Pembrolizumab (MK-3475) in MM Patients With Residual Disease

Multiple Myeloma (MM) is a B cell malignancy characterized by the presence of bone marrow infiltration by clonal plasma cells that generally secrete a monoclonal component in the serum or urine. It is the second most frequent hematological malignancy, after non-Hodgkin lymphomas, and accounts approximately for a 10% of all hematological tumors and 1% of all cancers. Treatment of MM has remained substantially unchanged for some time (reviewed in with alkylating agents such as melphalan in combination with steroids being the gold standard for more than 25 years. Later on, in the 1970 decade, other drugs such as carmustine or vincristine where combined with melphalan, cyclophosphamide or steroids giving rise to the chemotherapeutic regimens; and ten years later high doses of melphalan with autologous stem cell transplantation (ASCT) where introduced into the clinical practice. All these treatment schemes resulted in an overall survival of around 30 months until 1994 with a slight improvement in the subsequent five years, probably due to the introduction of ASCT and better measures of supportive care. Finally, in the first decade of this century, some new drugs with novel mechanisms of action and clear antimyeloma activity have been discovered and approved. In this regard, several studies have demonstrated the activity of the proteasome inhibitor bortezomib and the immunomodulatory agents thalidomide and lenalidomide in relapsed/refractory MM patients. The emergence of these drugs has resulted in a clear improvement in the outcome of these patients in the last years, with an increase in median overall survival of up to five years.

Nevertheless, despite this clear progress, most patients (if not all) eventually relapse and the outcome of MM patients once they become refractory or ineligible to receive bortezomib or an IMID is quite poor with a survival inferior to one year.Therefore novel therapeutic options are still necessary for these relapsed or refractory patients. In this regard, several drugs that target specific mechanisms of the tumoral cells are currently being explored in the preclinical and clinical setting.(10) Some examples of the most promising of these targeted agents are second-generation proteasome inhibitors or immunomodulatory agents, deacetylase inhibitors (DACi), the kinesin spindle protein inhibitor filanesib and several monoclonal antibodies.

Pembrolizumab (MK-3475) Programmed cell death 1 (PD-1) axis function and mechanism of action of MK-3475 The programmed cell death 1 (PD-1) receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of activated T cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions.

PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains two tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, which are involved in the CD3 T-cell signaling cascade.

PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).The mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from, that of CTLA-4, as both molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T cells, B cells, T regs, and natural killer cells. Expression has also been shown during thymic development on CD4-CD8- (double negative) T cells, as well as subsets of macrophages and dendritic cells.(20) The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types including non-hematopoietic tissues and in various tumors. Both ligands are type 1 transmembrane receptors containing both IgV- and IgC-like domains in the extracelular region and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-L1 or PD-L2 to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on vascular endothelium; whereas PD-L2 is only detectably-expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PDL1 serves to dampen unwarranted T-cell function in peripheral tissues.Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. High expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and survival in various cancer types, including RCC, pancreatic carcinoma, HCC, and ovarian carcinoma. Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in patients with melanoma. The observed correlation of clinical prognosis with PD-L1 expression in multiple cancers suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention.

MK-3475 (previously known as SCH 900475) is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumor regression and ultimately immune rejection.

• Clinical experience with MK-3475 Several clinical trials are being conducted in advanced melanoma, non-small cell lung cancer, head and neck cancer, urothelial tract cancer, triple negative breast cancer, gastric cancer, and hematologic malignancies (including smoldering multiple myeloma). A phase I trial in combination with lenalidomide and dexamethasone is now enrolling MM patients. .
• Rationale for using anti-PD1 MoAb as consolidation in MM PD-L1 is expressed on most MM plasma cells, and PD-L1 overexpression enhanced MM invasiveness and rendered tumor cells less susceptible to cytotoxic T-lymphocytes (CTLs). This effect was alleviated by anti-PD-L1 antibody treatment, demonstrating the importance of the PD-1/PD-L1 pathway in this process. In addition, a recent report demonstrated increased levels of PD-L1 on MM cells together with enhanced PD-1 expression on T cells with an "exhausted" phenotype. The immunosuppressive effects of myeloma are overcome by PD-L1 blockade.(32) A Phase 1 clinical trial conducted in advanced hematologic malignancies using CT-011, showed clinical responses in 6 of 17 patients including stable disease in MM patients.

Moreover, a recent experiment performed by our group showed that MM patients in serological complete remission but with residual disease have clear overexpression of the molecules in this pathway both in tumor cells and also T-lymphocytes. And that was very clear when compared with MM patients in immunophenotypic CR (that is without residual cells in the bone marrow by flow cytometry). This could be suggesting that this pathway may be responsible, at least partially, of the inability to eradicate the tumor cells in these patients.