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Molecular Pathophysiology of Myeloma and Clinical Applications
Abstracts (D) with etoposide (E) and 15 (44%) received D+E and tocilizumab (T). 9 (27%) patients responded: 3/13 (23%) in D+E group (all had CR and 1 received allogeneic SCT) and 6/18 (33%) with D+E+T (2 CR+4 PR). There was a trend to improved response with D+E+T versus D+E (P¼0.12). At median follow-up of 1.7 months (range, 0.2e23.5), median overall survival (OS) was 1.6 months (range, 0.2-24). Conclusion: M-HLH has poor outcomes with median OS <2 months despite therapy: Increased ferritin, LDH tissue hemophagocytosis, fever, splenomegaly, and hypertriglyceridemia are frequent and should precipitate HLH work-up. Adding tocilizumab to etoposide+dexamethasone may increase responses. Awareness, novel therapies (IFN-gamma inhibitors) and early SCT may improve outcomes.
After analyzing overall survival its rate appeared to be slightly less in patients with expression of each studied antigen. The lowest overall survival was detected in patients with expression of CD56 (p¼0.057 Gehan’s Wilcoxon Test). Conclusion: The detection of expression of CD56, CD117, CD33, CD20 antigens can be an unfavorable prognostic factor for multiple myeloma associated with worse overall survival.
Abstract: MM-011 Molecular Pathophysiology of Myeloma and Clinical Applications Kenneth Anderson1 1
Dana-Farber Cancer Institute, Boston MA, USA
Multiple Myeloma
Abstract: MM-007 Intercorrelation of Expression of CD56, CD117, CD33, CD20 Antigens with Survival Rates in Patients with Multiple Myeloma in Gomel Region in Belarus Z. Kozich,1 V. Martinkov,1 Z. Pugacheva,1 L. Smirnova1 SI «Republican Research Center for Radiation Medicine and Human
1
Ecology», Gomel, «Belorussian medical academy of postgraduate education», Minsk, Belarus
Introduction: The detection of immunophenotype of plasma cells is very important for diagnosis of multiple myeloma. Mechanism of appearing of different antigens on the surface of malignant plasma cells and their correlation with overall survival isn’t sufficiently studied. Objective: To compare the overall survival and remission rates according to the expression of CD56, CD117, CD33, CD20 antigens in patients with multiple myeloma. Materials and Methods: The study included 96 patients with newly diagnosed MM at the age of 35-83 years (median - 63 years) from Gomel region of Belarus. The diagnosis was confirmed by the presence of pathological immunoglobulin in the blood and/or urine and tumor immunophenotype of the bone marrow plasma cells. By secretion variant: non-secretive, Bence-Jones, IgG, IgA at stage II, III. The results were assessed after three standard courses of VAD chemotherapy for patients <60 and VMCP courses for patients> 60years old. Antigen expression was determined by flow cytometry method. Results: Expression of CD56 was detected in 74,1% cases, CD117 in 44% cases, CD33 in 28%, CD20 in 35,3% cases. Also the presence of a soft-tissue component was more often noted in patients with increased CD20 expression. There were no statistically significant differences in the expression rate of CD56, CD117, CD33, CD20 antigens depending on the variant of multiple myeloma (non-secretive, Bence-Jones, IgG, IgA). The frequency of remission was not different depending on the presence of CD56 antigens (p¼0.418), CD33 (p¼0.471), CD20 (p¼0.151), CD117 (p¼0.689) (Fisher Exact Test).
Therapies targeting multiple myeloma (MM) in its bone marrow (BM) microenvironment including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), histone deacetylase (HDAC) inhibitors, and monoclonal antibodies (MoAbs), prolong survival 3 to 4 fold. Novel therapies target ubiquitin proteasome receptor upstream of the proteasome to overcome PI resistance. HDAC6 inhibitors block aggresomal protein degradation and synergize with PIs. IMiDs bind and activate cereblon ubiquitin 3 ligase in MM, with degradation of IZF1/3 and downregulation of Myc and IRF4. Degronimids bind cereblon, VHL, or MDM2 and also to selective substrates, triggering their degradation. IMiDs binding to cereblon triggers degradation of Alios/Ikaros, thereby inducing IL-2 transcription in T cells. IMiDS also bind p-53 related protein kinase to mediate cereblon-independent MM cytotoxicity. Elotuzumab targeting SLAMF7 and daratumumab targeting CD38 have enhanced activity with IMiDs or PIs. B cell maturation antigen (BCMA) is targeted with immunotoxins, bispecific antibodies, CAR T cells, and by blocking its ligand APRIL. Checkpoint inhibitors trigger autologous MM cytotoxicity, which is enhanced by IMiDs. Vaccination of patients with smoldering MM triggers autologous anti-MM immunity, which is enhanced by IMiDs and shifted to central memory response by HDAC 6 inhibitor and checkpoint inhibition. MM is genetically heterogeneous with multiple clones/sublones at diagnosis and ongoing DNA damage and clonal evolution. RAS mutations are most common, with transient responses to MEK/ERK inhibitor therapy. Patients with t (11:14) MM and overexpression of BCL-2 can respond to venetoclax. Selective inhibitors of Homologous recombination, APEX nuclease activity, Pan nuclease activity, and APOBEC activity target processes underlying constitutive and ongoing DNA damage. We are also targeting sequelae of genetic heterogeneity, ie. using ATR inhibitors to block replicative stress response combined with agents to increase reactive oxygen species and thereby trigger synergistic cytotoxicity in MM with MYC amplification. Finally, epigenetic therapies include KDM3A inhibitors to target fast-forward loops or regulatory loops in MM, such as KDM3A-KLF2-IRF4 axis, blocking tumor homing, binding, and growth in BM. KDM6B is regulated by NF-kB and modulates MAPK genes, growth, and survival. Long-term disease free survival will require both achieving minimal residual disease negativity and combination immune therapies to restore host immunity.
Clinical Lymphoma, Myeloma & Leukemia October 2017
- S19
After analyzing overall survival its rate appeared to be slightly less in patients with expression of each studied antigen. The lowest overall survival was detected in patients with expression of CD56 (p¼0.057 Gehan’s Wilcoxon Test). Conclusion: The detection of expression of CD56, CD117, CD33, CD20 antigens can be an unfavorable prognostic factor for multiple myeloma associated with worse overall survival.
Abstract: MM-011 Molecular Pathophysiology of Myeloma and Clinical Applications Kenneth Anderson1 1
Dana-Farber Cancer Institute, Boston MA, USA
Multiple Myeloma
Abstract: MM-007 Intercorrelation of Expression of CD56, CD117, CD33, CD20 Antigens with Survival Rates in Patients with Multiple Myeloma in Gomel Region in Belarus Z. Kozich,1 V. Martinkov,1 Z. Pugacheva,1 L. Smirnova1 SI «Republican Research Center for Radiation Medicine and Human
1
Ecology», Gomel, «Belorussian medical academy of postgraduate education», Minsk, Belarus
Introduction: The detection of immunophenotype of plasma cells is very important for diagnosis of multiple myeloma. Mechanism of appearing of different antigens on the surface of malignant plasma cells and their correlation with overall survival isn’t sufficiently studied. Objective: To compare the overall survival and remission rates according to the expression of CD56, CD117, CD33, CD20 antigens in patients with multiple myeloma. Materials and Methods: The study included 96 patients with newly diagnosed MM at the age of 35-83 years (median - 63 years) from Gomel region of Belarus. The diagnosis was confirmed by the presence of pathological immunoglobulin in the blood and/or urine and tumor immunophenotype of the bone marrow plasma cells. By secretion variant: non-secretive, Bence-Jones, IgG, IgA at stage II, III. The results were assessed after three standard courses of VAD chemotherapy for patients <60 and VMCP courses for patients> 60years old. Antigen expression was determined by flow cytometry method. Results: Expression of CD56 was detected in 74,1% cases, CD117 in 44% cases, CD33 in 28%, CD20 in 35,3% cases. Also the presence of a soft-tissue component was more often noted in patients with increased CD20 expression. There were no statistically significant differences in the expression rate of CD56, CD117, CD33, CD20 antigens depending on the variant of multiple myeloma (non-secretive, Bence-Jones, IgG, IgA). The frequency of remission was not different depending on the presence of CD56 antigens (p¼0.418), CD33 (p¼0.471), CD20 (p¼0.151), CD117 (p¼0.689) (Fisher Exact Test).
Therapies targeting multiple myeloma (MM) in its bone marrow (BM) microenvironment including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), histone deacetylase (HDAC) inhibitors, and monoclonal antibodies (MoAbs), prolong survival 3 to 4 fold. Novel therapies target ubiquitin proteasome receptor upstream of the proteasome to overcome PI resistance. HDAC6 inhibitors block aggresomal protein degradation and synergize with PIs. IMiDs bind and activate cereblon ubiquitin 3 ligase in MM, with degradation of IZF1/3 and downregulation of Myc and IRF4. Degronimids bind cereblon, VHL, or MDM2 and also to selective substrates, triggering their degradation. IMiDs binding to cereblon triggers degradation of Alios/Ikaros, thereby inducing IL-2 transcription in T cells. IMiDS also bind p-53 related protein kinase to mediate cereblon-independent MM cytotoxicity. Elotuzumab targeting SLAMF7 and daratumumab targeting CD38 have enhanced activity with IMiDs or PIs. B cell maturation antigen (BCMA) is targeted with immunotoxins, bispecific antibodies, CAR T cells, and by blocking its ligand APRIL. Checkpoint inhibitors trigger autologous MM cytotoxicity, which is enhanced by IMiDs. Vaccination of patients with smoldering MM triggers autologous anti-MM immunity, which is enhanced by IMiDs and shifted to central memory response by HDAC 6 inhibitor and checkpoint inhibition. MM is genetically heterogeneous with multiple clones/sublones at diagnosis and ongoing DNA damage and clonal evolution. RAS mutations are most common, with transient responses to MEK/ERK inhibitor therapy. Patients with t (11:14) MM and overexpression of BCL-2 can respond to venetoclax. Selective inhibitors of Homologous recombination, APEX nuclease activity, Pan nuclease activity, and APOBEC activity target processes underlying constitutive and ongoing DNA damage. We are also targeting sequelae of genetic heterogeneity, ie. using ATR inhibitors to block replicative stress response combined with agents to increase reactive oxygen species and thereby trigger synergistic cytotoxicity in MM with MYC amplification. Finally, epigenetic therapies include KDM3A inhibitors to target fast-forward loops or regulatory loops in MM, such as KDM3A-KLF2-IRF4 axis, blocking tumor homing, binding, and growth in BM. KDM6B is regulated by NF-kB and modulates MAPK genes, growth, and survival. Long-term disease free survival will require both achieving minimal residual disease negativity and combination immune therapies to restore host immunity.
Clinical Lymphoma, Myeloma & Leukemia October 2017
- S19