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  • Review Article
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Molecular mechanisms of novel therapeutic approaches for multiple myeloma

Nature Reviews Cancer volume 2, pages 927–937 (2002)Cite this article

Key Points

  • Multiple myeloma (MM) is a B-cell malignancy that is characterized by an excess of monotypic plasma cells in the bone marrow (BM) that is in association with monoclonal protein in serum and/or urine, decreased normal immunoglobulin levels and lytic bone disease.

  • Although conventional therapies can extend patient survival to an average of 3–4 years and high-dose therapy that is followed by autologous stem-cell transplantation can modestly prolong the survival to 4–5 years, MM remains largely incurable.

  • MM cells home to the host bone marrow by binding to adhesion molecules on extracellular matrix proteins and bone-marrow stromal cells. This localizes tumour cells in the BM microenvironment and confers cell-adhesion-mediated drug resistance. Cytokines (such as interleukin-6 (IL-6), insulin-like growth factor 1 (IGF1), tumour necrosis factor-α (TNF-α) and stromal-cell-derived factor-1α (SDF-1α)) mediate MM cell growth, survival and migration and, following treatment, the development of drug resistance in the bone-marrow microenvironment.

  • MM cell proliferation, survival and, following treatment, drug resistance by anti-apoptotic mechanisms are mediated through the RAF/mitogen-activated protein kinase (MAPK) kinase (MEK)/p42/p44 MAPK, Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and phosphatidylinositol (PI3K)/AKT signalling cascades, respectively.

  • Novel biologically based treatments (such as thalidomide/immunomodulatory derivatives (IMiDs) and PS-341) target not only the MM cell, but also the interaction between MM cells and the host or the BM microenvironment, and can overcome conventional drug resistance in vitro and in vivo in preclinical models.

  • Thalidomide/IMiDs and PS-341 have already shown remarkable activity against MM in Phase I/II clinical trials of patients with relapsed and refractory disease, with manageable toxicity profiles. These drugs, when used with conventional and/or other novel therapies, represent a new treatment model to improve patient outcome in MM.

  • Ongoing gene microarray and proteomic studies of these new agents are identifying molecular targets that confer drug sensitivity versus resistance, to derive more selective targeted therapies for validation in animal models and the translation to the clinic in clinical trials.

Abstract

Multiple myeloma remains largely incurable despite conventional and high-dose therapies, and so novel biologically based treatment approaches are urgently required. Recent studies have characterized the molecular mechanisms by which multiple myeloma cell–host bone-marrow interactions regulate tumour cell growth, survival and migration in the bone-marrow microenvironment. These studies have not only enhanced our understanding of disease pathogenesis, but have also provided the framework for a new treatment model that targets the multiple myeloma cell in its bone-marrow microenvironment to overcome drug resistance and improve patient outcome.

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Figure 1: The development of plasma or multiple myeloma cells.
Figure 2: The interaction of multiple myeloma cells and their bone-marrow microenvironment.
Figure 3: Signalling cascades mediating growth, survival and migration in multiple myeloma cells.
Figure 4: Apoptotic signalling pathways triggered by conventional and novel therapies in multiple myeloma.
Figure 5: Novel biologically based therapies targeting multiple myeloma cells and the bone-marrow microenvironment.

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Acknowledgements

Supported by a National Institutes of Health Grant, the Doris Duke Distingished Clinical Research Award, the Multiple Myeloma Research Foundation, the Myeloma Research Fund and the Cure Myeloma Fund.

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Authors and Affiliations

  1. Jerome Lipper Multiple Myeloma Center, Dana–Farber Cancer Institute and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Teru Hideshima & Kenneth C. Anderson

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  1. Teru Hideshima
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Correspondence to Kenneth C. Anderson.

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DATABASES

Cancer.gov

lung carcinoma

multiple myeloma

prostate cancer

T-cell leukaemia

LocusLink

AKT

BCL-XL

bFGF

BFL1

caspase-3

caspase-8

caspase-9

CD11a

CD31

CD38

CD54

CD138

CDKI

DR4

DR5

FLIP

FPTA

histone acetyltransferases

HSP90

hTERT

ICAM1

IGF1

IL-21

IL-6

JAK

LFA1

MAPK

MCL1

MEK

MMP1

MMP2

MMP9

NF-κB

PARP

PI3K

PKC-α

PKC

PTHrP

SDF-1α

SHP2

SMAC

STAT3

survivin

TNF-α

TRAIL

VCAM1

VEGF

XIAP

OMIM

severe combined immunodeficiency

FURTHER INFORMATION

Multiple Myeloma Research Foundation

Glossary

PARAPROTEIN

The monoclonal immunoglobulin (Ig) secreted by tumour cells of most multiple myeloma patients, which can be used as a parameter of disease activity or response to treatment.

AUTOGRAFTING

High-dose therapy followed by autologous stem-cell transplantation.

ALLOGRAFTING

Transplantation of allogenetic donor stem cells after high-dose non-myeloablative therapy.

GRAFT-VERSUS-HOST DISEASE

A reaction that occurs against patient tissues after transplantation of donor stem cells. It might occur early (acute) or persist (chronic), and manifests most commonly as skin, liver and gut abnormalities.

Ig REARRANGEMENT AND CLASS SWITCHING

Normal and malignant B-cell differentiation is characterized by immunoglobulin (Ig) gene rearrangements followed by Ig class switching.

CYTOPLASMIC μ

Heavy chain of Ig expressed in cytoplasm of pre-B cells.

FLUORESCENCE IN SITU HYBRIDIZATION

(FISH). Uses one or more probes that are differentially labelled with fluors and then hybridized to metaphase chromosomes or interphase nuclei so that the numbers and locations of different sequences can be assessed in individual cells.

SPECTRAL KARYOTYPING

(SKY). Simultaneous visualization of an organism's chromosomes, each labelled with a different colour. This method is used for identifying chromosomal abnormalities.

PLASMA-CELL LEUKAEMIA

(PCL). Circulating plasma cells >2 × 109/l or >20% peripheral blood white blood cells (PB WBC); might be primary PCL in newly diagnosed patients, or reflect progressive disease (secondary PCL) in patients with multiple myeloma.

MULTIDRUG RESISTANCE (MDR) GENE

A gene whose product — P-glycoprotein — is resistant to several antineoplastic agents.

P-GLYCOPROTEIN

A 170 kDa plasma membrane protein that is encoded by the human multidrug resistance gene (MDR1), which is associated with resistance to chemotherapy.

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Hideshima, T., Anderson, K. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2, 927–937 (2002). https://doi.org/10.1038/nrc952

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