Review Article | Published:

Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets

Nature Reviews Cancer volume 7, pages 585598 (2007) | Download Citation

Abstract

Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.

Key points

  • Multiple myeloma is a currently incurable B-cell malignancy characterized by excess monotypic plasma cells in the bone marrow in association with an excess of monoclonal protein in serum and/or urine.

  • Multiple myeloma has complex heterogeneous cytogenetic abnormalities. Approximately 55–60% of patients have a hyperdiploid karyotype, which confers a better prognosis than those with non-hyperdiploid disease. Most non-hyperdiploid tumours have IgH translocations that involve several recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), 16q23 (MAF) and 20q11 (MAFB). Recent genomic and expression-profiling studies have both identified new therapeutic targets and provided the framework for a genetically based prognostic classification of multiple myeloma.

  • These constitutive genetic alterations in multiple myeloma cells and changes in gene-expression profiles mediate the protective effects of the bone marrow microenvironment on multiple myeloma cells.

  • Multiple myeloma cells that home to the bone marrow have important functional sequelae. Specifically, the adhesion of multiple myeloma cells to extracellular matrix proteins confers cell adhesion-mediated drug resistance (CAMDR), and the binding of multiple myeloma cells to bone marrow accessory cells triggers the secretion of cytokines, which not only promote growth, survival and migration of multiple myeloma cells, but also confer resistance to conventional chemotherapy. Targeting these mechanisms offers a potential therapeutic strategy to overcome drug resistance.

  • Several factors, including MIP1α and RANKL, stimulate osteoclast activity; on the other hand, DKK1 inhibits osteoblastogenesis in multiple myeloma. This imbalance between bone formation and resorption results in osteolytic lesions, which are a hallmark of multiple myeloma.

  • New agents that target multiple myeloma cells, tumour–bone marrow interactions, or the bone marrow milieu, used alone or in combination, have shown promise in overcoming conventional drug resistance and improving patient outcome in multiple myeloma. Oncogenomics will allow for both patient selection and rational combination therapeutics.

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Acknowledgements

The authors would like to thank D. Chauhan and N.C. Munshi for their helpful comments. We apologize to our many colleagues whose work is not cited owing to space constraints.

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Affiliations

  1. Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.

    • Teru Hideshima
    • , Constantine Mitsiades
    • , Giovanni Tonon
    • , Paul G. Richardson
    •  & Kenneth C. Anderson

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Kenneth C. Anderson.

Glossary

Plasma cell

A plasma cell differentiates from a B lymphocyte and secretes large amounts of immunoglobulins. Plasma cells are rarely found in the peripheral blood, and represent 0.2% to 2.8% of bone marrow mononuclear cells.

Monoclonal (M) protein

An antibody (immunoglobulin), or part of an antibody, found in excess in the blood and/or urine in patients with multiple myeloma and other plasma cell tumours.

Plasmacytosis

A condition in which there is an increased population of plasma cells.

Hyperviscosity

Increased viscosity of blood caused by an excess of M proteins in multiple myeloma.

Bone marrow stromal cells

(BMSCs). Cellular components in the bone marrow that support multiple myeloma cell growth, survival and drug resistance.

Thalidomide, lenalidomide and bortezomib

Immunomodulatory drugs and proteasome inhibitors that target not only multiple myeloma cells, but also bone marrow accessory cells, and overcome conventional drug resistance.

Cell adhesion-mediated drug resistance

(CAMDR) Resistance to conventional chemotherapy owing to the adhesion of multiple myeloma cells to accessory cells in the bone marrow.

Bone marrow accessory cells

Accessory cells in the bone marrow include stromal cells, osteoclasts, osteoblasts and endothelial cells.

Matrix metalloproteinase

(MMP) MMPs are endopeptidases that degrade extracellular matrix proteins (such as collagen) and chemokines (such as SDF1). They are activated by other MMPs and plasmin, and inactivated by tissue inhibitor of metalloproteinases (TIMPs). Multiple myeloma cells express MMP9 and BMSCs express MMP1 and 2. The interaction of multiple myeloma cells and BMSCs upregulates MMP1, promoting bone resorption and tumour invasion.

Plasma cell leukaemia

(PCL). PCL is a variant of multiple myeloma characterized by greater than or equal to 2 × 109 circulating plasma cells in one litre of peripheral blood. Pateints can present with primary PCL, or it can evolve from previously recognized multiple myeloma (secondary PCL).

Microvessel density

(MVD). A quantitative measure of the density of small vessels in tissues, which is assessed by immunohistochemical staining with anti-endothelial antibodies (such as anti-CD31). In multiple myeloma, increasing MVD is associated with progressive disease.

Osteopaenia

One of the most common findings in skeletal radiographs in patients with multiple myeloma is the increased radiolucency of bone, termed osteopaenia. Osteopaenia is caused by low mineral density.

SCID mouse models

In vivo xenograft models of human multiple myeloma in immunodeficient mice. In the NOD;LtSz-scid;scid (SCID/NOD) model, diffuse fluorescence-protein labelled multiple myeloma cells are injected intravenously and their homing and anatomical localization are monitored by whole body-bioluminescence. In the SCID-hu model, a human bone chip is implanted subcutaneously into SCID mice, and human multiple myeloma cells directly injected into the bone graft. This allows for the evaluation of human multiple myeloma cells in the context of human bone marrow accessory cells and extracellular matrix proteins.

Aggresome autophagy

Perinuclear inclusions that form in multiple myeloma cells in the setting of stress associated with misfolded or mutated proteins. Several protein components, including ubiquitin, HDAC6, dynein and vimentin have a crucial role in aggresome formation. These protein complexes are ultimately degraded by lysosomes.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). An immune response in which antibodies bind to epitopes on target cells, thereby marking them for attack by effector cells (such as natural killer cells, T cells and macrophages). It is necessary for effector cells to have Fc receptors.

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DOI

https://doi.org/10.1038/nrc2189

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