Immunomodulatory Drugs in Multiple Myeloma

Swati Andhavarapu; Vivek Roy


Expert Rev Hematol. 2013;6(1):69-82. 

In This Article

Mechanism of Action

The pathobiology of MM is complex and the root underlying cause of myeloma is the multistep genetic changes in the postgerminal center B cell. In addition, the bone marrow microenvironment plays a crucial role.[2] The interaction between myeloma cells and the microenvironment is mediated through adhesive interactions via cell-surface receptors, paracrine loops involving several cytokines, such as IL-6, VEGF and IL-10, and suppression of cell-mediated immunity.[2–4] IMiDs modulate many of these interactions leading to decreased myeloma cell growth and survival.

Thalidomide was the first IMiD introduced to treat MM. It was initially synthesized in Germany in the late 1950s to treat insomnia and morning sickness. It was withdrawn from the market in 1961 because of its teratogenic effects. Its immunomodulatory properties were realized when it was observed to improve erythema nodosum leprosum, a painful immunologic reaction of leprosy, leading to its approval by the FDA in 1998 with tight prescribing and marketing regulations. Subsequent research showed the diverse mechanism of action of thalidomide including its immunomodulatory effect by inhibition of de novo IgM antibody synthesis,[5] modulation of the T-cell subset by increasing the T-helper cells, inhibitory effects on the TNF-α and antiangiogenic activity leading to its use in MM. Significantly higher response rates in combination with dexamethasone led to its approval in the treatment of newly diagnosed MM in 2006.

Lenalidomide, a second-generation IMiD, was developed from the structural backbone of the thalidomide molecule by the addition of an amino group (NH2-) at position 4 of the phthaloyl ring and removal of the carbonyl group (C = O) of the 4-amino-substituted phthaloyl ring (Table 1).[6] In addition to immunomodulatory effects, other mechanisms of action have been described such as direct cytotoxicity via induction of apoptosis, inhibition of cell adhesion molecules and inhibition of growth signals that promote bone marrow angiogenesis (Figure 1).

Figure 1.

Pleiotropic mechanism of action of immunomodulatory drugs. IMiDs increase T-cell activation and T-cell clonal proliferation by costimulating CD4+ and CD8+ T cells by CD28 phosphorylation. They exert direct cytotoxicity via induction of apoptosis and inhibition of cell adhesion molecules. IMiDs decrease the expression of VEGF and IL-6, which are potent growth factors for malignant plasma cells. They also downregulate key mediators of osteoclastogenesis, including PU.1 (regulates the differentiation of myeloid cells to osteoclast precursor cells) and the extracellular signal-regulated kinase pERK (mediates osteoclast survival and differentiation).IMiD: Immunomodulatory drug; MM: Multiple myeloma; NK: Natural killer; RANKL: Receptor activator of NF-κB ligand.

Pomalidomide (CC4047) is another novel compound shown to have promising activity in MM and myelofibrosis. It was developed by modifying thalidomide structure via the addition of an amino acid at the position 4 of the phthaloyl ring (Table 1). It is currently not US FDA approved. In vitro studies showed that the 4-amino analogs were up to 50,000-times more potent inhibitors of TNF-α than the parent compound.[6]

Immunomodulatory Effect

IMiDs have a wide spectrum of effects on the immune system including augmentation of natural killer (NK) cell activity, alteration in the cytokine production and T-cell activity. It causes downregulation of TNF-α, IL-1β and IL-6 and increase in production of IL-10 from human peripheral-blood mononuclear cells.[7] IL-6 is a potent growth-promoting cytokine that inhibits the apoptosis of malignant plasma cells independent of the expression of bcl-2.[8]

T cells are important mediators of immune response. CD28 is a major costimulatory molecule on the T cells that interacts with CD80 and CD86 ligands on the antigen-presenting cells resulting in enhanced T-cell responses by upregulation of the cytokine production and increased cell proliferation.[9] IMiDs provide costimulatory help via the CD28-B7 pathway by directly inducing tyrosine phosphorylation of the CD28 on the T cells leading to downstream activation of pathways such as PI3K and GRB-2-OS.[10] T-cell proliferation triggered by dendritic cells is abrogated by cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA-4-Ig). Lenalidomide partially overcomes this inhibitory effect leading to T-cell clonal proliferation.[10]

NK cells are believed to function as regulatory cells in the immune system. In vitro studies showed that depletion of NK cells blocked drug-induced MM cell lysis. Treatment with IMiDs augments the number of NK cells and function via secretion of IL-2 and IFN-γ.[11]

Antiangiogenic Activity

MM was the first hematologic malignancy in which increased angiogenesis was noted. Increased bone marrow microvessel density was associated with higher proliferative fraction (S-phase) of marrow plasma cells.[12] Malignant plasma cells can secrete proangiogenic cytokines such as VEGF and BFGF.[13] In response to VEGF stimulation, the bone marrow stromal cells (BMSCs) and microvascular endothelial cells in turn produce IL-6, a potent growth factor for malignant plasma cells.[14] IMiDs have been shown to decrease VEGF and IL-6 expression thereby inhibiting angiogenesis, which can lead to clinical response independent of immunomodulatory properties.[15]

Effects on Microenvironment

Bone marrow microenvironment plays a critical role in MM. Various components of the bone marrow including the extracellular matrix, osteoclasts (OCLs), endothelial cells and BMSCs provide support to the malignant plasma cells via direct cell–cell or cell–matrix interactions and cytokine-mediated effects. Binding to extracellular matrix and BMSCs confers cell adhesion-mediated drug resistance to conventional chemotherapy.[16] IMiDs can overcome cell adhesion-mediated drug resistance by downregulating expression of adhesion molecules like ICAM-1(intercellular adhesion molecule), VCAM-1 (vascular cell adhesion molecule) and E-selectin.[17] They also impair the production of IL-6, VEGF and IGF-1 in BMSCs induced by cell adhesion to MM cells.[15]

Bone disease in MM is caused by increased OCL activation and inhibition of osteoblast function. IMiDs decrease tartrate-resistant acid phosphatase-positive cells that form OCLs and downregulate αVβ3-integrin levels (adhesion molecule) needed for OCL activation.[18] IMiDs inhibit key factors in osteoclastogenesis including PU.1 and pERK and also interfere with receptor activator of NF-κB ligand (RANKL) secretion from BMSCs thereby suppressing OCL maturation and bone resorption.[18]

Molecular Mechanisms

Cereblon (CRBN), a primary target in thalidomide teratogenecity, has recently been demonstrated as an essential requirement for IMiD antimyeloma activity.[19,20] While CRBN depletion is initially cytotoxic to the myeloma cells, surviving cells with stable CRBN depletion become highly resistant to IMiD agents. CRBN depletion leads to suppression of the gene expression changes induced by lenalidomide, and it has been observed that CRBN expression was reduced in >85% of lenalidomide-resistant patients. This suggests that CRBN plays a prime role in maintaining activity of IMiD compounds in MM patients.[20]