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Biologic and Clinical Advances in Multiple Myeloma

Biologic and Clinical Advances in Multiple Myeloma

ABSTRACT: Recent advances in our understanding of the cellular and molecular derangements involved in multiple myeloma are beginning to be translated into novel therapeutic approaches. Growth factors, specifically interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved, with resultant inhibition of myeloma cell growth. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. The implications of acquisition of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with bone marrow or peripheral stem-cell rescue are being studied in an attempt to produce a cure. Autologous marrow and peripheral blood stem-cell transplantation are better suited to the older myeloma patient population than is allogeneic marrow transplantation, and have also yielded promising results. [ONCOLOGY 9(5):417-430, 1995]

Introduction

Myeloma is a neoplastic disease of cells in the B-lymphocyte lineage,
with a peak incidence in individuals 70 to 80 years old. Although
the median age at diagnosis is 70 years [1], it is not uncommon
for the disease to be diagnosed in much younger patients. An estimated
13,500 new cases of multiple myeloma were diagnosed in the United
States in 1992. Little improvement in 5-year survival rates has
occurred since the mid-1970s.

Myeloma has a distinct racial distribution, with incidence and
death rates in American blacks nearly double those in whites [2].
In fact, myeloma represents the most common (30%) of all lymphoreticular
malignancies in the American black population [3].

The etiology of myeloma has remained obscure. Hereditary factors,
radiation exposure, agricultural exposure, and antigenic stimulation
have all been implicated to some extent. Support for the theory
of antigenic stimulation has come from the discovery that some
myeloma paraproteins show antibody activity against specific antigens
[4]. Also supporting this theory is the fact that, in murine models,
the ability to induce peritoneal plasmacytomas is vastly reduced
when the mice are raised in a germ-free environment [5].

Recent research has begun to elucidate the cellular and molecular
derangements involved in the pathogenesis of multiple myeloma.
These advances, in turn, have suggested novel approaches to treatment.

Biology

Renewable "Stem-Cell" Compartment

Although the terminally differentiated B-lymphocyte, the plasma
cell, is the morphologically identifiable cell in myeloma, it
represents the end-stage, nonproliferating cell compartment. It
has been well documented that there are also monoclonal, early-stage
B-cells circulating in the peripheral blood, and that these cells
bear the same unique idiotype (clonally rearranged immunoglobulin
genes) as the malignant plasma cells [6]. Accumulating evidence
suggests that the clonal B-cells may represent the renewable "stem-cell"
compartment in myeloma.

Myeloma tumor cells have been well characterized by extensive
phenotypic analysis. The cells in the circulating "stem-cell"
pool express the B-cell markers CD19, CD20, and CD24. They also
express the pre-B-cell markers CD10 (CALLA) and CD9 (an activated
lymphocyte marker), as well as the plasma cell marker PCA-1. A
subset express CD5 (an activation marker expressed on T-cells).
This profile is consistent with differentiating, late-stage B-cells.

Aside from the fact that they are monoclonal, these "stem
cells" differ from normal B-cells in that they express adhesion
molecules, as well as other molecules known to play a role in
cell motility, extravasation, and invasion, such as CD11b. These
data are consistent with the hypothesis that myeloma originates
with the transformation of a B-cell precursor in an extramedullary
site, with subsequent migration of late-stage B-cells through
the peripheral blood to the bone marrow, where the terminal stages
of maturation to the plasma cell occur. The bone marrow microenvironment,
with its collection of stromal cells, extracellular matrix glycoproteins,
and many cytokines, is apparently very conducive for the maturation
of malignant B-cells to plasma cells, leading to further disease
expansion and progression.

Assays have been developed that take advantage of the fact that
the "stem-cell" compartment in myeloma is identifiable
by the unique immunoglobulin gene rearrangement of the malignant
clone. Bird et al described their findings using a polymerase
chain reaction (PCR)-based technique that employs consensus primers
to amplify the rearranged locus of the immunoglobulin heavy-chain
gene [7]. They followed six myeloma patients in clinical complete
remission after allogeneic bone marrow transplantation.

All patients were PCR positive within the first year after bone
marrow transplantation. One patient became PCR negative at 1 year
after transplantation, and two others at 2 and 4.5 years post-transplantation,
respectively. These investigators concluded that PCR positivity
up to 1 year after marrow transplantation is common, and is not
necessarily predictive of relapse.

The significance of residual clonally rearranged cells is not
completely understood at this time. Elucidation of this phenomenon
will require further study of more cases with longer follow-up.
The goal of such efforts is to identify patients who may benefit
from additional therapeutic intervention after bone marrow transplantation.

T-Cell Abnormalities

There appear to be both qualitative and quantitative abnormalities
in immunoregulatory T-cells in myeloma patients. The ratio of
CD4 to CD8 cells is decreased on presentation and continues to
decline with disease progression. T-cells with membrane receptors
specific for both the idiotype and isotype of the immunoglobulin
have been found in myeloma patients. These T-cells can bind to
and suppress human myeloma cell lines in vitro.

Sensitive molecular techniques have revealed clonal T-cell populations
in myeloma patients [8]. However, the relevance of these clonal
T-cells is unknown.

Recently, Massaia et al demonstrated anti-plasma-cell activity
in bone marrow mononuclear cells from myeloma patients stimulated
with the anti-CD3 monoclonal antibody OKT3 [9]. A greater understanding
of the role of immunoregulatory cells in myeloma should set the
stage for targeted therapeutic interventions.

Dysregulation of Interleukin-6

The progression of myeloma depends greatly on growth factors,
specifically, interleukin-6 (IL-6). In murine model systems, dysregulated
IL-6 production can lead to various plasma-cell proliferative
disorders, including plasmacytomas and Castleman's disease [10].

An overproduction of IL-6 is found in 37% of myeloma patients
at diagnosis, and is associated with a poor prognosis.11 Initial
work suggested that IL-6 was an autocrine growth factor, produced
by the myeloma tumor cells themselves [12]. However, more recent
data suggest that marrow stromal overproduction of IL-6 is more
important in myeloma [13].

The study of critical paracrine and autocrine loops in disease
progression can help identify targets for novel therapeutic approaches.
A recent case report from France described a patient with refractory
myeloma in whom monoclonal anti-IL-6 antibodies produced an impressive,
albeit transitory, response [14].

It has also been demonstrated that IL-6 antisense oligonucleotides
can inhibit the growth of human myeloma cell lines [15]. Very
recent work has shown that gamma-interferon can inhibit several
IL-6-dependent biologic processes by downregulating IL-6 receptor
expression, and can completely inhibit four human myeloma cell
lines that are dependent on exogenous IL-6 for growth [16].

Preneoplastic Syndromes

Isolated monoclonal gammopathy, the so-called monoclonal gammopathy
of undetermined significance (MGUS), is a preneoplastic syndrome
that has been extensively studied. However, because of the asymptomatic
nature of MGUS, it is unknown whether this syndrome always precedes
myeloma. Natural history studies by Kyle have demonstrated that
after a median follow-up of 22 years, approximately 25% of patients
with MGUS will develop myeloma, amyloidosis, or another lymphoproliferative
disease [17].

Extramedullary plasmacytomas and solitary plasmacytomas of bone
are two other syndromes that have the propensity to develop into
myeloma. The further study of preneoplastic lesions should help
elucidate factors necessary for tumor progression, as well as
potential targets for intervention.

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