Active Multiple Myeloma Research Articles

Role of Bone-Modifying Agents in Multiple Myeloma: American Society of Clinical Oncology Clinical Practice Guideline Update.

Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw. Additional information is available at www.asco.org/hematologic-malignancies-guidelines and www.asco.org/guidelineswiki .

Apparent diffusion coefficient of vertebral haemangiomas allows differentiation from malignant focal deposits in whole-body diffusion-weighted MRI

ObjectivesThe aim of this study was to identify apparent diffusion coefficient (ADC) values for typical haemangiomas in the spine and to compare them with active malignant focal deposits.MethodsThis was a retrospective single-institution study. Whole-body magnetic resonance imaging (MRI) scans of 106 successive patients with active multiple myeloma, metastatic prostate or breast cancer were analysed. ADC values of typical vertebral haemangiomas and malignant focal deposits were recorded.ResultsThe ADC of haemangiomas (72 ROIs, median ADC 1,085×10-6mm2s-1, interquartile range 927–1,295×10-6mm2s-1) was significantly higher than the ADC of malignant focal deposits (97 ROIs, median ADC 682×10-6mm2s-1, interquartile range 583–781×10-6mm2s-1) with a p-value < 10-6. Receiver operating characteristic (ROC) analysis produced an area under the curve of 0.93. An ADC threshold of 872×10-6mm2s-1 separated haemangiomas from malignant focal deposits with a sensitivity of 84.7 % and specificity of 91.8 %.ConclusionsADC values of classical vertebral haemangiomas are significantly higher than malignant focal deposits. The high ADC of vertebral haemangiomas allows them to be distinguished visually and quantitatively from active sites of disease, which show restricted diffusion.Key Points• Whole-body diffusion-weighted MRI is becoming widely used in myeloma and bone metastases.• ADC values of vertebral haemangiomas are significantly higher than malignant focal deposits.• High ADCs of haemangiomas allows them to be distinguished from active disease.

Response comparison of multiple myeloma and monoclonal gammopathy of undetermined significance to the same anti-myeloma therapy: a retrospective cohort study

Multiple myeloma is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), which is usually only treated by a form of anti-multiple myeloma therapy if it is causing substantial disease through deposition of secreted M proteins. However, studies comparing how MGUS and multiple myeloma plasma cell clones respond to these therapies are scarce. Biclonal gammopathy multiple myeloma is characterised by the coexistence of an active multiple myeloma clone and a benign MGUS clone, and thus provides a unique model to assess the responses of separate clones to the same anti-multiple myeloma therapy, in the same patient, at the same time. We aimed to identify how MGUS and multiple myeloma plasma cell clones responded to anti-multiple myeloma therapy in patients newly diagnosed with biclonal gammopathy multiple myeloma. In this retrospective cohort study, we identified patients with biclonal gammopathy multiple myeloma by central laboratory analysis of 6399 newly diagnosed patients with multiple myeloma enrolled in three UK clinical trials (Myeloma IX, Myeloma XI, and TEAMM) between July 7, 2004, and June 2, 2015. In addition to the inclusion criteria of these trials, our study necessitated at trial entry the presence of two distinct M proteins in immunofixation electrophoresis. The primary endpoint was difference in response achieved with anti-multiple myeloma therapy on MGUS (which we defined as M2) and multiple myeloma (M1) clones-overall, within patients, and between therapy types-with international therapy response criteria assessed with χ2 analyses. We analysed by intention to treat. 44 patients with biclonal gammopathy multiple myeloma with IgG or IgA MGUS clones were subsequently identified from the three trials and then longitudinally monitored. 41 (93%) of M1 clones had a response to therapy (either complete response, very good partial response, partial response, or minor response) compared with only 28 (64%) of M2 clones (p=0·0010). For the 20 patients who received intensive therapy, there was no difference between the proportion of responding clones in M1 (19 [95%]) and M2 (15 [75%], p=0·13). However, for the 17 patients who received non-intensive therapy, 16 (94%) of M1 clones had a response compared with ten [59%] of M2 clones (p=0·031). When examining clones within the same patient, 30 (68%) of 44 individual patients had different levels of responses within the M1 and M2 clones. One patient exhibited M2 progression to myeloma and subsequently died. These results show that, in patients with biclonal gammopathy multiple myeloma, anti-multiple myeloma therapies exert a greater depth of response against multiple myeloma plasma cell clones than MGUS plasma cell clones. Although some MGUS clones exhibited a complete response, many did not respond, which suggests that the underlying features that render multiple myeloma plasma cells susceptible to therapy are present in only some MGUS plasma cell clones. To determine MGUS clone susceptibly to therapy, future studies might seek to identify, with biclonal gammopathy multiple myeloma as an investigative model, the genetic and epigenetic alterations that affect whether MGUS plasma cell clones are responsive to anti-multiple myeloma therapy. National Institute of Health Research, Medical Research Council, and Cancer Research UK.

Kidney Transplantation in Patients With Active Multiple Myeloma: Case Reports.

Kidney disease is a common complication in patients with multiple myeloma. Traditionally, patients with active multiple myeloma and end-stage renal disease have been excluded from kidney transplantation due to the risk of malignancy progression. The introduction of bortezomib-based therapy for patients with multiple myeloma and renal impairment has significantly improved survival in this population. In this report, we present 2 cases of patients with active and controlled multiple myeloma who underwent successful kidney transplantation without progression of their underlying malignancy. In patients with active multiple myeloma controlled with bortezomib, kidney transplantation should be considered a valid option for patients with end-stage kidney disease.

Active multiple myeloma suppresses and typically eliminates coexisting MGUS

Background:Myeloma is consistently preceded by premalignant monoclonal gammopathy of undetermined significance (MGUS). In >5% of MGUS patients there is a second MGUS clone (biclonal gammopathy of undetermined significance; BGUS), yet, at myeloma diagnosis, presentation of biclonal gammopathy myeloma (BGMy) is considered less frequent, implying that myeloma eradicates coexisting MGUS.Methods:In the largest study of its kind, we assessed BGMy frequency amongst 6399 newly diagnosed myeloma patients enrolled in recent UK clinical trials.Results:Compared to expected prevalence (i.e., >5% of MGUS have BGUS), only 58 of 6399 (0.91%) newly diagnosed myeloma patients had BGMy, indicating myeloma typically eliminates coexistent MGUS. In these 58 BGMy cases, the MGUS plasma cell clone was greatly suppressed in size compared to typical levels observed in conventional MGUS; contrarily, the MGUS clone did not inhibit the myeloma plasma cell clone in BGMy.Conclusion:Myeloma eliminates the majority of competing MGUS, and when it does not, the MGUS clone is substantially reduced in size.

Smoldering Multiple Myeloma: Who and When to Treat.

Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by the presence of≥3g/dL serum M-protein and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple myeloma (MM) is not uniform, and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited and asymptomatic MMs at 80% to 90% of progression risk at 2 years are now considered to be active MM candidates for treatment. In the future, more precise biomarkers are necessary for accurate risk stratification to plan an optimized follow-up according to the risk of progression, as well as to expand the group of patients that can obtain a benefit if they receive early treatment. A phase 3, randomized trial in high-risk patients with SMM comparing early treatment versus observation has shown a significant benefit in terms of time to progression and overall survival for early intervention and confirmatory clinical trials will definitively contribute to establish the early treatment as standard of care in high-risk SMM.

Bone Marrow DKK-1 Levels Identify Patients With Smoldering Myeloma With Higher Risk of Progression to Active Multiple Myeloma

Bone Marrow DKK-1 Levels Identify Patients With Smoldering Myeloma With Higher Risk of Progression to Active Multiple Myeloma

Serum Levels of Soluble FLT3 Ligand in Patients with Active Multiple Myeloma Constitute Marker of Bone Marrow Plasma Cell Proliferative Activity.

The FLT3-ligand is a molecule implicated in hematopoiesis. The aim of the present study was to detect any possible connections between serum levels of FLT3-L and multiple myeloma (MM) proliferation markers, such as serum levels of interleukin-6 (IL-6), B-cell activating factor (BAFF), beta-2 microglobulin (B2M), CRP and LDH, as well the percentage of bone marrow infiltration and the plasma cells' proliferation marker Ki-67 PI. We measured the above parameters in 58 patients with active MM. All circulating markers were significantly higher in MM patients compared to controls (p < 0.001 for all cases), and all values were increasing in parallel with disease stage (p < 0.001 for all cases). Positive correlations between FLT3-L were noted with serum levels of BAFF (p < 0.003), IL-6 (p < 0.002), CRP (p < 0.0001), LDH (p < 0.001), and BM Ki-67 PI (p = 0.012), whereas only trends of correlation were noted with the B2M value and the percentage of infiltration. It seems that the increased serum levels of circulating FLT3-L, in parallel with MM activity, reflect their increased presence in the bone marrow microenvironment, probably as an effect of increased angiogenesis and myelosuppression. Consequently, they are potential markers of disease activity.

A Single Institution Retrospective Analysis of the Effect of Erythropoiesis Stimulating Agents in Patients with Multiple Myleoma

Background: Erythropoiesis Stimulating Agents (ESAs) are FDA approved for chemotherapy induced anemia and anemia of chronic kidney disease. These indications are more frequent in patients with multiple myeloma. Use of ESAs has been associated with an increased risk of heart attack, stroke, venous thromboembolism (VTE), and all-cause mortality. In patients with cancer, ESA's have been associated with worse progression free survival (PFS) and overall survival (OS) Previous research regarding ESA use in patients with multiple myeloma has been limited and conflicting. In this study, we evaluate the effects of ESA use in patients with multiple myeloma. Additionally, we examined the frequency of ESA usage after the 2007 FDA safety update revising product labeling for ESAs.Methods: A retrospective chart review was conducted on patients diagnosed with active multiple myeloma between January 1st, 2000 and December 31st, 2015 at Gundersen Health System in La Crosse Wisconsin. Collected data include patient demographics, medications, lab tests, comorbidities, and the dates of any VTE, stroke, or myocardial infarction. Both a logistic regression and a matched case-control analysis were used to compare rates of complications in patients using ESAs to those that did not. ESA effect on median survival time was also calculated for each International Staging System (ISS) stage of disease.Results:There were 278 patients included for demographic analysis (Table 1), of which 268 were included in the logistic regression analysis and 124 (62 pairs) in the matched case-control analysis.A logistic regression model constructed via stepwise selection found that bone lesions at diagnosis (Odds Ratio (OR): 2.5 [1.2-5.1]), antiplatelet drug use (OR: 3.7 [1.2-11.3]) and ESA use (OR: 4.7 [2.2-9.9]) were associated with increased risk of VTE in our patient population. Use of an Angiotensin Converting Enzyme (ACE) inhibitor (OR: 0.4 [0.2-0.9]) was associated with a decreased risk of VTE. Increased odds of VTE with ESA usage (OR: 5.9 [1.9 - 18.8]) were also noted in the matched case-control analysis. There was no association found between rate of stroke and ESA usage in either logistic or matched case-control analysis. No significant association between ESA use and overall survival was noted in either logistic or matched case-control analysis.When comparing outcomes based upon pre and post FDA revised product labeling, we found a 50% reduction in ESA usage within our institution. In this same time period, the percentage of patients with multiple myeloma developing VTEs has been significantly reduced (18.6% vs 12.8% [p<0.007]).Conclusions: In our population, the use of ESAs in multiple myeloma patients was associated with increased risk of VTE. No significant association between ESA use and overall survival was noted. The observed decrease in both ESA use and rate of VTE in patients with myeloma after the 2007 revised safety labelling by the FDA may reflect practice changes in response to this revision at our institution. Further study in a prospective large multicenter dataset with further control of confounding variables is warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Bone Marrow DKK-1 Levels in Smoldering Multiple Myeloma Patients: A New Independent Risk Factor for Progression

The presence of bone disease is the hallmark to differentiate patients with active multiple myeloma (MM) from those with smoldering MM (SMM). The diagnostic criteria for active MM have been recently updated; including patients previously defined high-risk SMM among those with active MM in the presence of biomarkers of malignity. Actually SMM patients can be stratified for the risk of progression to active MM based on several factors but new parameters to identify patients with a high risk of progression need to be defined. Particularly there are not any molecular factors able to differentiate the new high-risk SMM patients. Recently, we analyzed bone marrow (BM) levels of several cytokines and chemokines involved in the MM-induced alterations of the bone remodeling finding that BM levels of Activin A, C-C motif chemokine ligand 20 (CCL20), Dickkopf 1 (DKK-1) and osteoprotegerin (OPG) were significantly different among patients with Monoclonal Gammopathy of Undetermined Significance (MGUS), SMM and MM (Dalla Palma B et al. Leukemia 2016). Thus, in this study we focused on those soluble factors in order to evaluate their possible role as new markers of risk progression in SMM patients.We analyzed a total cohort of 87 patients with SMM as defined by the International Myeloma Working Group updated diagnostic criteria for MM and related disorders (serum monoclonal protein (IgG or IgA) ≥ 3 g/dL, or urinary monoclonal protein ≥500 mg/24 h and/or clonal BM plasma cells 10%-60%, and absence of myeloma defining events or amyloidosis) admitted to our Myeloma Unit between 2007 and 2015 and who underwent to BM aspirate. The median age of the patients was 65 years (range 38-92); 50 were males and 37 were females; light chain was kappa in 68% of patients and lambda in 32%, whereas heavy chain was IgG in 76%, IgA in 23% and IgD in 1%. Standard risk factors evaluated were size of serum M protein (≥ 3 g/dL in 14% of patients), percentage of BM plasma cells and immunoparesis (present in 66% of patients). Free Light Chain (FLC) ratio was not available in all patients. DKK-1, Activin A, CCL20, and OPG BM plasma levels were measured by ELISA assay. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher’s exact test. P value of <0.05 was considered significant. The influence of BM cytokine and chemokine levels on the progression to active MM in SMM patients was examined by Kaplan-Meier and Cox regression analysis.With a median follow-up time of 42 months, 21 patients progressed to active MM; median time to progression was 16 months. BM Activin A, CCL20 and OPG median levels were not significantly different between progressed and not SMM patients (median levels: Activin A 401.97 pg/mL vs 402.93 pg/ml, p=0.70; CCL20 68.68 pg/mL vs 62.08 pg/mL, p=0.80; OPG 101.94 pg/mL vs 118.74 pg/mL, p=0.86). Conversely SMM patients progressed to active MM showed significantly higher DKK-1 BM levels as compared to patients who had not progressed (median levels: 1777.50 pg/mL vs 782.77 pg/mL, p=0.007). The progression-free survival was significantly worse in patients with BM DKK-1 above the median (DKK-1 median level: 971 pg/mL; p=0.021 by log rank test). In multivariate analysis, adjusted for standard risk factors such as the size of serum M protein, the percentage of BM plasma cells, the presence of the immunoparesis, we found that BM DKK-1 levels remained an independent prognostic factor for progression to active MM (p=0.001).In conclusion, our study indicates that BM median levels of DKK-1 are able to identify the SMM patients with higher risk of progression to active MM, and may represent a new independent risk factor for progression in SMM patients. DisclosuresGiuliani:Celgene: Research Funding; Janssen: Research Funding.

Clinical Characteristics of Hyposecretory Multiple Myeloma (Monoclonal Immunoglobulin < 3 g/dl) in Afro-Caribbean Patients at a Single Urban Institution

IntroductionMonoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of monoclonal immunoglobulin (Ig), without the diagnosis of multiple myeloma (MM), while the diagnosis of MM requires the presence of a monoclonal immunoglobulin (Ig) ≥ 3g/dl or Bence-Jones protein (BJP) ≥ 500mg/24h, with bone marrow involvement of greater than 10% clonal plasma cells.Kings County Hospital (KCH) is an institution that serves a large population of Afro-Caribbean population. In our institution, an increased number of patients were observed to present with MM with monoclonal Ig <3g/dl but yet have end organ damage. The clinical characteristics of Afro-Caribbean population have not been well studied and further characterization may have diagnostic implications.MethodsThis is a retrospective study conducted at KCH. Data regarding the clinical profile of patients diagnosed with MM from 2000- 2013 was collected from the institution’s tumor registry. Patients with monoclonal Ig < 3g/dl and BJP <500mg/24h were analyzed and compared to standard MM patients with monoclonal Ig ≥ 3g/dl or BJP ≥ 500mg/24h. Data was collected for lab parameters which included quantity and type of monoclonal Ig, serum free light chains and ratio, monoclonal plasma cell percentage in the bone marrow, International staging system (ISS) stage, cytogenetics, presence of anemia, hypercalcemia, renal failure and lytic lesions. Epidemiologic parameters age and gender were also collected. Results were analyzed by a Chi-square test to calculate a mid-P exact.ResultsA total of 287 patients with MM were screened, of which 56 patients with incomplete electronic records were excluded. Of the remaining 231 patients, 63 (27%) had monoclonal Ig <3 g/dl without the presence of BJP ≥ 500mg/24h. These patients were labeled hyposecretory MM. 168 (73%) patients had standard MM, with monoclonal Ig ≥ 3g/dl or BJP ≥ 500mg/24h. In the hyposecretory MM group, 35% of patients presented with International staging system (ISS) stage I vs. 13% in the standard MM group (P= 0.0001). IgG monoclonal Ig was present in 75% of patients with hyposecretory MM compared to 62% in the standard MM group (P=0.04). Mean plasma cell percentage in the bone marrow was similar in both groups, 40% in the hyposecretory MM group compared to 51% in standard MM.Average age of presentation was 64 yrs in the hyposecretory MM group as compared to 63 yrs in the standard MM group. There were more females than males in both groups, 61% females in hyposecretory MM and 53% in standard MM group.The most common presenting symptom was anemia in both groups and there were no statistically significant differences noted in gender, presence of hypercalcemia, presence of bone lesions, and renal dysfunction. Cytogenetic data was insufficient.ConclusionIn our study, a substantial number of Afro-Caribbean patients with low levels of serum monoclonal Ig without the presence of Bence-Jones protein were diagnosed with active multiple myeloma. The results of our study underline the importance of an aggressive diagnostic approach with a bone marrow biopsy at initial presentation with MGUS in Afro-Caribbean population. This may prevent disease progression and end organ damage.Unlike the general population with MM, there were more females. DisclosuresNo relevant conflicts of interest to declare.

Ticagrelor Modulates Proliferation in Multiple Myeloma Via P1 and P2 Receptor-Mediated Mechanisms

Background:Multiple Myeloma (MM) is a hematologic malignancy involving uncontrolled proliferation of plasma cells and is particularly trophic to bone where it induces osteoclast-mediated bone destruction. Ticagrelor is a platelet inhibitor that blocks P2Y12 receptors and inhibits ENT1-mediated adenosine uptake, thereby increasing extracellular adenosine, which activates P1 receptors. Prior studies demonstrate that ticagrelor increases life span in a murine model of MM via its effect on extracellular adenosine. Prior studies also demonstrate an increase in proliferation, in vitro, and tumor growth, in vivo, of MM cells in the presence of platelet releasate. Ticagrelor blocks in vitro platelet-stimulated myeloma proliferation, suggesting a positive relationship and interaction between active platelets and multiple myeloma. We therefore determined whether the effect of ticagrelor on myeloma cells was mediated by extra-cellular adenosine or/and inhibition of platelet function.Methods:Human primary myeloma cells (KMS) were incubated with ticagrelor (10-9-10-4 M) in the presence of 5ng/ml IL-6 in the absence/presence of an A2AR antagonist (ZM241385 10-6M) and platelets (1:500 myeloma cell:platelets). In other experiments MM cells were incubated in the presence of platelet releasate, releasate from platelets treated with ticagrelor, or ticagrelor alone. Proliferation was assayed by Cell Titer MTS assay (Promega).Results: Ticagrelor inhibited MM cell proliferation by 20% (p<0.0001, IC50=0.5µM). This effect was abrogated by ZM241385 (48±6% increased vs. ticagrelor, p<0.0001). Platelet releasate increased MM proliferation by 33±6% (p<0.05) and ticagrelor inhibited the effect of platelet releasate on MM cell proliferation (IC50=0.12µM).Conclusions:These results suggest that ticagrelor inhibits proliferation of malignant plasma cells by a mechanism dependent on both adenosine A2A and platelet P2Y12 receptors. Moreover, platelet releasate intensifies proliferation, and this effect is reversed when the P2Y12 receptor is blocked by ticagrelor. [Display omitted] [Display omitted] [Display omitted] DisclosuresMeltzer:NIH: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding. Mediero:AstraZeneca: Research Funding; Celgene: Research Funding; NIH: Research Funding. Whatling:AstraZeneca: Employment. Berger:Merck: Membership on an entity’s Board of Directors or advisory committees; AZ: Research Funding. Cronstein:AstraZeneca: Consultancy, Research Funding; CanFite: Equity Ownership; Gizmo Therapeutics: Consultancy; Eli Lilly & Co.: Consultancy; NIH: Research Funding; Celgene: Research Funding.

Phase II Trial of Combination of Elotuzumab, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Purpose: This study aimed to determine the benefit of early therapeutic intervention with the combination of elotuzumab, lenalidomide, and dexamethasone in patients with high-risk smoldering multiple myeloma (SMM). The overarching objective of this trial is to determine progression free survival to symptomatic myeloma (MM). Furthermore, the study examined the activity and safety of the combination therapy in patients with high-risk SMM.Patients & Methods: Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al, Blood 2014. Patients were administered weekly elotuzumab (10 mg/kg) on days 1, 8, 15, and 22 for the first two 28-day cycles while receiving lenalidomide on days 1-21. An initial cohort of patients were randomized to a low dose dexamethasone treatment arm (Arm B) based on the following stratification factors: age >65 years and high-risk cytogenetics based on t(4:14), t(14:16), 17p deletion or p53 mutation, and +1q amplification. For cycles 3-8, patients on both treatment arms were administered elotuzumab infusions on days 1, 8, and 15. Patients on treatment Arm A received dexamethasone (40mg) on days 1, 8 and 15. After 8 cycles or best response, patients were given the option to mobilize with either cyclophosphamide or plerixafor and collect stem cells for future transplant. Patients on both treatment arms were then allowed to continue on maintenance therapy where they were administered elotuzumab (20 mg/kg) on day 1, in combination with lenalidomide days 1-21 of a 28 day cycle. After 11 patients were enrolled on each arm, arm B closed due to similar activity and toxicity to the high-dose dexamethasone arm based on published data demonstrating that high-dose dexamethasone, given once a week, does not have a detrimental effect on the immune system in patients with smoldering myeloma.Results: In total, 39 patients were enrolled on this study from January 2015 to date, with the participation of eight sites. The median age of patients enrolled was 62 years (range 26 to 75) with 15 males (38%) and 24 females (62%). The median number of cycles completed is 6 (range 1 to 19). Therapy related grade 3 toxicities included hypophosphatemia (23%), neutropenia (8%), infection (8%), anemia (3%), pulmonary embolism (3%), rash (3%), and diarrhea (3%). No related grade 4 or 5 toxicities have occurred thus far. Stem cell collection was successful in all patients collected to date. Unrelated toxicities include one instance of grade 4 prolonged QTc Interval. Of the 34 evaluable patients enrolled to both arms of the study, the clinical benefit rate is 97%. The overall response rate is 71%, including 9 very good partial responses (26%) and 15 partial responses (44%). The VGPR cases are currently under evaluation of possible complete responses due to the potential interference of elotuzumab with immunoelectrophoresis. Thus far, no patients have progressed to active multiple myeloma during, or after, protocol therapy.Conclusion:The combination of elotuzumab, lenalidomide, and dexamethasone is very well tolerated among patients with high-risk SMM. The high response rates among this patient population, who would otherwise remain untreated, is a promising starting point for the paradigm shift towards early therapeutic intervention in patients with high-risk SMM. DisclosuresGhobrial:Amgen: Honoraria; Celgene: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Noxxon: Honoraria. Matous:Seattle Genetics: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau. Rosenblatt:Astex: Research Funding; BMS: Research Funding; DCPrime: Research Funding. Usmani:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Array: Research Funding; Novartis: Speakers Bureau; Pharmacyclics: Research Funding; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Munshi:OncoPep Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

O1-13-1 - Dynamic contrast-enhanced MR imaging can distinguish between active and inactive multiple myeloma

O1-13-1 - Dynamic contrast-enhanced MR imaging can distinguish between active and inactive multiple myeloma

Utility of flow cytometry studies in the management of patients with multiple myeloma.

Although the input of multiparameter flow cytometry (MFC) into the clinical management of multiple myeloma patients has faced some reluctance, continuously growing evidence supports the utility of MFC in this disease. MFC immunophenotyping of bone marrow and peripheral blood plasma cells affords cost-effective assessment of clonality, and provides prognostic information on the risk of progression in smoldering multiple myeloma, and the identification of active multiple myeloma patients with dismal outcome (e.g., high numbers of circulating tumor cells) or long-term survival despite suboptimal responses through the characterization of monoclonal gammopathy of undetermined significance-like phenotypes. Extensive data indicate that minimal residual disease (MRD) monitoring can be used as biomarker to evaluate treatment efficacy and act as surrogate for survival. The time has come to address within clinical trials the exact role of baseline risk factors and MRD monitoring for tailored therapy in multiple myeloma, which implies systematic usage of highly sensitive cost-effective, readily available, and standardized MRD techniques such as MFC. Next-generation MFC should be considered mandatory in the routine evaluation of multiple myeloma patients both at diagnosis and after therapy, and represents an attractive technique to integrate with high-throughput DNA and RNA-seq methods to help in understanding the mechanisms behind dissemination and chemoresistance of multiple myeloma.

Bence Jones proteinuria in smoldering multiple myeloma as a predictor marker of progression to symptomatic multiple myeloma.

The diagnosis of smoldering multiple myeloma (SMM) includes patients with a heterogeneous risk of progression to active multiple myeloma (MM): some patients will never progress, whereas others will have a high risk of progression within the first 2 years. Therefore, it is important to improve risk assessment at diagnosis. We conducted a retrospective study in a large cohort of SMM patients, in order to investigate the role of Bence Jones (BJ) proteinuria at diagnosis in the progression to active MM. We found that SMM patients presenting with BJ proteinuria had a significantly shorter median time to progression (TTP) to MM compared with patients without BJ proteinuria (22 vs 88 months, respectively; hazard ratio=2.3, 95% confidence interval=1.4-3.9, P=0.002). We also identified risk subgroups based on the amount of BJ proteinuria: ⩾500 mg/24 h, <500 mg/24 h and without it, with a significantly different median TTP (13, 37 and 88 months, P<0.001). Thus, BJ proteinuria at diagnosis is an independent variable of progression to MM that identifies a subgroup of high-risk SMM patients (51% risk of progression at 2 years) and ⩾500 mg of BJ proteinuria may allow, if validated in another series, to reclassify these patients to MM requiring therapy before the end-organ damage development.

The expression of osteopontin and vascular endothelial growth factor in correlation with angiogenesis in monoclonal gammopathy of undetermined significance and multiple myeloma

Several studies have shown a gradual increase in the extent of bone marrow angiogenesis in various stages of proliferative plasma cell disorders, from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM). The main aim of this study was to evaluate tumor angiogenesis parameters in detail and to correlate them with the expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow of patients with MGUS and MM. In addition, we wanted to determine their prognostic significance in active MM.Ninety-five patients were enrolled in the study: 14 diagnosed with MGUS, 13 with asymptomatic myeloma (AMM) and 68 with active MM. Computer assisted image analysis was used to determine the angiogenesis parameters, the quantity of microvessels per 1mm2 (MVD), the area occupied by microvessels per 1mm2 and the percentage of microvessel area in total section area (TVA). Double immunohistochemical methods CD138+VEGF and CD138+OPN were used to evaluate expression of these proteins in plasma cells, and OPN was also analyzed for its interstitial expression (iOPN).A significant positive correlation was determined between VEGF and iOPN with angiogenic parameters in the MGUS stage of the disease. In advanced stages of the disease, a significant negative correlation was recorded between OPN and iOPN with parameters of angiogenesis. Overall survival was significantly shorter for patients with negative iOPN (p=0.002) and higher angiogenic parameters, MVD (p=0.009), TVA (p=0.008) and area of microvessels per 1mm2 (p=0.02). Positive VEGF expression in our model predicted a better three-year survival of patients with active MM (OR: 5.25, p=0.03; HR: 0.44, p=0.04).The results of our study suggested a possible key role of VEGF and OPN in the induction of angiogenesis in early-stage disease.

Correlation of Mast Cell Density With Angiogenic Cytokines in Patients With Active Multiple Myeloma

PurposeThe aim of the study is to estimate whether bone marrow mast cell density (MCD) in multiple myeloma (MM) correlates with circulating levels of various angiogenic factors. MethodsIn 70 patients with newly diagnosed active MM, we measured MCD using immunohistochemical stain for tryptase and serum levels of matrix metalloproteinase 9 (MMP-9), angiopoietin 2 (ANGIOP-2), and angiogenin (ANG) with ELISA. FindingsLevels of MCD, ANGIOP-2, and ANG were significantly higher in MM patients compared with the control group. The MMP-9 level was higher in MM patients compared with the control group but without statistical significance. All values were increasing in parallel with clinical stages. Furthermore, MCD correlated positively with MMP-9, ANGIOP-2, and ANG. ImplicationsMCs participate in the angiogenic processes of MM, with complex implicated mechanisms. This interplay between MCs and the other participants favors angiogenesis and MM growth.

Prospective study of signalling pathways in myeloma bone disease with regard to activity of the disease, extent of skeletal involvement and correlation to bone turnover markers.

The aim of our study was to address the utility of serum levels of selected parameters of myeloma bone disease (MBD) signalling with regard to the pathogenesis of multiple myeloma (MM), activity, markers of bone turnover and extent of skeletal changes. We assessed prospectively 77 individuals with monoclonal gammopathies - 46 patients with active MM (AMM), 12 patients with smouldering MM (SMM) and 19 individuals with monoclonal gammopathy of undetermined significance (MGUS) to determine the role of HGF, MIP-1α, Syndecan-1, osteoprotegerin, Activin A, DKK1, Annexin A2 and NF-κB. We found significant differences of most of the parameters between MGUS and AMM, and with respect to the activity of MM assessed by International Staging System. Most of the parameters of MBD signalling correlated with traditional markers of bone turnover. All the signalling pathways were activated in MM with more pronounced osteoclastogenesis in comparison with bone formation but not in MGUS regardless of its risk category, suggesting that MBD is not activated in MGUS until the process of transformation into MM. The parameters of MBD signalling might precede the increase of conventional parameters of bone turnover suggesting their possible role in early indication of anti-resorption therapy.

Serum Versus Urine Free Light Chains for Assessment of Monoclonal Gammopathies

IntroductionMonoclonal gammopathies comprise a spectrum of disorders including Monoclonal Gammopathy of Undetermined Significant (MGUS), Smoldering Multiple Myeloma (SMM), and Active Multiple Myeloma (MM) characterized by production of monoclonal immunoglobulin heavy and/or light chains. Prior to availability of the FREELITE™ (Binding Site Ltd; Birmingham, UK) assay for measurement of immunoglobulin free light chains (FLC), laboratory monitoring of these disorders used predominantly SPEP, quantitation of immunoglobulin heavy chains (quantitative immunoglobulins), and 24 urine collection for total protein and UPEP to extrapolate production of immunoglobulin light chains. The FREELITE™ assay has up to 3-log increased sensitivity (1.5-3.0 mg/L) for detection of free light chains over standard electrophoresis (500-2,000 mg/L) and immunofixation (150-500 mg/L), and since its introduction, has been an integral tool in diagnosis and monitoring of monoclonal gammopathies. This assay detects more plasma cell disorders than SPEP, UPEP and IFE combined due to its higher sensitivity and ability to derive the ratio of affected to unaffected light chain. Measurement of urine FLC using FREELITE™ has not been integrated into standard practice due to presumed variability in FLC concentration due to changes in glomerular filtration, variability in tubular reabsorption of light chains, and lack of data regarding this use. In our practice, we routinely use random urine samples instead of 24 hour urine collections which are cumbersome and suffer from poor patient compliance.Methods:The study was approved by the Stratton VA Medical Center Institutional Review Board. As it has been our practice to obtain both random urine along with serum for FLC, we retrospectively reviewed patients diagnosed with monoclonal gammopathies and compared random urine free light chains measured by FREELITE™ to serum FLC and serum quantitative immunoglobulins. Data was analyzed for correlation using Pearson product moment correlation. P values of >0.05 were considered significant.Results:We identified 23 individuals, all male (consistent with VA population). Mean (±SD) age was 68±10 years at diagnosis, creatinine 1.3±0.5 mg/dl, and 9±6 pairs of data points per patient. Five (5) had MGUS, 5 SM, and 13 MM (2 light chain only). Results are illustrated in the Table. Normalization of urine results using concurrent serum and urine creatinine did not change the statistical significance of any of the results.TableCorrelation (p<0.05) between affected serum immunoglobulin, urine FLC, and serum FLCSerum ImmunoglobulinUrine FLCSerum FLC#(%) of PatientsYESYESno2(10)YESnoYES6(29)YESYESYES5(24)Nonono7(33)YESYES11(48)DiscussionWhile serum FLC is adequate in the majority of patients for monitoring monoclonal gammopathies, urine FLC correlates as well as serum FLC in about ½ of the patients. In addition, in a small number of individuals, urine FLC correlates with serum total serum immunoglobulin better than serum FLC. We feel that random urine FLC is useful for monitoring monoclonal gammopathies, and in a minority of instances, provides more accurate assessment of disease activity than serum. DisclosuresNo relevant conflicts of interest to declare.