Lenalidomide (IMiD® Agent)

Proposed Mechanism of Action

Lymphoma

Lenalidomide is an oral, small-molecule immunomodulatory agent that demonstrates anti-angiogenic and anti-neoplastic activity in preclinical studies.1 Rituximab is an anti-CD20 monoclonal antibody that has been leveraged in the treatment of non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia.2 Combinations of lenalidomide and rituximab are being investigated for the treatment of NHL subtypes, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL).3-5

Myelodysplastic Syndromes

Lenalidomide is an oral, small-molecule immunomodulatory agent that also has anti-angiogenic and anti-neoplastic activity in preclinical studies.1 Haploinsufficiency, caused when only 1 copy of a gene is present, is hypothesized to drive pathogenesis of del(5q) myelodysplastic syndromes (MDS)6-8 and may underlie the specific activity of lenalidomide.9 In vitro studies have shown that lenalidomide can modulate the degradation of target proteins,10-12 including casein kinase 1A1 (CSNK1A1), which is encoded by a gene located in the deleted region of chromosome 5 in del(5q) MDS.13,14 In myeloid cell lines, haploinsufficiency increases the sensitivity of cells to lenalidomide-mediated degradation of CSNK1A1.13

Preclinical and correlative studies in MDS cells suggest that in non-del(5q) MDS, the effects of lenalidomide on cellular progenitors and the microenvironment work together to promote normal erythropoiesis.1,15 Specifically, lenalidomide has been shown to cause expansion of progenitor populations,1,15-17 reduction in proinflammatory cytokines,15 and reduction of marrow microvessel density.15 Lenalidomide can restore erythropoietin (EPO) receptor signaling in MDS cells1,18 by triggering rapid assembly of lipid rafts in the cell membrane, which are important domains of EPO receptor signaling that may be disrupted in MDS.18

Multiple Myeloma

Lenalidomide is an oral, small-molecule that in preclinical studies exhibits a dual proposed mechanism of action in vitro consisting of tumoricidal and immunomodulatory effects.19 In vitro, the cytotoxic and immunomodulatory effects of lenalidomide are mediated by its direct binding to cereblon, a component of a cullin-RING E3 ubiquitin ligase enzyme complex.10-12 Additionally, in multiple myeloma (MM) cells, the combination of lenalidomide and dexamethasone synergizes to inhibit cell proliferation and induce apoptosis.20,21

  • The tumoricidal effects of lenalidomide may include:
    • Activation of tumor suppressor genes (eg, p21) and inhibition of oncogene expression (eg, IRF4, c-myc) in MM cells22,23
    • Disruption of stromal-cell support in vitro24
  • The immunomodulatory effects of lenalidomide may include:
    • Activation of immune cells in vitro, increased T-cell proliferation, and cytokine production20
    • Increased natural killer cell–mediated lysis of MM cells25

Lenalidomide by Disease State

Lenalidomide in Lymphoma

  • Post Approval Research Lymphoma Mantle cell lymphoma: Relapsed/refractory (US)
  • Post Approval Research Lymphoma Mantle cell lymphoma: Relapsed/refractory (EU)
  • Phase 3 Lymphoma Diffuse large B-cell (ABC-subtype): First-line
  • Phase 3 Lymphoma Indolent lymphoma: Relapsed/refractory
  • Phase 3 Lymphoma Follicular lymphoma: First-line
  • Post Approval Research Lymphoma Adult T-cell leukemia-lymphoma (Japan)

Rationale for Clinical Development

Follicular Lymphoma

Lenalidomide exerts direct effects on FL tumors and their microenvironment in vitro.24,26-29 In preclinical studies, these effects on FL, T, and natural killer (NK) cells contribute to immune synapse repair and alter expression of costimulatory molecules.26,27 Immunomodulatory effects in vitro include enhanced T-cell proliferation and function and NK-cell function, including NK-cell–mediated antibody-dependent cellular cytotoxicity (ADCC) in conjunction with rituximab.24,28-30

Diffuse Large B-Cell Lymphoma

Lenalidomide has direct effects in vitro on both DLBCL cells and the tumor microenvironment.24,28-33 In preclinical studies, direct effects using non–germinal center B cell-like (GCB) tumor cells are mediated by binding to the cereblon-containing E3 ubiquitin ligase and include inhibition of interferon regulatory factor 4 expression and nuclear factor κB activity, increased interferon-β production, inhibition of proliferation, and induction of apoptosis.31-33 Enhanced monocyte-mediated lysis of rituximab-coated DLBCL cells in vitro has also been observed.30

Mantle Cell Lymphoma

In preclinical studies, lenalidomide increases mitochondrial release of cytochrome c and activates caspases, resulting in direct MCL tumor cell killing.30,34,35 In lymphoma cells, the combination of lenalidomide and rituximab increases both direct anti-tumor killing activities of lenalidomide and NK-cell–mediated killing observed with rituximab.30,34 Lenalidomide also increases rituximab-mediated activation of caspases 3, 8, and 934 and increases NK-cell killing capacity through ADCC in these cells.30

Lenalidomide in Multiple Myeloma

  • Post Approval Research Multiple Myeloma Relapsed/refractory
  • Post Approval Research Multiple Myeloma Newly diagnosed
  • Post Approval Research Multiple Myeloma Maintenance

Rationale for Clinical Development

Due to the preclinical activity observed, lenalidomide has been investigated in an array of treatment settings in patients with MM. Lenalidomide is being investigated in several ongoing studies as part of induction therapy or as maintenance therapy in combinations including proteasome inhibitors and monoclonal antibodies in patients with newly diagnosed MM as well as those with renal impairment who previously received treatment for MM.

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated.

References

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