) and prednisone. With this regimen, the overall response rateis about 50% and the complete response rate is less than 10%.[5] The mediansurvival is about 3 years and the 5-year survival rate is 24%.[5,6] Combinationchemotherapy with regimens such as VBMCP (vincristine/carmustine[BiCNU]/melphalan/cyclophosphamide [Cytoxan, Neosar]/prednisone) leads tosuperior response rates (60% to 70%), but there does not appear to be asignificant survival benefit.[5,7,8]

Stem-Cell Transplantation

High-dose therapy followed by autologous stem-celltransplantation has been shown to improve response rate and survival.[9-11]Response rates with stem-cell transplantation exceed 75% to 90%,[6,7] andcomplete response rates range from 20% to 40%.[10,12] Based on these results,autologous stem-cell transplantation has become the standard of care forpatients less than 65 years of age with good performance status. However,transplantation is not curative and there is no plateau in the survivalcurves.[9]

Newly diagnosed patients considered candidates for stem-celltransplantation are typically treated with chemotherapy that is not toxic tostem cells, such as VAD (vincristine/doxorubicin [Adriamycin]/dexamethasone),for approximately 4 to 5 months to minimize tumor burden. Peripheral blood stemcells are then harvested, followed by high-dose melphalan conditioning andtransplantation. There is no standard therapy after transplantation; patientsare typically observed until evidence of disease progression.

Stem-cell transplantation can also be delayed until relapsewithout compromising survival, provided hematopoietic stem cells are harvestedand cryopreserved early in the disease course. In this approach, newly diagnosedpatients are first treated with chemotherapy such as VAD for 4 to 5 months.Peripheral blood stem cells are then mobilized and cryopreserved for future use.Patients then receive conventional chemotherapy, such as melphalan andprednisone, for approximately 1 year. Subsequently, patients are observed untilrelapse or progression, at which point stem-cell transplantation is considered.Data from randomized trials comparing early vs delayed transplantationapproaches indicate that there is no significant difference in outcome betweenthe two strategies.[13,14]

Interferon Alfa

The role of interferon alfa in the treatment of myeloma hasbeen intensely studied.[15] Interferon alfa has been studied as part ofinduction treatment in myeloma, and has resulted in superior complete responserates and response duration with no effect on overall survival.[16] Severalstudies have shown that the use of interferon alfa as maintenance therapyprolongs the plateau phase in myeloma.[15,17-19] However, others have failed toshow such an effect, and overall survival was not prolonged in any study.[20-22]A meta-analysis studying the role of interferon alfa is ongoing. A nationwide,large randomized trial in the United States evaluating the role of interferonalfa as maintenance therapy in myeloma is continuing to accrue patients.Interferon alfa has antiangiogenic properties; its effect on myelomaangiogenesis requires further study.

Therapy with bisphosphonates such as pamidronate (Aredia) canprevent fractures, hypercalcemia, and the need for radiation therapy.Bisphosphonates inhibit osteoclast activity and bone resorption. In a randomizedtrial of 392 patients, the incidence of skeletal events was significantly lowerwith pamidronate (24%) compared to placebo (41%), P < .001.[23]Bisphosphonates are now considered standard therapy in patients with myeloma whohave lytic bony lesions or osteoporosis.[24-26]

Therapy for relapsed disease is disappointing. Typicallypatients who relapse are treated with chemotherapy regimens such as VAD, VBMCP,pulsed methylprednisolone, or dexamethasone. Remissions with such therapy areusually short-lived. Recently, several studies have shown that thalidomide hassignificant activity in relapsed myeloma, making it the first drug todemonstrate clinically significant single-agent activity in relapsed myeloma inover 2 decades.

Thalidomide: Historical Background

Thalidomide was first introduced in clinical practice as asedative. Beginning in the late 1950s, it was marketed in more than 40countries. Due to US Food and Drug Administration (FDA) concerns about nervedamage, the drug was not approved for clinical use in the United States. In thecountries in which it was available, thalidomide became popular because itprovided good sleep quality and an unusually low risk of fatal overdose, unlikeother sedatives marketed at the time.

Thalidomide was subsequently found to be effective in thetreatment of morning sickness associated with pregnancy. Unfortunately, itssevere teratogenic potential was not realized until 1961. Fetal malformationswith thalidomide involve the extremities (phocomelia), ears, eyes, and thegastrointestinal tract.[27] Almost 10,000 children worldwide were affected withthese birth defects as a result of thalidomide. The drug was withdrawn from themarket in 1962.

Pregnant women are vulnerable to the teratogenic effects ofthalidomide between days 27 and 40 of gestation. A single pill (50 mg) may besufficient to cause these teratogenic effects. The mechanism of itsteratogenicity is unclear, but may be related to its antiangiogenic propertiesor inhibition of tumor necrosis factor-alpha (TNF-alpha) production.[28]Free-radical-mediated oxidative damage to DNA has also been postulated as amechanism for the teratogenic effects.[29]

Despite its tragic past, thalidomide has reentered clinicalpractice due to its immunomodulatory and antiangiogenic properties. It was foundto be effective in the treatment of erythema nodosum leprae in themid-1960s.[30] In the past 10 years, thalidomide has been studied and found tobe useful in the treatment of AIDS-related cachexia and aphthous ulcers. It hasalso been effective in the treatment of aphthous ulcers in patients with Behcet’sdisease and in the treatment of chronic graft-versus-host disease. In 1998, theFDA approved thalidomide for use in erythema nodosum leprae with substantialprecautions.

Rationale for Studying Thalidomide in Myeloma

Clinical trials with thalidomide in myeloma were firstinitiated due to its antiangiogenic properties and evidence indicating a rolefor increased angiogenesis in the progression of this disease. Angiogenesis isthe formation of new blood vessels; it occurs physiologically during embryonalgrowth, wound healing, and in the female genital system during the menstrualcycle. Angiogenesis is important for the proliferation and metastases of mostmalignant neoplasms.[31] In the absence of angiogenesis, tumors cannot growbeyond 1 to 2 mm in size.[31] Increased angiogenesis is an adverse prognosticfactor in several tumors.

Vacca and colleagues have shown that bone marrow angiogenesisis increased in active myeloma compared to monoclonal gammopathy of undeterminedsignificance.[32] However, angiogenesis is not increased in all patients withmyeloma, with some patients having marked increases in microvessel density, andsome showing no increase compared to monoclonal gammopathy of undeterminedsignificance or control marrows. In a study of 74 newly diagnosed patients withmyeloma, overall survival was significantly longer in patients with low-gradeangiogenesis (53 months) compared to patients with high-grade (24 months) orintermediate-grade angiogenesis (48 months), P = .018.[33] The increasein bone marrow angiogenesis in myeloma does not even resolve with stem-celltransplantation, thus providing a rationale for antiangiogenic therapy in thisdisease.[34] Angiogenesis in myeloma may be related to overexpression of basicfibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) byneoplastic plasma cells.[35]

Activity of Thalidomide in Relapsed Myeloma

Researchers at the University of Arkansas conducted the firsttrial investigating the activity of thalidomide in relapsed myeloma.[36] Mostpatients in this study had failed stem-cell transplantation. Treatment consistedof thalidomide given orally at a dose of 200 mg/d for 2 weeks and then increasedby 200 mg/d every 2 weeks, up to a maximum daily dose of 800 mg/d depending upontoxicity. The overall response rate was 32%. The median time to response was 1month.

Approximately 10% of patients had ³90% reduction in paraprotein levels. Paraprotein responses were accompanied byimprovements in anemia and other symptoms. Among the 48 patients who had repeatbone marrow analysis after thalidomide therapy, 81% had confirmation ofparaprotein responses. The best predictor of a response was a plasma-celllabeling index < 0.2. The median duration of response was not reached after14.5 months of follow-up. Considering 90% of patients in this study had failedtransplantation, these results are very impressive. The toxicities ofthalidomide are described later in this article. An update to this studyconfirms the activity of thalidomide in 169 patients with relapsed myeloma.[37]Overall survival at 18 months was 55% and event-free survival was 30%.

We have reported 16 patients with relapsed myeloma at theMayo Clinic treated on a similar schedule of thalidomide.[38,39] Twenty-fivepercent had failed prior stem-cell transplantation. Eighty-eight percent hadreceived two or more prior chemotherapy regimens prior to starting thalidomide,including 25% who had failed four or more regimens. Four patients (25%) achieveda partial response to therapy, confirming the initial results obtained at theUniversity of Arkansas. A larger Mayo Clinic phase II study of thalidomide inrelapsed myeloma is ongoing.

Several other groups have also confirmed the single-agentactivity of thalidomide in relapsed and refractory myeloma (Table1).[40-48]Response rates have ranged from 25% to 75%. Based on the evidence so far,thalidomide can be recommended for relapsed myeloma, although the FDA has notyet approved the agent for this indication.

Combination Therapy With Thalidomide

Studies are ongoing to determine the efficacy of thalidomidewhen combined with other effective agents for myeloma. In one study conducted byWeber and colleagues, 9 of 26 patients (35%) who had failed therapy withthalidomide for relapsed myeloma responded to a combination of thalidomide anddexamethasone.[40] Many of these patients had previously failed dexamethasonetherapy, suggesting a synergistic effect with this combination.

Barlogie and colleagues have combined thalidomide withcombination chemotherapy consisting of cyclophosphamide, etoposide, doxorubicin(Adriamycin), cisplatin, and dexamethasone (DT-PACE) for patients withaggressive myeloma and plasma-cell leukemia.[49] Four of five patientsresponded, including three who achieved a complete response. Updated results on43 patients indicate a 40% response rate after two cycles of therapy, and nounfavorable effects on subsequent stem-cell harvest.[50]

Coleman and Leonard are studying the combination ofthalidomide, low-dose dexamethasone, and clarithromycin (Biaxin). Preliminaryresults on 13 patients with myeloma show significant activity.[51] However, moredata are needed and the role of clarithromycin in the combination needs to beclarified.

Mechanism of Action

Laboratory studies using the rabbit cornea micropocket assayhave shown that thalidomide has potent antiangiogenic properties.[52,53] Animalstudies show that it can decrease vascular density in granulation tissue.[54] Inaddition to its antiangiogenic effects, thalidomide also has severalimmunomodulatory properties. It inhibits the production of TNF-alpha byenhancing the degradation of TNF-alpha mRNA.[55] Thalidomide stimulatescytotoxic T-cell proliferation and induces the secretion of interferon gamma andinterleukin-2 by these cells.[56] It may also modulate the expression of severalcell surface adhesion molecules.[57]

Although thalidomide was first studied in myeloma due to itsantiangiogenic properties, its mechanism of action is unclear. In the Arkansasstudy, there were no statistically significant differences in posttreatmentmicrovessel density change between responders and nonresponders.[36] Cheng et alfound that a high pretreatment microvessel density predicted a response tothalidomide therapy, but this needs confirmation in a larger study.[47] In ourstudies, pretreatment microvessel density was not a predictor of response(unpublished observation).

The immunomodulatory effects of thalidomide, includingsuppression of TNF-alpha, may be involved, and require further study.

Dosage

Most studies in myeloma have used thalidomide doses between200 and 800 mg/d, taken orally as a single dose at bedtime. The usual startingdose in myeloma is 200 mg/d, increased by 200 mg every 2 weeks to a maximum of800 mg/d. The dose is adjusted based on toxicity, and the median tolerated doseis approximately 400 mg/d. However, this can vary considerably from 50 to 800mg/d. Appropriate dosing in the presence of hepatic and renal dysfunction hasnot been determined.

It is not clear if there is a dose-response relationship, andif smaller doses of thalidomide can be equally effective with lesser sideeffects. Durie and Stepan have observed responses with doses as small as 50mg/d.[41] Studies are ongoing to determine if smaller doses can be used asmaintenance therapy as well.

Toxicity and Precautions

Due to the risk of severe teratogenicity, the use ofthalidomide in pregnant women is absolutely contraindicated. Both theprescribing physician and the dispensing pharmacy are required to register withthe System for Thalidomide Education and Prescribing Safety (STEPS) program.

Thalidomide is generally well tolerated at doses below 400mg/d. Most side effects are mild or moderate in severity, and can be controlledby appropriate dose reduction. The most common side effects of therapy aresedation, fatigue, constipation, and skin rash. Since severe constipation is acommon problem, laxatives are recommended prophylactically. If a skin rashoccurs, the drug should be discontinued and restarted at a lower dose after therash clears. If severe exfoliation, Stevens-Johnson syndrome, or toxic epidermalnecrolysis occur, the drug should be stopped and not used again.

Thalidomide is also known to cause peripheral neuropathy thatmay be permanent. This generally occurs following chronic use of thalidomideover a period of months; however, reports following relatively short-term usealso exist. Less common side effects include edema, bradycardia, neutropenia,increased liver enzymes, deep-vein thrombosis, menstrual irregularities, hyper-or hypoglycemia, and hypothyroidism.

Ongoing Trials

At the Mayo Clinic, we are evaluating single-agentthalidomide in patients with newly diagnosed, asymptomatic smoldering/indolentmyeloma. We are also studying the combination of thalidomide plus dexamethasonefor newly diagnosed symptomatic myeloma. Correlative laboratory studies toassess the effect of thalidomide on bone marrow angiogenesis and the expressionof VEGF, bFGF, and their receptors are ongoing. A randomized trial ofthalidomide plus dexamethasone vs dexamethasone alone for newly diagnosedsymptomatic myeloma is being developed by the Eastern Cooperative OncologyGroup.

At the University of Arkansas, thalidomide is being evaluatedfor patients with newly diagnosed myeloma as part of the Total Therapy IIregimen. Another aim of this trial is to study the role of posttransplantmaintenance with thalidomide. Thalidomide is also being studied in combinationwith dexamethasone as well as other chemotherapy agents for patients withrelapsed disease. Several other institutions, including The University of TexasM. D. Anderson Cancer Center, have ongoing clinical trials investigating therole of thalidomide in myeloma. Potential strategies for the use of thalidomidein myeloma are summarized in Table 2.

Conclusions

Thalidomide has emerged as an effective agent in thetreatment of myeloma. Further studies are needed to determine the mechanism ofaction of thalidomide, the best dosing schedule, and the duration of therapy.Due to its tragic past and increasing use for a variety of neoplastic andnon-neoplastic conditions, patients and physicians must continue to exercisegreat caution when using or prescribing thalidomide. Safer thalidomide analogsare being developed in order to minimize toxicity while preserving the drug’sbeneficial effects.

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