Lenalidomide for the Treatment of Relapsed and Refractory Multiple Myeloma

Lenalidomide is an amino-substituted derivative of thalidomide with direct antiproliferative and cytotoxic effects on the myeloma tumor cell, as well as antiangiogenic activity and immunomodulatory effects. Together with the introduction of bortezomib and thalidomide, lenalidomide has significantly improved the survival of patients with relapsed and refractory myeloma. The most common adverse events associated with lenalidomide include fatigue, skin rash, thrombocytopenia, and neutropenia. In addition, when lenalidomide is combined with dexamethasone or other conventional cytotoxic agents, there is an increase in the incidence of venous thromboembolic events. There is now evidence that continued treatment with lenalidomide has a significant impact on survival by improving the depth and duration of response. This highlights the value of adverse event management and appropriate dose adjustments to prevent toxicity, and of allowing continued treatment until disease progression. In this review, we will discuss the different lenalidomide-based treatment regimens for patients with relapsed/refractory myeloma. This is accompanied by recommendations of how to manage and prevent adverse events associated with lenalidomide-based therapy

Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF\textit{BRAF}V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic $\textit{BRAF}$V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; $\textit{BRAF}$V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4$^{+}$/CD8$^{+}$ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by $\textit{BRAF}$V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4$^{+}$/CD8$^{+}$ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4$^{+}$/CD8$^{+}$ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4$^{+}$/CD8$^{+}$ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted

Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i).

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic BRAF V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; BRAF V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4+/CD8+ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by BRAF V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4+/CD8+ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4+/CD8+ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4+/CD8+ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted.Trial registration numberNCT02967692

Lenalidomide Enhances Immune Checkpoint Blockade-Induced Immune Response in Multiple Myeloma

International audiencePurpose: PD-1/PD-L1 signaling promotes tumor growth while inhibiting effector cell-mediated antitumor immune responses. Here, we assessed the impact of single and dual blockade of PD-1/ PD-L1, alone or in combination with lenalidomide, on accessory and immune cell function as well as multiple myeloma cell growth in the bone marrow (BM) milieu. Experimental Design: Surface expression of PD-1 on immune effector cells, and PD-L1 expression on CD138 þ multiple mye-loma cells and myeloid-derived suppressor cells (MDSC) were determined in BM from newly diagnosed (ND) multiple myelo-ma and relapsed/refractory (RR) multiple myeloma versus healthy donor (HD). We defined the impact of single and dual blockade of PD-1/PD-L1, alone and with lenalidomide, on auto-logous anti-multiple myeloma immune response and tumor cell growth. Results: Both ND and RR patient multiple myeloma cells have increased PD-L1 mRNA and surface expression compared with HD. There is also a significant increase in PD-1 expression on effector cells in multiple myeloma. Importantly, PD-1/PD-L1 blockade abrogates BM stromal cell (BMSC)-induced multiple myeloma growth, and combined blockade of PD-1/PD-L1 with lenalidomide further inhibits BMSC-induced tumor growth. These effects are associated with induction of intracellular expression of IFNg and granzyme B in effector cells. Importantly, PD-L1 expression in multiple myeloma is higher on MDSC than on antigen-presenting cells, and PD-1/PD-L1 blockade inhibits MDSC-mediated multiple myeloma growth. Finally, lenalido-mide with PD-1/PD-L1 blockade inhibits MDSC-mediated immune suppression. Conclusions: Our data therefore demonstrate that checkpoint signaling plays an important role in providing the tumor-promoting , immune-suppressive microenvironment in multiple myeloma, and that PD-1/PD-L1 blockade induces anti-multiple myeloma immune response that can be enhanced by lenalido-mide, providing the framework for clinical evaluation of combination therapy

Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T cells

To examine the impact of tumors on the immune system, we compared global gene expression profiles of peripheral blood T cells from previously untreated patients with B cell chronic lymphocytic leukemia (CLL) with those from age-matched healthy donors. Although the cells analyzed were not part of the malignant clone, analysis revealed differentially expressed genes, mainly involved in cell differentiation in CD4 cells and defects in cytoskeleton formation, vesicle trafficking, and cytotoxicity in CD8 cells of the CLL patients. In coculture experiments using CLL cells and T cells from healthy allogeneic donors, similar defects developed in both CD4 and CD8 cells. These changes were induced only with direct contact and were not cytokine mediated. Identification of the specific pathways perturbed in the T cells of cancer-bearing patients will allow us to assess steps to repair these defects, which will likely be required to enhance antitumor immunity

Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma

The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing–MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM

A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma

Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM