Thalidomide in Multiple Myeloma

Thalidomide in Multiple Myeloma

ABSTRACT: Recent evidence suggests that angiogenesis is increased in multiple myeloma and has prognostic value in the disease. Based on the increased angiogenesis observed in myeloma, thalidomide (Thalomid) has been studied as antiangiogenic therapy. Although its mechanism of action in myeloma is unclear, several trials show that thalidomide is active in 25% to 35% of patients with relapsed myeloma. Since many patients who respond have failed other active regimens, including transplantation, these results are impressive. Major toxicities include constipation, sedation, skin rash, fatigue, and peripheral neuropathy. Studies are ongoing to determine its role as initial treatment for myeloma. Trials are also underway combining thalidomide with other active agents. This article summarizes the current status of thalidomide therapy in myeloma. [ONCOLOGY 14(Suppl 13):11-16, 2000]


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

Plasma-Cell Proliferative Disorders

Multiple myeloma is a clonal plasma-cell disorder
characterized 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 clonal
plasma-cell proliferative disorder have multiple myeloma. Patients with a serum
M protein < 3 g/dL, bone marrow plasma cells < 10%, and no evidence of
anemia, hypercalcemia, renal failure, and bone lesions are considered to have
monoclonal gammopathy of undetermined significance. These patients do not
require any therapy. However, they need indefinite follow-up as approximately
20% to 25% will eventually transform to overt myeloma, amyloidosis, or a
non-Hodgkin’s lymphoma at a rate of 1% per year.[3] The serum M protein is
rechecked at 6 months, and if it remains stable, yearly thereafter.

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

Patients who present with a single plasmacytoma, with no
evidence of other bone or extramedullary lesions, are considered to have a
solitary plasmacytoma. The usual treatment consists of radiation therapy to the
involved area followed by close observation. These patients are also at risk for
eventual progression to overt multiple myeloma, particularly if they have a
residual monoclonal gammopathy of undetermined significance after radiation

Current Therapy for Multiple Myeloma

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

Stem-Cell Transplantation

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

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

Stem-cell transplantation can also be delayed until relapse
without compromising survival, provided hematopoietic stem cells are harvested
and cryopreserved early in the disease course. In this approach, newly diagnosed
patients 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 and
prednisone, for approximately 1 year. Subsequently, patients are observed until
relapse or progression, at which point stem-cell transplantation is considered.
Data from randomized trials comparing early vs delayed transplantation
approaches indicate that there is no significant difference in outcome between
the two strategies.[13,14]

Interferon Alfa

The role of interferon alfa in the treatment of myeloma has
been intensely studied.[15] Interferon alfa has been studied as part of
induction treatment in myeloma, and has resulted in superior complete response
rates and response duration with no effect on overall survival.[16] Several
studies have shown that the use of interferon alfa as maintenance therapy
prolongs the plateau phase in myeloma.[15,17-19] However, others have failed to
show 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 interferon
alfa as maintenance therapy in myeloma is continuing to accrue patients.
Interferon alfa has antiangiogenic properties; its effect on myeloma
angiogenesis requires further study.

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

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

Thalidomide: Historical Background

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

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

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

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


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