Multiple Myeloma In Complete Remission Research Articles

Slow increase of bilirubin concentration during administration of lenalidomide, bortezomib and dexamethasone for multiple myeloma (unmasking previously undiagnosed Gilbert syndrome) and disappearance of necrobio­tic xanthogranuloma after complete remission of multiple myeloma

Lenalidomid ranks among immunomodulatory drugs. There are a few of the more common side effects, like a higher risk of venous trombembolism or diarrhea. Other side effects are rare. The hyperbilirubinemia described in this article can be assigned to them. In our case, the increase of bilirubin was associated with unrecognized Gilbert syndrome. We report a patient with multiple myeloma and necrobio-tic xanthogranuloma (NXG) of the skin and liver. After the treatment with bortezomib, lenalidomid and dexamethasone, complete remission was attained after 4 cycles with decrease of monoclonal immunoglobulin to an unmeasurable concentration. At the same time, the dis-appearance of cutaneous and hepatic lesions of NXG on FDG-PET/CT was evident. The administration of bortezomib was stopped after 8 cycles and only continued with lenalidomide as a maintenance therapy. However, after four cycles of this therapy, bilirubin increased above the upper limit and the increase continued till the 11th month of lenadomide administration, when bilirubin reached the highest concentration of 75 μmol/l (more than the three-fold of the upper limit, grade III toxicity). The patient had asymptomatic hyperbilirubinemia with no underlying liver disease or renal impairment while being on lenalidomide therapy. Genetic studies proved mutation; insertion in the promotor gene UGT1A1 typical for Gilbert syndrome. Hyperbilirubinemia may be attributed to the unmasking of previously undia-gnosed Gilbert syndrome. Therefore, the therapy with lenalidomide was interrupted after 11 months. The bilirubin level decreased after the discontinuation of the drug. NXG disappeared after fulfilling complete remission of multiple myeloma with disappearance of monoclonal immunoglobulin. This observation supports the hypothesis that monoclonal immunoglobulin has a crucial role in the ethiopathogenesis of NXG and suggests the treatment of monoclonal gammopathy if present in a patient with NXG, hoping that this will result in xantogranuloma disappearance.

FDG-PET/CT dokumentované vymizení nekrobiotického xantogranulomu při potlačení tvorby monoklonálního imunoglobulinu bortezomibem, lenalidomidem a dexametazonemPopis případu a přehled literatury o léčbě nekrobiotického xantogranulomu

Necrobiotic xanthogranuloma (NXG) is a rare chronic condition, belonging to the group non-Langerhans cell histiocytoses, which is relevant due to the possibility of extracutaneous involvement and association with systemic diseases, particularly monoclonal gammopathy, MGUS and multiple myeloma. The case reported here NXG was diagnosed after 1 years of evolution in patient with asymptomatic multiple myeloma. After treatment with bortezomib, lenalidomid and dexamethasone, there was evident abrupt decrease of monoclonal immunoglobulin to not measurable level (complete remission of multiple myeloma) and in the same time was evident disappearance of cutaneous and hepatic lesions of NXG on FDG-PET/CT. The etiopathogenetic association of monoclonal immunoglobulin with NXG is documented in this case report with disappearance of NXG in the time of disappearance of monoclonal immunoglobulin.

Micrornas in Bone Marrow Mesenchymal Stromal Cells Are Differentially Expressed According to Response in Multiple Myeloma

Background: Bone marrow microenvironment plays a crucial role in the pathogenesis of multiple myeloma (MM) by supporting plasma cell growth, survival and drug resistance. These abilities have been attributed in part to the secretion of growth factors and cytokines by bone marrow mesenchymal stromal cells (BM-MSC). microRNAs (miRNAs) are promising prognostic biomarkers and therapeutic targets that can be released and transferred among MM cells and BM-MSCs as cell-cell communication. Recently, we defined a serum 14-miRNA signature which was associated with progression and complete remission (CR) after autologous stem-cell transplantation (ASCT) in patients with MM. Patients in CR showed a partial recovery of the normal serum miRNA levels and these are similar to those samples from patients with monoclonal gammopathy of undetermined significance (MGUS). Thus, these results highlight the potential value of serum miRNAs as diagnostic and prognostic biomarkers with a cell origin different from malignant plasma cells. The aim of this study was to discover whether the MSC miRNA profile varies depending on the status of the disease.Methods: Mononuclear cells from BM samples were cultured in DMEM containing 10% FBS. After a week, non-adherent cells were removed, whereas BM-MSC were selected by their adherence to the plastic and their phenotype was confirmed by multiparametric flow cytometry. We analyzed 670 microRNAs in 20 primary BM-MSC from patients with MGUS (N=4), symptomatic MM (N=8) and MM in CR (N=8). miRNAs differentially expressed were identified according to a supervised analysis using significance analysis of microarrays (SAM) and Student's t-test based on multivariate permutation (with random variance model). miRNAs differentially expressed between groups of patients were validated in an extended cohort of BM-MSC from patients (N= 82) in all the different status disease: MGUS (N=23), MM at diagnosis (N=13), relapsed MM (N=11), MM in partial response (PR) (N=13) and MM in CR (N=22), as well as in malignant plasma cells (CD38+) from those patients with symptomatic MM. In order to identify miRNA targets, we used the RmiR package to cross-correlate the miRNA expression data from the present study with our findings on the gene expression signature in 12 BM-MSCs from patients (4 MGUS, 4 symptomatic MM and 4 in CR), based on the predicted targets from TargetScan and miRBase databases.Results: In the screening phase, we identified a miRNA profile of 10 miRNAs (miR-663b, miR-654-3p, miR-206, miR-411*, miR-885-5p, miR-668, miR-638, miR-485-3p, miR-744* and miR-199a) differentially expressed between patients with symptomatic MM and MM in CR (adjusted p-value <0.0001). In the validation phase, miR-485-3p and miR-654-3p resulted differentially expressed in the three groups of patients: MGUS, symptomatic MM and patients in CR (ANOVA test: p=0.0101 and p=0.0228, respectively) (Figure 1A and 1B). The levels of these miRNAs were significantly decreased in patients with MM when compared with MGUS, and these levels seemed to recover when patients achieved CR. These two miRNAs (miR-485-3p and miR-654-3p) were also correlated with all degrees of response in MM: diagnosis, relapse, PR and CR (ANOVA test: p=0.0154 and p=0.0487, respectively). Moreover, paired cross-correlation among these two miRNAs expression with our results in mRNA gene expression profile data showed several potential gene targets with a biological interest, such as MELK and MAP2K2 (correlation index < -0.8). Finally, miR-485-3p and miR-654-3p showed a higher expression in BM-MSC than in MM CD38+ cells (Figure 1C and 1D), suggesting MSC as cell of origin for these miRNAs.Conclusion: In patients with monoclonal gammopathies, miR-485-3p and miR-654-3p expression in mesenchymal stromal cells from bone marrow is related to the status of the disease and the response to treatment in MM. The modulation of miRNAs profile in the bone marrow microenvironment around malignant plasma cells could be an important mechanism of control by cell-cell communication and the basis for potential biomarkers in serum and bone marrow. [Display omitted] DisclosuresRosinol:Celgene: Honoraria; Janssen: Honoraria.

Autologous stem cell transplantation following simultaneous liver and kidney transplantation in severe amyloid light chain amyloidosis associated with multiple myeloma: a case report

IntroductionThe involvement of vital organs in multiple myeloma (MM) with systemic amyloid light-chain (AL) amyloidosis can lead to acute organ failure. In this case, the fear of recurrence or progression of multiple myeloma often excludes those patients from undergoing organ transplantation. Nevertheless, clinically fit patients might benefit from a different therapeutic approach. This case presentation might highlight this particular unmet need and strengthen a different treatment approach.Case presentationTo our knowledge, we present the first case of successful simultaneous liver and kidney transplantation, followed by autologous stem cell transplantation in a 60-year-old Caucasian male patient suffering from MM (Durie-Salmon stage IIB; ISS-stage: III, RISS stage: III) with primary AL amyloidosis. Chemotherapy treatment led to end-stage kidney disease requiring dialysis. Liver failure also occurred after at least three cycles of CyBorD (bortezomib, cyclophosphamide, and dexamethasone) of induction therapy with a good hematologic response. Over three years after the initial diagnosis, the patient is reportedly showing an excellent quality of life and a complete remission.Discussion and ConclusionWe conclude that kidney and liver transplantation followed by autologous stem cell transplantation can be a treatment option for a selected group of patients with MM if AL amyloidosis is leading. In the end, the remission assessment by IMWG response criteria displayed a complete remission of MM together with complete reconstitution of organ functions (liver & renal function) as long as upfront clinical evaluation excludes significant cardiac involvement and other severe co-morbidities.

Bone marrow plasma cell ratio, is it must to evaluate before autologous stem cell transplantation in multiple myeloma?

Objective: Complete remission in multiple myeloma (MM) is a defined as having a &lt;5% bone marrow plasma cell (BMPC) ratio plus negative serum and urine immunofixation tests. However, it is necessary to reassess whether or not the bone marrow plasma cell ratio should be determined before transplantation in secretory multiple myeloma patients. A significant decrease in monoclonal protein levels or having negative serum and urine immunofixation tests after induction therapy might be enough to indicate chemo-sensitivity.&#x0D; Material and Methods: In this study, the data of 177 multiple myeloma patients that underwent autologous stem cell transplantation (ASCT) in our center were retrospectively evaluated.&#x0D; Results: We found a statistically significant difference in the post-ASCT response rates between the patients with a pre-ASCT BMPC ratio &lt;5% vs BMPC ratio ≥5% (p:&lt;0.001*). The 2-year progression-free survival (PFS) of the patients with BMPC ratio &lt;5% and ≥5% post-ASCT was found 24% and 25% (median PFS 11 months (95% CI; 6,68-15,31) vs 12 months (95% CI; 9,47-14,53)) respectively (p: 0.900). The 2-year overall survival (OS), was 67% and 63% (median OS 35 months (95% CI; 25,59-44,41) vs 40 months (95% CI; 27,52-52,47)) respectively (p: 0.341).&#x0D; Conclusion: Patients with decreasing monoclonal protein in serological tests, the pre-ASCT BMPC ratio was not found to have an impact on neutrophil and platelet engraftment durations, transplantation related mortality (TRM), PFS and OS. Our study suggests that in MM patients with measurable disease, it is not required to evaluate the BMPC ratio if serologic response exists.

The renal range of the \u03ba/\u03bb sFLC ratio: best strategy to evaluate multiple myeloma in patients with chronic kidney disease

BackgroundMonoclonal serum free light chains (sFLC) are a well-known cause of renal impairment (RI) in patients with multiple myeloma (MM). As an indicator of monoclonality, sFLC ratio has acquired a key role in the diagnosis and monitorization of the disease. However, its interpretation is altered in patients with chronic kidney disease (CKD). This study aims to evaluate the modification of the sFLC ratio reference range in patients with CKD, and propose an optimal range for patients with CKD.MethodsSerum FLC κ/λ ratio and estimated glomerular filtration rate (eGFR) were retrospectively analyzed in 113 control patients (without hematologic disease), 63 patients with MM in complete remission and 347 patients with active MM. The three groups included patients with CKD (eGFR < 90).ResultsIn the group of patients without active MM (n = 176), the sFLC ratio increased at different stages of CKD without pathological significance, with an increase in the number of false positives specially when eGFR is ≤55 ml/min. An optimal range was established for patients with eGFR ≤55 ml/min/1.73 m2: 0.82–3,6 with maximum sensitivity + specificity for that group with an improvement in the Area under the curve (AUC), 0.91 (0.84–0.97) compared with the current ranges proposed by Katzmann and Hutchinson.ConclusionsThis study confirms the influence of eGFR on the interpretation of the sFLC ratio, showing a decreasing specificity in progressive CKD stages when using the reference sFLC range (Katzmann), especially in patients with eFGR ≤55. According to our results, we suggest a modified optimal range (0.82–3,6) for eGFR ≤55 ml/min/1.73 m2. It is necessary to validate this modified range in larger and prospective studies.

PB2170 HEPATITIS C VIRUS-DRIVEN MULTIPLE MYELOMA IN STABLE COMPLETE REMISSION AFTER ANTIVIRAL TREATMENT

Background: Despite great advances in knowledge and treatment in past decades, multiple myeloma (MM) remains an incurable disease. Several studies suggest its association with infectious pathogens, such as hepatitis C virus (HCV) and Epstein Barr virus (EBV). Aims: In this study, we report on the case of a female MM patient in third relapse (after natural killer (NK) therapy with lenalidomide; bortezomib, lenalidomide, and dexamethasone (BLD); bortezomib, bendamustine, and dexamethasone (BBD) and the antiviral agents sofosbuvir and ledipasvir, who achieved stable complete response (CR) once HCV infection was successfully treated with antivirals, thus establishing a probable relationship between HCV infection and MM in this patient. Methods Serum samples from the patient were analyzed before and after antiviral treatment (Sofusbuvir + Ledipasvir). The HCV burden was determined by RT-qPCR. MRD was evaluated by cytology and MFC immunophenotyping, in bone marrow samples. The number of plasma cell clones and the tumor load were determined in bone marrow samples by next-generation sequencing. The patient's monoclonal immunoglobulin (mc IgG) was isolated by agarose gel electrophoresis and its purity was evaluated by isoelectric focusing. The reactivity to different microbial antigens was determined by means of the multiplex infectious-antigen microarray (MIAA) assay and the commercial kit INNO-LIA HCV score (Fujirebio). Results: The patient, age 59, presented with ISS IIA stage MM (5.7 g/dL mc IgG, 0.27 g/dL free lambda chains, 90% plasma cells in the bone marrow, without cytogenetic alterations, and osteolytic lesions). HCV infection, causing hepatic toxicity, was discovered in this patient before MM disease. The patient was in third relapse of MM treatment when she received anti-HCV treatment. After antiviral therapy, the HCV load in the patient's serum decreased to undetectable levels (Fig. 1A). Simultaneously, the patient achieved CR of MM, with minimal residual disease (MRD) negativity (Fig. 1B). Agarose gel electrophoresis of pre-HCV treatment samples showed one band of mc IgG, which disappeared after anti-HCV treatment (Fig. 1 C). The patient's mc IgG was purified and analysis of its specificity of recognition revealed that it targeted the HCV C1 (core) protein (Fig. 1D). Three years have now passed after HCV treatment, and the patient remains in stable CR of MM.Summary/Conclusion: In this case of refractory MM where the patient's mc IgG targeted HCV, successful HCV eradication with antivirals Sofosbuvir and Ledipasvir resulted in persistent complete remission of MM as well as of hepatitis C. These results suggest that for HCV-positive individuals, a causal relationship exists between HCV infection and the development of MM, and that MM patients infected with HCV benefit from early anti-HCV therapy.

Mir-485-3p and Mir-654-3p Expression in Bone Marrow Mesenchymal Stromal Cells in Patients with Monoclonal Gammopathies Is Related to the Status of the Disease

Background: Crosstalk between malignant plasma cells and surrounding cells in the bone marrow (BM), such as mesenchymal stromal cells (MSCs), endothelial cells and immune cells, is crucial for pathogenesis of multiple myeloma (MM) and in asymptomatic monoclonal gammopathies. In these diseases, microRNAs (miRNAs) could be useful as biomarkers for diagnosis, prognosis and evaluation of treatment response. miRNAs can be released to the serum and transferred among MM cells and BM-MSCs as cell-cell communication. Previously, we have showed a serum 14-miRNA signature associated with complete remission (CR) after autologous stem-cell transplantation (ASCT). In this sense, patients in CR with partial recovery of two normal serum miRNA levels, similar to those with monoclonal gammopathy of undetermined significance (MGUS), was associated with better prognosis. The aim of this study was to analyze the miRNAs profile in mesenchymal stromal cells derived from bone marrow of patients with multiple myeloma in different status of the disease, comparing with MGUS controls.Methods: We analyzed samples from 95 patients with MGUS (N=23), MM at diagnosis (N=14), relapsed/refractory MM (N=14), MM in partial response (PR) or very good partial response (VGPR) (N=15), MM in CR (N=24) and healthy donors (N=5). Mononuclear cells from BM samples were cultured in DMEM containing 10% FBS. After a week, non-adherent cells were removed, whereas BM-MSCs were selected by their adherence to the plastic and their phenotype was confirmed by multiparametric flow cytometry. In a first screening phase, we analyzed 670 microRNAs in 20 primary BM-MSC from patients with MGUS (N=4), symptomatic MM (N=8) and MM in CR (N=8). miRNAs differentially expressed were identified according to a supervised analysis using significance analysis of microarrays (SAM) and Student's t-test based on multivariate permutation (with random variance model). miRNAs differentially expressed between groups of patients were validated in the whole cohort of BM-MSC from patients. Paired malignant plasma cells (CD38+) miRNA expression from patients with symptomatic MM as well as miRNA in serum samples paired with BM-MSC samples were also compared. RmiR package was used to identify miRNA targets, cross-correlating the miRNA expression data from the present study with our findings on the gene expression signature (Affymetrix Human Genome U219 array) in 12 BM-MSCs from patients (4 MGUS, 4 symptomatic MM and 4 in CR), based on the predicted targets from TargetScan and miRBase databases.Results: In the screening phase, we identified a miRNA profile of 10 miRNAs (miR-663b, miR-654-3p, miR-206, miR-411*, miR-885-5p, miR-668, miR-638, miR-485-3p, miR-744* and miR-199a) differentially expressed between patients with symptomatic MM and MM in CR (adjusted p-value <0.0001). In the validation phase, miR-485-3p and miR-654-3p resulted differentially expressed in the three groups of patients: MGUS, symptomatic MM and patients in CR (ANOVA test: p=0.0101 and p=0.0228, respectively). The levels of these miRNAs were significantly decreased in patients with MM than in those with MGUS, and these levels seemed to recover when patients achieved CR. These two miRNAs (miR-485-3p and miR-654-3p) were also correlated with all degrees of response in MM and with asymptomatic gammopathies (ANOVA test: p=0.0154 and p=0.0487, respectively). Moreover, paired cross-correlation among these two miRNAs expression with our results in mRNA gene expression profile data showed 324 for miR-485-3p and 265 for miR-654-3p genes (correlation index < -0.8) (Figure 1A and 1B). miR-485-3p and miR-654-3p showed a higher expression in BM-MSC than in MM CD38+ cells, suggesting MSC as cell of origin for these miRNAs. Serum expression of these two miRNAs was concordant with the observed in BM-MSC, with higher in patients in CR and MGUS than in those with symptomatic MM (Figure 1C and 1D). miRNA expression in BM-MSC supernatant as well as the identification of the biological role and validation of the miRNA targets are ongoing.Conclusion: miR-485-3p and miR-654-3p expression in mesenchymal stromal cells from bone marrow in patients with multiple myeloma and asymptomatic monoclonal gammopathies is related to the status of the disease and the response to treatment. These miRNAs are also expressed in serum, resulting in potential biomarkers for disease activity and risk of progression. [Display omitted] DisclosuresRosinol:Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

The Role of Hepatitis C Virus in the Development of Multiple Myeloma: A Case Study

* A.R. and M.L. have contributed equally. INTRODUCTIONDespite great advances in knowledge and treatment in the last decade, multiple myeloma (MM) remains an incurable disease. Several studies suggest its association with infectious pathogens, such as hepatitis C virus (HCV) and Epstein Barr virus (EBV). Here we report on the case of a female MM patient in fourth relapse (after VTD treatment + ASCT+ Lenalodomide maintenance and experimental NK therapy + Lenalidomide and lastly Bendamustine), who achieved stable complete response (CR) once her HCV infection was successfully treated, thus establishing a probable relationship between HCV infection and MM in this patient. METHODSSerum samples from the patient were analyzed before and after antiviral treatment (Sofusbuvir + Ledipasvir). The HCV burden was determined by RT-qPCR. Additionally, viral loads of EBV and Cytomegalovirus were established by qPCR.The number of tumor plasma clones was determined in bone marrow samples by NGS using the Ion Proton sequencer and a depth of 2000 readings/nucleotide. Monoclonal immunoglobulins (mc Ig) were separated from polyclonal Ig by agarose gel electrophoresis and elution. Mc Ig purity was evaluated by isoelectric focusing and immunodetection with anti-IgG antibodies. Their reactivity to different microbial antigens was determined by means of the multiplex infectious-antigen microarray (MIAA) assay and using the commercial kit INNO-LIA HCV score (Fujirebio). RESULTSThe patient, age 66, presented with ISS IIA stage MM (56.7 g/L mc IgG, 2.7 g/L free lambda chains, 2.9 mg/L b2-microglobulin, 90% plasma cells in the bone marrow, without genetic alterations, and osteolytic lesions). HCV infection, causing hepatic toxicity, was discovered in this patient before MM disease. The patient was in third relapse of MM treatment when she received anti-HCV treatment. After antiviral therapy, the HCV load in the patient's serum decreased to undetectable levels (Fig. 1a). Simultaneously, the patient achieved CR of MM, with minimal residual disease (MRD) negativity, as assessed by multiparameter flow cytometry (MFC). NGS revealed the existence of at least one plasmacytic clone, which became MRD negative after anti-HCV treatment (Fig. 1b). Before and after anti-HCV treatment, the patient's serum samples were reactive against antigens of various viruses and other microorganisms (Fig. 1c). Agarose gel electrophoresis of pre-HCV treatment samples showed one band of mc IgG, which disappeared after anti-HCV treatment (Fig. 1d). The patient's mc IgG was purified (Fig. 1e) and analysis of its specificity of recognition revealed that it targeted the HCV core protein (Fig. 1f). Three years have now passed after HCV treatment, and the patient remains in stable CR of MM. CONCLUSIONIn this case of refractory MM where the patient's mc IgG targeted HCV, successful HCV eradication with antivirals Sofosbuvir and Ledipasvir resulted in persistent complete remission of MM as well as of hepatitis C. These results suggest that for HCV-positive individuals, a causal relationship exists between HCV infection and the development of MM, and that MM patients infected with HCV would benefit from early anti-HCV therapy. DisclosuresMartinez Lopez:Celgene: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Immunofixation (IF) in Urine Is Really Necessary to Define Complete Remission in Multiple Myeloma (MM)? a Subanalysis from the Pethema/GEM2012MENOS65 Phase III Clinical Trial

Immunofixation (IF) in Urine Is Really Necessary to Define Complete Remission in Multiple Myeloma (MM)? a Subanalysis from the Pethema/GEM2012MENOS65 Phase III Clinical Trial

NK cells and multiple myeloma-associated endothelial cells: molecular interactions and influence of IL-27.

Angiogenesis represents a hallmark of tumor progression in Multiple Myeloma (MM), a still incurable malignancy. Here we analyzed the activity of cytokine-stimulated NK cells against tumor-associated endothelial cells isolated from bone marrow aspirates of MM patients with active disease (MMECs). We show that NK cells activated with optimal doses of IL-15 killed MMECs thanks to the concerted action of multiple activating receptors. In particular, according to the high expression of PVR and Nectin-2 on MMECs, DNAM-1 actively participated in target recognition. Interestingly, in MMECs the surface density of PVR was significantly higher than that detected in endothelium from patients with MM in complete remission or with monoclonal gammopathy of undetermined significance (MGUS). Importantly, IL-27, which unlike IL-15 does not display pro-angiogenic properties, maintained or increased the NK cell functions induced by suboptimal concentrations of IL-15. NK cell properties included killing of MMECs, IFN-γ production as well as a peculiar increase of NKp46 expression on NK cell surface. Finally, IL-27 showed a striking capability of up-regulating the expression of PD-L2 and HLA-I on tumor endothelium, whereas it did not modify that of PD-L1 and HLA-II.Our results suggest that cytokine-activated endogenous or adoptively transferred NK cells might support conventional therapies improving the outcome of MM patients.

Abstract P1-02-10: Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial

Abstract Background: B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor family and has two ligands, B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). These ligands activate cell proliferation and inhibit apoptosis of normal and malignant B-cells including in multiple myeloma (MM) cell lines. Berenson et al have recently reported that circulating BCMA levels are elevated in B-cell malignancies and can be used to monitor disease and predict PFS and OS for patients with MM, Waldenstroms's macroglobulinemia and chronic lymphocytic leukemia (CLL). On the other hand, recent studies have shown that serum BCMA levels are very low among patients with MM in complete remission with low antibody levels and those with primary immune deficiencies specifically those with combined variable immune deficiency and X-linked agammaglobulinemia. Studies of the potential role of serum BCMA for patients with solid tumors has not been evaluated to date. Methods: The pretreatment serum from 139 patients with hormone receptor-positive metastatic breast cancer who were enrolled in a phase 3 randomized clinical trial of second-line hormone therapy was evaluated using an ELISA for BCMA. The BCMA ELISA was from R&amp;D Systems (Minneapolis, MN). Serum BCMA was correlated with TTP using categorical serum BCMA cutpoints. Results: Pretreatment serum BCMA levels had a median of 55.61 ng/ml, an interquartile range of 34.20 and 78.79 ng/ml, and full range from 3.99 to 1193.26 ng/ml. In univariate analysis for TTP, reduced serum BCMA correlated with shorter TTP at the following dichotomous cutpoints: 15 ng/ml [HR=2.60, p=0.064, n=6 (4.3%) of patients below cutpoint]; 20 ng/ml [HR=2.88, p=0.005, n=10 (7.2%) of patients below cutpoint]; 25 ng/ml [HR=2.16, p=0.023, n=13 (9.4%) of patients below cutpoint]; and 30 ng/ml [HR=1.77, p=0.016, n=27 (19.4%) of patients below the cutpoint]. Conclusions: In a phase 3 randomized clinical trial of second-line hormone therapy among patients with hormone receptor-positive metastatic breast cancer, reduced pretreatment serum BCMA was associated with shorter TTP. This may be due to the association of reduced serum BCMA with immune deficiency; and, thus, lead to shorter TTP among patients with metastatic breast cancer. Evaluation of serum BCMA as a new biomarker to predict outcomes for breast cancer and other solid tumor patients deserves further study. Citation Format: Ali SM, Leitzel K, Li M, Udd K, Wang J, Sanchez E, Chen H, Berenson J, Lipton A. Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-10.

Multicentered patient-based evidence of the role of free light chain ratio normalization in multiple myeloma disease relapse.

The normalization of free light chain ratio (FLCr) has been introduced as a marker of stringent complete remission (CR) of multiple myeloma (MM). There is currently a lack of literature assessing the role of FLCr on MM disease progression and remission status. A multicentered retrospective review of 125 patients with MM in CR and various FLCr values was completed. Parameters of interest included patient demographics, FLCr values, complete remission (CR)/relapse status, and time to progression (TTP). The FLCr values were recorded to provide time-dependent findings on the role of FLCr on progression-free survival and overall survival (OS). The mean follow-up time of 125 patients from five hospitals in the Czech Republic was 31months. A total of 47.2% of patients relapsed (54 of 125) during the follow-up period. The median TTP of patients with normal FLCr (n=66) was 54.4 and 40.2months for patients with abnormal FLCr (n=59) (P=0.217). None of the patients reached median overall survival regardless of FLCr values (P=0.821). In the subgroup of newly diagnosed patients after upfront autologous stem cell transplantation (ASCT), there were 55.6% of patients (35 of 63) with normal FLCr and 44.4% (28 of 64) with abnormal FLCr. A total of 34.9% of patients (22 of 63) relapsed in this subgroup. Within the abnormal FLCr patients, a median TTP was 56.3months, but no median TTP was reached among the normal FLCr patients (P=0.746). Median OS in patients with normal (nFLCr) and abnormal FLCr (aFLCr) was not reached (P=0.787). We did not observe any benefit from FLCr normalization in CR in myeloma patients in terms of progression-free survival or overall survival.

Case for diagnosis

Cutaneous involvement associated to multiple myeloma varies from 5 to 10% of cases and is infrequently recognized. Cutaneous metastatic plasmacitomas are rare. We present the case of a 72-year-old man with multiple myeloma in complete remission since 2 years ago with cutaneous tumors on the trunk and face. A cutaneous biopsy was consistent with plasmacytoma. The patient was treated with melphalan, prednisolone and radiotherapy. Despite optimal therapeutic response of the lesions, the disease progressed, with the appearance of new extra-cutaneous plasmocytomas. The cutaneous metastatic plasmocytomas were the first sign of progression of the disease.

Allogeneic Hematopoietic Cell Transplantation Using Fludarabine, Melphalan and Bortezomib (Flu/Mel/Vel) Conditioning For Consolidation Of VGPR Or CR In Myeloma

BackgroundThe use of allogeneic hematopoietic cell transplantation (HCT) in multiple myeloma (MM) remains controversial but the role of allogeneic HCT for consolidation of initial response in the era of novel agents has not been defined. Therefore, we conducted a phase 2 study of allogeneic HCT in MM patients achieving at least very good partial response (VGPR) after initial therapy. MethodsSeventeen MM patients with first VGPR or complete remission (CR) received allogeneic HCT between 01/2010 and 04/2013 at Moffitt Cancer Center (NCT 00948922). Eligible patients were age ≤ 60, achieving ≥ VGPR, and have suitable HLA-matched donors. Six patients received bortezomib plus lenalidomide induction, 7 received bortezomib-based, and 4 received lenalidomide-based induction. Three patients (18%) underwent autologous HCT with melphalan plus bortezomib conditioning (melphalan 100 mg/m2 for 2 days followed by bortezomib 1.3 mg/m2) following induction therapies in order to achieve further cytoreduction. Conditioning regimen before allogeneic HCT consisted of fludarabine 30 mg/m2 for 4 days and melphalan 70 mg/m2 for 2 days followed by a single dose of bortezomib 1.3 mg/m2 (Flu/Mel/Vel). GVHD prophylaxis was tacrolimus plus either methotrexate (n=9), or mycophenolate mofetil (n=4), or sirolimus (n=4). No maintenance therapy was prescribed after allogeneic HCT. ResultsThe median age at transplant was 51 (25 – 57) years and the median time from initial therapy to transplant was 236 (126 – 418) days. Seven patients (41%) have high-risk cytogenetics/FISH. The median number of prior therapy was 1. Disease status at the time of allogeneic HCT was VGPR (n=8), CR (n=3), or stringent CR (n=6). All patients received unmanipulated peripheral blood stem cell grafts from HLA-matched sibling donors (n=7) or 8/8 HLA-matched unrelated donors (n=10). All patients achieved neutrophil engraftment with a median of 14 (11 - 18) days and platelet engraftment with a median of 17 (13 - 21) days. All patients established stable donor cell chimerism. Best responses after allogeneic HCT were CR (n=2), sCR (n=13), and disease progression (n=2). The 2-year progression-free survival estimate is 80% (95%CI: 51 – 98) for standard-risk group and 51% (95%CI: 15 – 87) for high-risk, respectively. With a median follow up of 18 (3 - 43) months for surviving patients, the 2-year overall survival estimate is 88% (95%CI: 68 – 99). The cumulative incidence of non-relapse mortality was 6% (95%CI: 0.0 – 22) at 100 days and 13% (95%CI: 1 – 34) at 1 year, respectively. The cumulative incidence of grades 2-4 acute GVHD at day 100 was 41% (95% CI: 20 – 65) and the cumulative incidence of moderate to severe chronic GVHD at 1 year was 8.0% (95% CI: 0.0 – 29). ConclusionsThese results indicate that allogeneic HCT for MM in VGPR or CR as consolidation achieves favorable disease control. The study is ongoing to assess long-term safety of this modality. A multicenter trial is planned to evaluate the utility of allogeneic HCT in high-risk MM.Overall Survival▪Months Disclosures:Off Label Use: bortezomib - transplant conditioning. Alsina:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Differential humoral responses against heat-shock proteins after autologous stem cell transplantation in multiple myeloma

Heat-shock proteins (HSP) are important molecules in the pathogenesis of multiple myeloma (MM). Their blockages by drugs or cellular immune response have been investigated, and a possible association with the presence of oligoclonal bands (OB) has been postulated in patients with MM after allogenic stem cell transplantation. The aim of the present study was to ascertain the serum antibody levels against three HSP (60, 70 and 90) by ELISA in patients with MM in complete remission after autologous stem cell transplantation (ASCT), with or without OB, and compare them with those patients with stable gammopathy of undetermined significance (MGUS) and healthy controls. Our results in samples after ASCT showed no differential levels of anti-HSP according to the presence or absence of the oligoclonal response. However, higher levels of anti-HSP90 were found in patients with stable MGUS in comparison with MM patients (p = 0.004). In the same line, a longer progression-free survival was observed in those patients who presented higher anti-HSP90 levels after ASCT (p = 0.042). These results suggest, for first time, the potential of anti-HSP90 humoral immune response for long-term control of malignant plasma cell disorders.

High Dose Therapy and Autologous Stem Cell Transplantation Results in Good Outcomes and Acceptable Toxicities in Elderly Patients with Non-Hodgkin's Lymphoma

High Dose Therapy and Autologous Stem Cell Transplantation Results in Good Outcomes and Acceptable Toxicities in Elderly Patients with Non-Hodgkin's Lymphoma

Prognostic Impact of Serum Immunoglobulin Heavy/Light Chain Ratio in Patients with Multiple Myeloma in Complete Remission after Autologous Stem Cell Transplantation

Immunoglobulin heavy/light chain (HLC) ratios were studied in 37 patients with multiple myeloma in complete remission after autologous hematopoietic stem cell transplantation. Increased IgAκ/IgAλ and IgMκ/IgMλ ratios were associated with longer progression-free survival (P = .006 and .01, respectively). Astatistical trend toward a longer overall survival was also observed for the IgAκ/IgAλ ratio (P = .068). Considering the original immunoglobulin isotype, our results indicate that an increased κ/λ ratio of the uninvolved isotype is associated with longer progression-free survival and overall survival. This is the first report demonstrating the association between the HLC ratio and sustained complete remission in patients with multiple myeloma. Our results suggest that the HLC ratio is a surrogate marker of immune recovery after myeloablative transplantation, rather than as a marker of minimal residual disease.

Serum free light chains and oligoclonal bands in patients with multiple myeloma and autologous stem cell transplantation

To establish stringent complete remission (SCR) in patients with multiple myeloma (MM), it is currently recommended to obtain a normal serum free light chains (sFLC) ratio. The appearance of serum oligoclonal bands (OB) after autologous stem cell transplantation (ASCT) is considered a favorable prognostic factor. The objective of this study was to examine sFLC for assessing SCR in patients with MM, and ASCT with OB. We also examined how capillary electrophoresis (CE) compares with agarose gel electrophoresis (Aga) in identifying oligoclonal bands. Out of 238 patients studied in our institution between April 1992 and December 2008 a serum protein electrophoresis (SPE) was performed by means of CE and sFLC determination on 37 patients with MM in complete remission (CR), ASCT and OB presence were assigned by conventional Aga electrophoresis and IF. Statistically significant differences (SSD) were found when comparing CE vs. Aga, regarding BO visualization in SPE, favoring the latter. In connection with sFLC, the group of patients with an abnormal ratio presented elevated values in the γ-globulin zone of the SPE, whereas the group of patients with a normal ratio of sFLC presented with normal values resulting in SSD between the groups. It is essential to perform immunofixation to certify the presence of OB, especially if CE is used as it is difficult to distinguish them using this method. A normal sFLC was observed in most of the patients with OB and normal values of the SPE γ-globulin zone. The above-mentioned information might demonstrate a limitation of sFLC test in SCR evaluation for patients with MM, ASCT and CR if OB has been detected.

Multiple Myeloma in Serologic Complete Remission after Autologous Stem Cell Transplantation: Impact of Bone Marrow Plasma Cell Assessment by Conventional Morphology on Disease Progression

The current definition of complete remission (CR) in multiple myeloma (MM) requires a negative serum and urine immunofixation (IFE) and <5% bone marrow plasma cells (BMPCs). The aim of this study was to determine the value of BMPCs count by standard microscopic evaluation in patients with MM in serologic CR after autologous stem cell transplantation (ASCT). Thirty-five patients with a median follow-up after ASCT of 7.3 years were studied. The percentage of BMPCs was an independent predictor of progression in multivariate model (hazard ratio 2.02, P = .009). Patients with >1.5% BMPCs (median: 0.8%) after ASCT had an increased risk of progression (P = .016) and a trend toward a shorter survival (P = .195). In conclusion, conventional morphology of bone marrow is a useful and rapid tool as a first step to assess the residual tumor mass in patients with MM in CR after ASCT, and it constitutes a strong predictor for disease progression.