Phase Of Multiple Myeloma Research Articles

The implication of serum HLA-G in angiogenesis of multiple myeloma

BackgroundDespite the advances of therapies, multiple myeloma (MM) remains an incurable hematological cancer that most patients experience relapse. Tumor angiogenesis is strongly correlated with cancer relapse. Human leukocyte antigen G (HLA-G) has been known as a molecule to suppress angiogenesis. We aimed to investigate whether soluble HLA-G (sHLA-G) was involved in the relapse of MM.MethodsWe first investigated the dynamics of serum sHLA-G, vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) in 57 successfully treated MM patients undergoing remission and relapse. The interactions among these angiogenesis-related targets (sHLA-G, VEGF and IL-6) were examined in vitro. Their expression at different oxygen concentrations was investigated using a xenograft animal model by intra-bone marrow and skin grafts with myeloma cells.ResultsWe found that HLA-G protein degradation augmented angiogenesis. Soluble HLA-G directly inhibited vasculature formation in vitro. Mechanistically, HLA-G expression was regulated by hypoxia-inducible factor-1α (HIF-1α) in MM cells under hypoxia. We thus developed two mouse models of myeloma xenografts in intra-bone marrow (BM) and underneath the skin, and found a strong correlation between HLA-G and HIF-1α expressions in hypoxic BM, but not in oxygenated tissues. Yet when stimulated with IL-6, both HLA-G and HIF-1α could be targeted to ubiquitin-mediated degradation via PARKIN.ConclusionThese results highlight the importance of sHLA-G in angiogenesis at different phases of multiple myeloma. The experimental evidence that sHLA-G as an angiogenesis suppressor in MM may be useful for future development of novel therapies to prevent relapse.

Variability of Definition of High-Risk Multiple Myeloma in Phase III Clinical Trials

INTRODUCTION Despite the significant improvement in outcomes for patients with multiple myeloma (MM), a proportion of patients with high-risk disease features continue to have relatively poor outcomes. The International Myeloma Working Group defined high-risk cytogenetic abnormalities as the presence of t(4;14), t(14;16), t(14;20), del(17/17p), or gain(1q) in fluorescence in situ hybridization (FISH), nonhyperdiploid karyotype, karyotype del(13) or high-risk signature in gene expression profiling (GEP). There is a concern that a homogenous definition of high-risk MM is not unified in clinical trials. Our study aimed to investigate the high-risk MM definitions in all phase III clinical trials of MM. METHODS We conducted a cross-sectional analysis of all phase III interventional MM clinical trials registered at Clinicaltrials.gov. We searched the ClinicalTrials.gov database for the terms "myeloma", "multiple myeloma", "plasma cell dyscraisa” and included all studies that are phase III and interventional. Study protocol, data on clinicaltrials.gov and all publications related to the included clinical trials were used for data extraction. Chi-square test was used to study the association between high-risk definition and categorical variables. Multivariable analysis was done using a binary logistics regression model. RESULTS Our search revealed a total of 327 clinical trials. After screening of all study protocols 52 studies were not related to MM and were excluded. A total of 275 studies were included in our analysis. The definition of high-risk was extracted from the full publication in 88% with the rest of definition obtained from the protocol or data available at clinicaltrials.gov. Only 36% (n=99) of included studies reported the use of at least one definition of high-risk MM. Cytogenetics by either FISH or karyotype were the most used high-risk definition in 94% of studies (n=93/99). Fours studies included the International Staging System (ISS) stage II or III as high-risk while another four studies used GEP in the definition of high-risk. Few studies used laboratory markers solely in high-risk definitions: Beta-2-microglobulin (n=4) and lactate dehydrogenase (n=1). A total of 10% (n=10/99) of included studies used more than one criterion in high-risk definition. The median start date for included clinical trials was 2011 (1998-2021) (IQR: 9) while the median publication date was 2017 (2006-2022) (IQR: 6). Studies that reported a definition of high-risk were those with higher number of enrolled patients, and those with a full publication (p-value <0.001). Location of study (U.S. vs. others) and funding (pharma vs. others) were not associated with higher percentage of high-risk definition. Cytogenetic definition of high-risk included mainly del(17p), t(4;14), or t(14;16) with low number of studies defining a threshold for what is considered to be a positive result and with variable definitions of thresholds in studies that defined a threshold. [Table.1] The use of IMWG definition of high-risk was only followed in 10 studies (10%). CONCLUSIONS Our analysis indicated that a significant proportion of interventional phase III clinical trials in MM didn't clearly define high-risk MM and when defined the definition used was heterogenous and largely not based on certain thresholds of cytogenetic abnormalities. A unified definition that includes all proven clinical and/or disease high-risk features is needed for future clinical trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Eligible Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has shown promising efficacy and a favorable safety profile in newly diagnosed (ND) and relapsed refractory MM patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant eligible newly diagnosed MM (NDMM) in phase III clinical trials. Methods: We performed a comprehensive literature search on four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and keywords for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 588 articles. After a detailed screening, two phase III randomized clinical trials were included, which reported overall response rate (ORR) and negative minimal residual disease (MRD) in transplant eligible MM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR and MRD were computed along with 95% confidence intervals (CI) for pooled analysis using a fixed-effect model in RevMan v.5.4. Results: A total of 1292 transplant eligible NDMM patients were enrolled and evaluated in two phase III randomized controlled trials. Six hundred and forty-seven patients were in the Dara group and 645 patients were in the control group. Moreau et al. (2019) studied the efficacy of Dara + bortezomib (V) + thalidomide (T) + dexamethasone (d) vs VTd in NDMM pts (n=1085) in CASSIOPEIA phase III trial. Vorhees et al. reported efficacy of Dara addition to lenalidomide (R), and Vd vs RVd in GRIFFIN study in transplant eligible NDMM patients (n= 207). Dara dose was 16 mg/kg in both studies and the median follow-up was 18.8 months and 22.1 months in CASSIOPEIA and GRIFFIN trial, respectively. A pooled analysis of these trials showed ORR (OR: 1.73, 95% CI 1.16-2.59; p &amp;lt; 0.008, I2 = 80%). Achievement of MRD negative status was significant in Dara based regimen as compared to control group (OR: 2.47, 95% CI 1.97-3.10; p &amp;lt; 0.00001, I2 = 66%). Dara addition to standard care regimen (Rd and VMP) also decreased the risk of progressive disease (OR: 0.74, 95% CI 0.43-1.28; p &amp;lt; 0.28, I2 = 0%). However, Dara based regimens increased the risk of neutropenia (OR: 3.41, 95% CI 2.68-4.33; p &amp;lt; 0.00001, I2 = 91%), and lymphopenia (OR: 3.43, 95% CI 2.71-4.34; p &amp;lt; 0.0001, I2 = 94%), and pyrexia (OR: 1.42 95% CI 1.11-1.82: p &amp;lt; 0.005, I2=50%) (Figure 1). Conclusion: Addition of Dara to the standard care regimen (VRd, VTd) for transplant eligible NDMM achieved the surrogate endpoints with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials are needed. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Efficacy of Daratumumab Based Regimens Compared to Standard of Care for Transplant Ineligible Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials: A Meta-Analysis

Introduction: Daratumumab (Dara) is a human anti-CD38 monoclonal antibody approved for multiple myeloma (MM) treatment. Dara has a promising efficacy and a favorable safety profile in newly diagnosed MM (NDMM) patients. This study is focused on the efficacy and safety of Dara when added to the standard care regimen in transplant ineligible NDMM in phase III clinical trials. Methods: We performed a comprehensive database search on four major databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included MeSH (Medical Subject Headings) terms and key words for multiple myeloma and Dara including trade names and generic names from date of inception to May 2020. Initial search revealed 587 articles. After excluding review articles, duplicates, and non-relevant articles, two phase III clinical trials were included which reported overall response rate (ORR), and progression free survival (PFS) of transplant ineligible NDMM patients with Dara addition to standard care regimen. Odds ratios (OR) of ORR were computed and hazard ratios (HR) of PFS (along with 95% confidence intervals; CI) were extracted to compute a pooled HR using a fixed effect model in RevMan v.5.4. Results: A total of 1453 transplant ineligible NDMM patients were enrolled and evaluated in two phase III randomized clinical trials. Seven hundred and eighteen patients were in Dara group and 735 patients were in control group. Bahlis et al. (2019) studied Dara + lenolidamide (R) and dexamethasone (d) vs Rd in NDMM pts (n=737) in MAIA phase III trial. Similarly, Mateos et al. (2018) reported the role of Dara + bortezomib (V) + melphalan (M), and prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). A pooled analysis of these phase III trials showed ORR (OR: 3.26, 95% CI 2.36-4.49; p &amp;lt; 0.00001, I2 = 0%), and progression free survival (PFS) (HR: 0.53, 95% CI 0.43-0.65; p &amp;lt; 0.00001, I2 = 0%). Achievement of minimal residual disease (MRD) negative status was significant in Dara based regimen as compared to control group (OR: 4.49, 95% CI 3.31-6.37; p &amp;lt; 0.00001, I2 = 0%). Dara addition to standard care regimen (Rd and VMP) decreased the risk of progression/death to 42% (HR: 0.58, 95% CI 0.48-0.70; p &amp;lt; 0.00001, I2 = 0%). The addition of Dara increased the risk of neutropenia (OR: 1.41, 95% CI 1.07-1.85; p &amp;lt; 0.02, I2 = 44%), and pneumonia (OR: 2.25, 95% CI 1.54-3.29; p &amp;lt; 0.0001, I2 = 37%) vs control group. However, decreased risk of anemia (OR: 0.64, 95% CI 0.49-0.85: p &amp;lt; 0.002, I2=30%) was observed in Dara group vs control group (Figure 1). Conclusion: Addition of Dara to the standard care regimen for transplant ineligible NDMM achieved the surrogate end points with improved efficacy and MRD negative status with manageable toxicity. However, data from more randomized controlled trials is needed. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

A Systematic Review of Daratumumab Based Four Drug Regimen for Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials

Introduction: Daratumumab (Dara) is a human an IgG1k monoclonal antibody that targets the CD38 which is overexpressed in the malignant cells of multiple myeloma (MM). Its use has been approved for use as a single agent as well as in combination therapy for the treatment of both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). This review highlights the efficacy and safety of Dara in the four-drug regimen in NDMM patients (pts). Methods: We conducted a literature search using four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included Medical Subject Headings (MeSH terms) and keywords for multiple myeloma and daratumumab including trade names and generic names from the date of inception to June 2020. After excluding review articles, duplicates, and non-relevant articles, we included three phase III trials out of 588 articles reporting Dara addition to the standard of care four drug regimens for NDMM pts. Results: A total of 1998 patients were enrolled and evaluated in three-phase III randomized controlled trials. A total of 997 patients were evaluated in the Dara group and 1001 patients were evaluated in the control group. Total 1292 were transplant eligible and 706 patients were transplant ineligible. Transplant eligible Moreau et al. (2019) studied the efficacy of Dara + bortezomib (V) + thalidomide (T) + dexamethasone (d) vs VTd in newly diagnosed MM (NDMM) pts (n=1085) in CASSIOPEIA phase III trial. Addition of Dara to VTd group showed marked improvement in progression-free survival (PFS): 93% vs 85% at 18 months (hazard ratio (HR) 0.42 [0.34-0.51]; p&amp;lt;0.0001), and overall response rate (ORR) of 92.6% in Dara + VTd group as compared to 89.9% in VTd group (CI: 95%, P&amp;lt;0.0001). Minimal residual disease (MRD) negative status (10-⁵ sensitivity threshold, assessed by multiparametric flow cytometry) in bone marrow was 64% in Dara using VTd vs 44% in the VTd group (P&amp;lt;0.0001). Vorhees et al. (2020) reported addition of Dara to lenolidamide (R), and Vd in GRIFFIN study in NDMM patients (n= 207). Addition of Dara to VRd resulted in improved PFS: 95.8% ((95% CI, 89.2- 98.4) vs 89.8% ((95% CI, 77.1-95.7) at 24 months), and ORR of 99% (Odd's ratio (OR) 8.75 with 95% CI: 1.08-71.01; p=0.0160) in Dara + VRd group vs VRd group (91.8%). MRD status in bone marrow was also higher in Dara group as compared to control group (51% vs 20.4%) (p&amp;lt;0.0001). Transplant ineligible Mateos et al. (2018) reported the role of Dara + V + melphalan (M) + prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). Addition of Dara to VMP group showed marked improvement in PFS: 63% vs 36 at 24 months (HR: 0.47, 95% CI 0.33-0.67, p&amp;lt;0.0001), and ORR: 90.9% vs 73.9%, respectively. MRD negative status in bone marrow was observed higher with Dara compared to without Dara using VMP (28% vs 7%) (p&amp;lt;0.0001). Significant toxicities in phase III trials mainly included pancytopenias and opportunistic infections (Table 2). Conclusion: NDMM treatment with Dara in four-drug regimens (VTd, VMP, VRd) has shown promising outcomes with improved efficacy and higher negative MRD status, providing a benchmark for future studies. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Connection between Parameters of Erythron System and Myelofibrosis during Chronic Myeloleukemia, Multiply Mieloma, and Chronic Lymphatic Leukemia.

Clinical and morphological investigation of myelofibrosis was performed in patients with chronic myeloid leukemia, multiple myeloma, and chronic lymphocytic leukemia by analyzing the morphometric parameters of trepan-biopsy material. The correlation between changes in the parameters of erythron system and distribution of myelofibrosis were analyzed. In patients with chronic myeloid leukemia, multiple myeloma, and chronic lymphocytic leukemia, the maximum suppression of the erythron was observed against the background of severe myelofibrosis. The degree of erythron inhibition correlated with distribution of the fibrous tissue in the bone marrow. In patients with onset of chronic phase of chronic myeloid leukemia and active phase of multiple myeloma, the total number of erythroid cells was lower than in active phase of chronic lymphocytic leukemia irrespective of the degree of myelofibrosis. Erythrocyte count and hemoglobin content in the peripheral blood were lower in patients with multiple myeloma and chronic lymphocytic leukemia in comparison with the corresponding parameters in patients with chronic myeloid leukemia irrespective of the severity of myelofibrosis.

Siltuximab and hematologic malignancies. A focus in non Hodgkin lymphoma

ABSTRACTIntroduction: The role of interleukin-6 (IL-6) in tumorigenesis and in particular in haematological malignancies is crucial. On the basis of the favourable results obtained in the subset of multicentric Castleman disease (MCD), Siltuximab, a chimeric, human-murine, immunoglobulin (Ig) Gk monoclonal antibody directed against human IL-6 has been evaluated in haematological malignancies such as multiple myeloma, myelodisplastic syndromes and non Hodgkin lymphomas.Areas covered: This review discusses available data related to the role of IL-6 as a therapeutic target, the characteristics of Siltuximab in term pharmacokinetics and pharmacodynamics properties and a detailed analysis of the studies involving haematological malignancies with a peculiar focus on non Hodgkin lymphoma.Expert opinion: The results obtained with Siltuximab in haematological malignancies and in particular with non Hodgkin lymphoma are inferior to those obtained in MCD. The complex interaction between malignant clones, inflammatory background and host response could justify this difference. New interesting areas of study are the role of Siltuximab in early phase of multiple myeloma (smoldering multiple myeloma) and if there may be a possible future application in the treatment of Waldenström macroglobulinemia.

Multiple myeloma: disease response assessment

ABSTRACTPrecise assessment of response to therapy is of high importance in every phase of multiple myeloma (MM). In addition to the well-established role of monoclonal protein for clinical monitoring, several methods of minimal residual disease evaluation, both inside and outside the bone marrow (BM), are to date available. Next generation flow cytometry and sequencing are probably the best approaches at the BM level, being highly sensitive and uniformly applied. FDG PET/CT is the best imaging technique for evaluating and monitoring response to therapy outside the BM. Functional whole-body MRI techniques (DCE and DWI) seem promising for response evaluation and need further studies. Standardization of most of these techniques is in progress.

The therapeutic benefit and toxicity from multiple myeloma phase I trials, 2004 through 2014.

8585 Background: Despite the therapeutic benefit of novel agents, majority of multiple myeloma (MM) patients inevitably relapse leading to poor clinical outcomes. During the past decade, there has ...

Enhanced cross‐priming of naive CD8+T cells by dendritic cells treated by the IMiDs® immunomodulatory compounds lenalidomide and pomalidomide

The IMiDs(®) immunomodulatory compounds lenalidomide and pomalidomide are agents with anti-inflammatory, immunomodulatory and anti-cancer activity. An excellent success rate has been shown for multiple myeloma in phase I/II clinical trials leading to Food and Drug Administration approval of lenalidomide. One mechanism by which these drugs could enhance anti-tumour immunity may be through enhanced dendritic cell (DC) function. Thalidomide, a compound structurally related to lenalidomide and pomalidomide, is known to enhance DC function, and we have investigated whether its analogues, pomalidomide and lenalidomide, also have functional effects on DCs. We used mouse bone marrow-derived DCs treated with 5 or 10 μm pomalidomide, or lenalidomide from day 1 of culture. Treatment with IMiD(®) immunomodulatory compounds increased expression of Class I (H2-Kb), CD86, and pomalidomide also increased Class II (I-Ab) expression in bone marrow-derived DCs, as measured by flow cytometry. Fluorescent bead uptake was increased by up to 45% when DCs were treated with 5 or 10 μm pomalidomide or lenalidomide compared with non-treated DCs. Antigen presentation assays using DCs primed with ovalbumin, and syngeneic T cells from transgenic OTI and OTII mice (containing MHC restricted, ovalbumin-specific, T cells) showed that both pomalidomide and lenalidomide effectively increased CD8(+) T-cell cross-priming (by up to 47%) and that pomalidomide alone was effective in increasing CD4(+) T-cell priming (by 30%). Our observations suggest that pomalidomide and lenalidomide enhance tumour antigen uptake by DCs with an increased efficacy of antigen presentation, indicating a possible use of these drugs in DC vaccine therapies.

Prognostic Value of Hepatocyte Growth Factor, Syndecan-1, and Osteopontin in Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

Our aim was to compare serum levels of selected biological parameters in different phases of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) to determine their diagnostic and prognostic potential. A cohort of 234 individuals was assessed for serum levels of hepatocyte growth factor (HGF), syndecan-1/CD138 (SYN), and osteopontin (OPN). The patients with MM (N = 156) were divided into 3 groups: at the time of diagnosis (N = 45), in relapse/progression (N = 56), and in remission (N = 50). The analysis revealed significant differences of all three parameters in comparison of active and remission phase MM. Moreover, the parameters in active myeloma were significantly higher than in MGUS. Within the comparison of active disease (newly diagnosed and relapsing), there was no significant difference. Similar results were in remission phase MM and MGUS. There was no relationship of pretreatment levels of the parameters to therapeutic response. We conclude that serum levels of HGF, OPN, and SYN correspond to the activity of MM and might become useful in differentiation of MGUS, asymptomatic MM, and overt/symptomatic form of MM. The levels of all three parameters behave accordingly with MM activity. Pretreatment measurement without the assessment of their kinetics, however, has no relationship to therapeutic response.

Dickkopf-1 and sclerostin in different phases of multiple myeloma; The effect of lenalidomide and dexamethasone treatment with or without bortezomib

Dickkopf-1 and sclerostin in different phases of multiple myeloma; The effect of lenalidomide and dexamethasone treatment with or without bortezomib

Circulating Levels of the Wnt Inhibitors Dickkopf-1 and Sclerostin In Different Phases of Multiple Myeloma: Alterations Post-Therapy with Lenalidomide and Dexamethasone with or without Bortezomib

AbstractAbstract 2963Dickkopf-1 (Dkk-1) and sclerostin are inhibitors of the Wingless-type and integrase 1 (Wnt) signaling and they are implicated in the pathogenesis of multiple myeloma (MM) bone disease through inhibition of osteoblast function. There is very limited information for the circulating levels of Dkk-1 and sclerostin in different phases of MM and their alterations post therapies with novel agents. Therefore, we studied 284 MM patients (153M/131F, median age 66 years): 167 consecutive patients were newly-diagnosed (20 had asymptomatic MM and 147 symptomatic MM), 29 patients were at the plateau phase of MM and 88 patients had relapsed/refractory MM and received therapy with the combination of lenalidomide plus dexamethasone with or without bortezomib (VRD or RD; Dimopoulos et al, Leukemia 2010). For newly diagnosed patients, serum was stored at the time of diagnosis, while for patients at the plateau phase serum was collected at the time of confirmation of the plateau (at least 6 months with stable M-protein without criteria confirming progression) and for relapsed/refractory patients on day 1 of cycles 1, 4 and 7 of VRD or RD administration. Circulating levels of Dkk-1 and sclerostin were measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA and Biomedica Medizinprodukte, Vienna, Austria, respectively) in all patients and in 20 gender- and age- matched healthy controls. Circulating Dkk-1 and sclerostin concentrations of newly diagnosed symptomatic patients (median: 1383 pg/mL, range:274-32, 862 pg/mL and 415 pg/mL, 0–3,340 pg/mL respectively) were increased compared to controls (1069 pg/mL, 540-2, 709 pg/mL; p<0.001 and 250 pg/mL, 0–720 pg/mL; p=0.03, respectively) and to asymptomatic patients at diagnosis (1044 pg/mL, 480-2, 335 pg/mL; p<0.001 and 140 pg/mL, 0–1,100 pg/mL; p=0.001, respectively). Patients at plateau phase had increased circulating levels of sclerostin (704 pg/mL, 68–2000 pg/mL; p <0.001) compared to controls (p=0.002) as well as to MM patients at diagnosis (p=0.02). In contrast, they had lower serum levels of Dkk-1 (1013 pg/mL, 414–1729 pg/mL) compared to MM patients at diagnosis (p<0.001) and no difference compared to controls. Patients with ISS-3 myeloma at diagnosis had higher values of Dkk-1 and sclerostin than ISS-1 and ISS-2 patients [median Dkk-1 values for ISS-1, ISS-2 and ISS-3 were: 1059 pg/mL, 1290 pg/mL and 2649 pg/mL, respectively; p(ANOVA)=0.031; median sclerostin values for ISS-1, ISS-2 and ISS-3 were: 394 pg/mL, 392 pg/mL and 714 pg/mL, respectively; p(ANOVA)=0.001]. Patients with lytic disease at diagnosis (n=116) had increased levels of Dkk-1 compared with patients with no lytic disease (n=51): 1475 pg/mL, 327-32, 862 pg/mL vs. 840 pg/mL, 274–1112 pg/mL; p=0.002. There was no difference in sclerostin levels between these patients; however, patients with advanced bone disease (>3 lytic lesions and/or a fracture) had a borderline increase in their circulating sclerostin compared to all others (p=0.072). Dkk-1 circulating levels correlated weakly with sclerostin (r=0.201, p=0.05). Relapsed patients had increased Dkk-1 (1218 pg/mL, 161-19, 325 pg/mL) and sclerostin (886 pg/mL, 90-6, 272 pg/mL) levels compared to controls and to asymptomatic patients at diagnosis (p<0.001 for all comparisons). In patients who received RD, Dkk-1 was increased and sclerostin was decreased after 6 cycles of therapy. Responders to RD had a median increase of 9% in Dkk-1 serum levels after 6 cycles of therapy, while non-responders had a median increase of 91% compared to baseline values (p<0.01). Patients who did not respond to RD showed an increase in bone resorption marker CTX (p=0.021) after 6 cycles of therapy. VRD administration resulted in a significant reduction of sRANKL (p=0.024) and increase of bone formation marker, osteocalcin (p=0.01) after 6 cycles, but showed only minimal reduction of Dkk-1 (p=0.08) and no alterations on sclerostin. In conclusion our study suggests that Dkk-1 is elevated in active myeloma, while sclerostin is elevated even in the plateau phase of the disease. Both correlated with adverse disease features. The increase of Dkk-1 by RD seems to be balanced by a reduction effect of bortezomib on Dkk-1 in VRD. Furthermore, the reduction of sclerostin in RD patients may represent a modulatory effect of lenalidomide on marrow microenvironment. These results further support the rationale for the use of drugs targeting Dkk-1 and sclerostin in MM. Disclosures:No relevant conflicts of interest to declare.

The Novel, Irreversible Proteasome Inhibitor PR-171 Demonstrates Potent Anti-Tumor Activity in Pre-Clinical Models of Multiple Myeloma, and Overcomes Bortezomib Resistance.

Introduction: The ubiquitin-proteasome pathway has been validated as a therapeutic target with the approval of the small molecule proteasome inhibitor, bortezomib (VELCADE®), in multiple myeloma and non-Hodgkin lymphoma. However, the overall response rate of patients with multiple myeloma in phase III clinical trials was 43%, underscoring the need for a next generation of inhibitors with the potential for greater efficacy.Methods: PR-171 is a novel, tetrapeptide epoxomicin-related inhibitor that binds the proteasome irreversibly, and our objectives were to evaluate its activity and mechanism of action in pre-clinical models of multiple myeloma.Results: PR-171 potently bound and inhibited the chymotrypsin-like subunit of the proteasome in vitro, in cellulo, and in vivo at low concentrations. At higher concentrations, however, unlike bortezomib, which targeted the chymotrypsin-like and peptidyl-glutamyl peptide hydrolyzing activities in vivo, PR-171 also displayed significant inhibition of the trypsin-like and the peptidyl-glutamyl peptide hydrolyzing activities. PR-171-induced proteasome inhibition was associated with accumulation of polyubiquitinated substrates and pro-apoptotic Bax. Brief pulse PR-171 exposure, which simulates the in vivo pharmacokinetics of bortezomib, led to PR-171-mediated inhibition of cellular proliferation linked to induction of caspase-3-dependent apoptosis through both intrinsic (caspase-9) and extrinsic (caspase-8-dependent) pathways. Pretreatment with caspase-3, -8, and -9 inhibitors rescued the anti-proliferative effect of PR-171. Furthermore, pulse PR-171 treatment activated c-Jun-N-terminal kinase, a key-signaling molecule in proteasome inhibitor-induced apoptosis, and cleavage of poly-ADP-ribose polymerase, while abrogation of c-Jun-N-terminal kinase signaling with a dominant-negative c-Jun inhibited PR-171-induced effects. PR-171 displayed enhanced anti-proliferative activity compared to bortezomib in multiple myeloma cell lines and freshly isolated patient-derived CD138+ plasma cells, associated with enhanced phosphorylation of c-Jun-N-terminal kinase and capase-3, -8, and -9 activation. Lastly, PR-171 was a potent inhibitor of proliferation in a multiple myeloma cell line model resistant to bortezomib and in isolates from two patients, one with primary and the other with acquired bortezomib-resistance.Conclusions: These data indicate that PR-171 has enhanced activity against preclinical models of multiple myeloma, perhaps owing to its irreversible binding and subunit specificity, and provide a rationale for its translation into the clinic.

Therapeutic use of immunomodulatory drugs in the treatment of multiple myeloma

Immunomodulatory drugs, such as thalidomide, lenalidomide (Revlimid®, CC-5013) and actimid (CC-4047), have a broad spectrum of activity and have shown remarkable responses in patients with multiple myeloma and related hematological diseases, such as myelodysplastic syndrome. They are currently being tested in other cancer types. This review will focus on the preclinical and clinical activity of thalidomide and its more potent immunomodulatory derivatives that are used to treat multiple myeloma. They represent a new class of antitumor agents that not only target the tumor cell directly, but also have significant activity within the bone marrow milieu. These agents have shown high responses in all phases of multiple myeloma, including the upfront setting, relapsed refractory stage and also as maintenance therapy for the disease. They have been used in combination with dexamethasone, chemotherapy and, more recently, with other novel agents, such as proteasome inhibitors. Thalidomide and lenalidomide in combination with dexamethasone have recently been approved by the US FDA for the treatment of multiple myeloma.

Aggressive Terminal Phase of Multiple Myeloma

Aggressive Terminal Phase of Multiple Myeloma

Clinical Classification of Plasma Cell Myeloma

Clinical and electrophoretic data were evaluated in 334 consecutive patients with myeloma or monoclonal peaks on serum or urine electrophoresis. Of the 242 patients with myeloma, 7% had localized plasmacytomas with absent or low level monoclonal peaks on electrophoresis and received only radiotherapy to focal disease areas. Chemotherapy was also withheld from eight other patients in an indolent clinical phase of multiple myeloma. Disease progression was apparent in about one third of the patients with localized and indolent myeloma within 12 months. Forty-three patients had idiopathic peaks on serum electrophoresis; more than 90% were of the IgG type with levels less than 3.0 gm/100 ml. Serial elecrtophoreses, immunoglobulin quantitations, and skeletal radiographs are recommended for the evaluation of patients with idiopathic peaks, the classification of early phases of myeloma, and the confirmation of tumor mass change.