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In the phase 3 ANDROMEDA trial, patients treated with daratumumab, bortezomib, cyclophosphamide, and dexamethasone (D-VCd) had significantly higher rates of organ and hematologic response compared with patients who received VCd alone. Here, we present patient-reported outcomes (PROs) from the ANDROMEDA trial. PROs were assessed through cycle 6 using three standardized questionnaires. Treatment effect through cycle 6 was measured by a repeated-measures, mixed-effects model. The magnitude of changes in PROs versus baseline was generally low, but between-group differences favored the D-VCd group. Results were generally consistent irrespective of hematologic, cardiac, or renal responses. More patients in the D-VCd group experienced meaningful improvements in PROs; median time to improvement was more rapid in the D-VCd group versus the VCd group. After cycle 6, patients in the D-VCd group received daratumumab monotherapy and their PRO assessments continued, with improvements in health-related quality of life (HRQoL) reported through cycle 19. PROs of subgroups with renal and cardiac involvement were consistent with those of the intent-to-treat population. These results demonstrate that the previously reported clinical benefits of D-VCd were achieved without decrement to patients' HRQoL and provide support of D-VCd in patients with AL amyloidosis.

Waldenström macroglobulinaemia (WM) is characterized by recurrent somatic mutations in MYD88 and CXCR4 genes. However, limitations arise when analysing these mutations in IgM monoclonal gammopathy of undetermined significance (MGUS) or smouldering WM (SWM) given the lower tumour load. Here, we used droplet digital polymerase chain reaction (ddPCR) to analyse MYD88 L265P and CXCR4 S338* mutations (C1013G and C1013A) in unsorted bone marrow (BM) or cell-free DNA (cfDNA) samples from 101 IgM MGUS and 69 SWM patients. ddPCR was more sensitive to assess MYD88 L265P compared to allele-specific PCR, especially in IgM MGUS (64% vs 39%). MYD88 mutation burden correlated with other laboratory biomarkers, particularly BM infiltration (r = 0.8; p 0.001). CXCR4 C1013G was analysed in MYD88-mutated samples with available genomic DNA and was detected in 19/54 (35%) and 18/42 (43%) IgM MGUS and SWM cases respectively, also showing correlation with BM involvement (r = 0.9; p 0.001). ddPCR also detected 8 (38%) and 10 (63%) MYD88-mutated cfDNA samples in IgM MGUS and SWM respectively. Moreover, high BM mutation burden (≥8% MYD88 and ≥2% CXCR4) was associated with an increased risk of progression to symptomatic WM. We show the clinical applicability of ddPCR to assess MYD88 and CXCR4 in IgM MGUS and SWM and provide a molecular-based risk classification.

The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (-sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated β2 -microglobulin levels in the +sIFE group. With a median follow-up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression-free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2-5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B-cell biology and the tumour microenvironment.

Background Warm autoimmune hemolytic anemia (WAIHA) is a disorder with a usually good response to corticosteroid treatment, whereas in some cases first-line treatment's response is poor and other therapies such as intravenous immunoglobulins (IVIGs), rituximab, or splenectomy must be applied. Study design and methods Herein, we describe two patients with severe WAIHA treated at our center, who obtained a response after therapeutic plasma exchanges (TPEs) combined with low doses of IVIG. Results The first patient was an 18-year-old man with no relevant past medical history who was diagnosed with WAIHA. The patient presented a progressive clinical worsening despite treatment with prednisone, IVIG, and rituximab. After starting TPEs, signs of hemolysis rapidly improved and hemoglobin started to recover. The second patient was a 38-year-old man with a past history of immune thrombocytopenia and WAIHA. The patient presented a new flare of WAIHA, with no response after 2 weeks of treatment with corticosteroids, IVIG, and rituximab. After initiation of TPEs, the patient had an improvement in hemolysis biomarkers and recovery of hemoglobin concentration. Conclusion Combination of TPEs with rituximab and IVIG might be considered as a therapeutic option in patients with severe WAIHA without response to corticosteroid and IVIG treatment.

Carfilzomib has been associated with the development of thrombotic microangiopathy (TMA) in relapsed/refractory multiple myeloma patients, a severe disease with no currently available aetiological treatment. We evaluated the potential role of terminal complement pathway in four patients with carfilzomib-induced TMA. Membrane attack complex (C5b-9) deposition on endothelial cells in culture exposed to plasma from patients during the acute phase of the disease suggests complement overactivation as a mechanism of potential endothelial damage in three out of four patients. If confirmed in larger cohorts, C5b-9 evaluation will allow early identification of patients who could benefit from complement blockade and treatment monitoring.

We analyzed 171 patients with asymptomatic IgM monoclonal gammopathies (64 with IgM monoclonal gammopathy of undetermined significance—MGUS and 107 with smoldering Waldenström macroglobulinemia - SWM) who had a bone marrow (BM) evaluation performed at diagnosis. Abnormal free-light chain ratio (53% vs. 31%) and MYD88 mutation prevalence (66% vs. 30%) were higher in patients with SWM. No other differences were found among groups. With a median follow-up of 4.3 years, 14 patients progressed to Waldenström macroglobulinemia, 1 to amyloidosis, and 28 died without progression. The MYD88 mutation was found in 53% of patients (available in 160 patients). Multivariate analysis showed that immunoparesis (subhazard ratio—SHR 10.2, 95% confidence interval—CI: 4.2–24.8, p &lt, 0.001) and BM lymphoplasmacytic infiltration ≥ 20% (SHR: 6, 95% CI: 1.6–22.1, p = 0.007) were associated with higher risk of progression. We developed a risk model based on these two risk factors. In the absence of both variables, an ultra-low risk group was identified (SHR 0.1, 95% CI 0.02–0.5, p = 0.004), with 3% and 6% of cumulative incidence of progression at 10 and 20 years, respectively. Bootstrap analysis confirmed the reproducibility of these results. This study finds immunoparesis and BM infiltration as biomarkers of progression as well as a low-risk group of progression in asymptomatic IgM monoclonal gammopathies.

PURPOSE Oral melphalan and dexamethasone (MDex) were considered a standard of care in light-chain (AL) amyloidosis. In the past decade, bortezomib has been increasingly used in combination with alkylating agents and dexamethasone. We prospectively compared the efficacy and safety of MDex and MDex with the addition of bortezomib (BMDex). METHODS This was a phase III, multicenter, randomized, open-label trial. Patients were stratified according to cardiac stage. Patients with advanced cardiac stage (stage IIIb) amyloidosis were not eligible. The primary end point was hematologic response rate at 3 months. This trial is registered with ClinicalTrials.gov identifier NCT01277016 . RESULTS A total of 109 patients, 53 in the BMDex and 56 in the MDex group, received ≥ 1 dose of therapy (from January 2011 to February 2016). Hematologic response rate at 3 months was higher in the BMDex arm (79% v 52%; P = .002). Higher rates of very good partial or complete response rates (64% v 39%; hazard ratio [HR], 2.47; 95% CI, 1.30 to 4.71) and improved overall survival, with a 2-fold decrease in mortality rate (HR, 0.50; 95% CI, 0.27 to 0.90), were observed in the BMDex arm. Grade 3 and 4 adverse events (the most common being cytopenia, peripheral neuropathy, and heart failure) were more common in the BMDex arm, occurring in 20% versus 10% of cycles performed. CONCLUSION BMDex improved hematologic response rate and overall survival. To our knowledge, this is the first time a controlled study has demonstrated a survival advantage in AL amyloidosis. BMDex should be considered a new standard of care for AL amyloidosis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated coronavirus disease 2019 (COVID-19) is primarily manifested as a respiratory tract infection, but may affect and cause complications in multiple organ systems (cardiovascular, gastrointestinal, kidneys, haematopoietic and immune systems), while no proven specific therapy exists. The challenges associated with COVID-19 are even greater for patients with light chain (AL) amyloidosis, a rare multisystemic disease affecting the heart, kidneys, liver, gastrointestinal and nervous system. Patients with AL amyloidosis may need to receive chemotherapy, which probably increases infection risk. Management of COVID-19 may be particularly challenging in patients with AL amyloidosis, who often present with cardiac dysfunction, nephrotic syndrome, neuropathy, low blood pressure and gastrointestinal symptoms. In addition, patients with AL amyloidosis may be more susceptible to toxicities of drugs used to manage COVID-19. Access to health care may be difficult or limited, diagnosis of AL amyloidosis may be delayed with detrimental consequences and treatment administration may need modification. Both patients and treating physicians need to adapt in a new reality.

Background. Autologous stem cell transplantation (ASCT) remains the standard of care for young multiple myeloma (MM) patients; indeed, at-home ASCT has been positioned as an appropriate therapeutic strategy. However, despite the use of prophylactic antibiotics, neutropenic fever (NF) and hospital readmissions continue to pose as the most important limitations in the outpatient setting. It is possible that the febrile episodes may have a non-infectious etiology, and engraftment syndrome could play a more significant role. The aim of this study was to analyze the impact of both G-CSF withdrawal and the addition of primary prophylaxis with corticosteroids after ASCT.Methods. Between January 2002 and August 2018, 111 MM patients conditioned with melphalan were managed at-home beginning + 1 day after ASCT. Three groups were established: Group A (n = 33) received standard G-CSF post-ASCT; group B (n = 32) avoided G-CSF post-ASCT; group C (n = 46) avoided G-CSF yet added corticosteroid prophylaxis post-ASCT.Results. The incidence of NF among the groups was reduced (64%, 44%, and 24%; P P = 0.07). The most important variables identified for NF were: HCT-CI > 2 (OR 6.1; P = 0.002) and G-CSF avoidance plus corticosteroids (OR 0.1; P P = 0.04) and G-CSF avoidance plus corticosteroids (OR 0.07; P = 0.05).Conclusions. G-CSF avoidance and corticosteroid prophylaxis post ASCT minimize the incidence of NF in MM patients undergoing at-home ASCT.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 45-year-old man was diagnosed in March 2010 with stage III immunoglobulin G kappa multiple myeloma (MM) after presenting with bone pain as a result of multiple lytic bone lesions and T12 vertebral collapse. Laboratory work-up showed a serum M protein of 72 g/L and a 24-hour kappa light-chain urine protein excretion of 730 mg, hemoglobin of 10.2 g/dL, serum albumin of 49 g/L, serum β2-microglobulin of 6.4 mg/L, serum creatinine level of 1.6 mg/dL with an estimated glomerular filtration rate (eGFR) of 47 mL/min/1.73 m2, and normal serum calcium and lactate dehydrogenase (LDH) levels. His bone marrow contained 58% plasma cells, which showed the 17p deletion abnormality (Fig 1). He was treated with vertebroplasty and alternating chemotherapy with carmustine, vincristine, cyclophosphamide, melphalan, and prednisone and vincristine, carmustine, doxorubicin and dexamethasone. Because of progressive disease, salvage therapy with bortezomib and dexamethasone was administered with no response. The patient was then switched to lenalidomide and dexamethasone, which yielded minimal response. He underwent autologous stem-cell transplantation (ASCT) with melphalan 200 mg/m2 as high-dose therapy in February 2011, which led to a partial response, but in December 2011, progressive disease was documented, and the patient was enrolled in a clinical trial of carfilzomib monotherapy, with stable disease for 33 cycles. In October 2014 serum M protein rose to 38.6 g/L, with 24-hour kappa light-chain urine protein excretion of 840 mg, serum creatinine of 2.1 mg/dL, and an eGFR of 41 mL/min/1.73 m2. He presented to discuss ongoing treatment options.

Simple Summary Monoclonal gammopathy of clinical significance (MGCS) is a recently recognized clinical-pathological entity. Symptoms are caused by the presence of a monoclonal protein leading to high comorbidity. The affected organs vary according to the target antigen However, as most of the knowledge relies on case reports or short series; there is a lack of consensus regarding treatment approach. Here, we discuss MGCS other than renal (skin, ocular, neurologic, and bleeding disorders). We provide insights into the pathophysiology, diagnosis, treatment, and follow-up based on clinical cases. Finally, we discuss future directions in this field, such as potential novel therapeutic targets and prognosis of patients with MGCS. Abstract Monoclonal gammopathy of undetermined significance (MGUS) is defined as the presence of a monoclonal protein (M-protein) produced by a small amount of plasma cells. The majority of patients remain asymptomatic; however, a fraction of them develop clinical manifestations related to the monoclonal gammopathy despite not fulfilling criteria of multiple myeloma or other lymphoproliferative disorder. These patients constitute an emerging clinical issue coined as monoclonal gammopathy of clinical significance (MGCS). The mechanisms involved are poorly understood, and literature is scarce regarding management. The clinical spectrum involves symptoms related to renal, neurologic, skin, ocular, or bleeding manifestations, requiring a multidisciplinary approach. Treatment strategies rely on the basis of symptomatic disease and the M-protein isotype. In this review, we focus on MGCS other than renal, as the latter was earliest recognized and better known. We review the literature and discuss management from diagnosis to treatment based on illustrative cases from daily practice.

Immunoparesis (IP) is a risk factor associated with an unfavourable outcome in several plasma cell disorders. It has been suggested that its presence in light-chain (AL) amyloidosis could be associated with worse prognosis. However, the relevance of IP after treatment has not been evaluated to date. The aim of this study was to determine the prognostic impact of IP at diagnosis and one year after treatment onset in patients with AL amyloidosis.The clinical records of 69 patients with AL amyloidosis treated at a single institution from January 2006 to January 2016 were included in the study.IP was observed in 27.5% of patients at diagnosis. The presence of IP was associated with a lower probability to achieve very good partial response or better after first-line treatment (37.8% versus 62.2%; p = .04). However, only in the group of patients treated with autologous stem cell transplantation (ASCT), the presence of IP resulted in a shorter progression-free survival (PFS) (30.2 months versus not reached [NR]; p = .02) but not in overall survival (OS). Persistence of IP at one year after treatment onset was identified in only four (9.8%) of the 41 evaluable patients. In the ASCT group, the absence of IP at one year after treatment onset resulted in a longer median PFS and OS (NR versus 22.6 months; p = .006; and NR versus 35.2 months; p .001; respectively). In the multivariate analysis, the absence of IP at one year after treatment onset was independently associated with longer survival.IP at diagnosis has a negative impact on survival while its absence at one year after treatment is an independent marker for long-term survival.

Background Monoclonal 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. Methods Serum 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 Results In 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. Conclusions This 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.

Purpose: T-cell immunoreceptor with Ig and ITIM domain (TIGIT) blockade could represent an alternative therapeutic option to release the immune response in patients with multiple myeloma. Here we analyzed the expression of TIGIT and its ligands poliovirus receptor (PVR) and nectin-2 in the bone marrow (BM) of patients with monoclonal gammopathies and the efficacy of TIGIT blockade activating antimyeloma immunity. Experimental Design: Expression levels of TIGIT and its ligands were characterized by flow cytometry and ELISA. TIGIT blockade was analyzed in in vitro functional assays with peripheral T cells. BM cells were studied with NanoString technology, real-time PCR, and ex vivo patient BM cell models. Results: TIGIT and its ligands are highly expressed in the BM of patients with multiple myeloma, suggesting that may play a role in restraining immune activation. TIGIT blockade depleted FoxP3+ Tregs while increasing proliferation of IFNγ-producing CD4+ T cells from patients with multiple myeloma. PVR ligation inhibited CD8+ T-cell signaling and cell proliferation which could be overcome with anti-TIGIT mAb. However, BM cells showed a remarkable heterogeneity in immune signature. Accordingly, functional ex vivo BM assays revealed that only some patients respond to checkpoint blockade. Thus, response to TIGIT blockade correlated with low frequency of TIGIT+ cells and high nectin-2 expression on malignant plasma cells. Conclusions: TIGIT blockade efficiently reinvigorated peripheral T cells from patients with multiple myeloma. However, in the BM, the efficacy of blocking anti-TIGIT mAb to achieve tumor cell death may depend on the expression of TIGIT and nectin-2, becoming potential predictive biomarkers for identifying patients who may benefit from TIGIT blockade.

Background Asymptomatic monoclonal gammopathies, such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM), are clinical conditions that usually precede symptomatic multiple myeloma. Therefore, risk stratification is crucial owing to the heterogeneous progression rate among these patients. In previous years, suppression of the uninvolved chain of specific heavy/light chain (HLC) pairs in serum has been identified as a new risk factor in MGUS. The aim of the present study was to investigate the prognostic effect of involved and uninvolved HLC pairs and HLC ratios on progression in a series of patients with MGUS and SMM. Patients and Methods All specific serum HLC pairs were measured in 114 patients diagnosed with SMM (n = 27) and MGUS (n = 87) from 1983 to 2003. Also, the HLC ratios were calculated. Results Progression to symptomatic multiple myeloma was observed in 13 patients (8 with SMM and 5 with MGUS). The risk of progression was 6 times greater in those with SMM ( P = .001) and 4 times greater for those with the IgA isotype ( P = .01). The suppression of any IgM isotypes (IgMκ or IgMλ) in patients with IgA or IgG gammopathy or any IgA isotypes (IgAκ or IgAλ) in patients with IgG or IgM gammopathy was associated with a shorter time to progression to symptomatic gammopathy ( P = .001 and P = .03, respectively). On multivariate analysis, the evolving pattern and suppression of any IgM HLC pair remained significant. Conclusion HLC ratios could be a valuable tool in the risk stratification of patients with SMM and MGUS, especially patients with IgG isotypes.

Autologous stem cell transplant (ASCT) has demonstrated to be an effective treatment for patients with light-chain (AL) amyloidosis. However, a high transplant-related mortality (TRM) rate was reported in previous series of patients and questioned the role of transplant in this disease. Recently, experienced groups have shown a significant TRM decrease that has been attributed to an accurate selection of patients. Moreover, application of several supportive measures has decreased toxicity over amyloid-involved organs. We analyzed a series of 66 patients with AL amyloidosis, who underwent ASCT at a single institution and evaluated the impact of these measures beyond patient selection. Four temporary groups were established: group-A (non-selection plus post-transplant G-CSF use) with 29 patients, group-B (selection) with 13, group-C (selection and G-CSF avoidance) with 14, and group-D (selection, G-CSF avoidance and corticosteroid's prophylaxis) with 10. A decreasing TRM was observed over time from group-A (38%), to group-D (0%); p = 0.02. We also observed a progressive increase of three-year OS from 62% in group-A to 100% in group-D; p = 0.049. On the multivariate analysis, cardiac involvement was the only independent predictor of survival. Therefore, tailored selection policy together with transplant supportive measures have allowed ASCT to be a safe procedure in AL amyloidosis.

Objective The presence of plasmacytomas (Ps) in patients with multiple myeloma (MM) is associated with a poor outcome, both in patients treated conventionally and in patients treated with novel agents. Two types of plasmacytomas have being recognized: paraskeletal plasmacytomas (PPs) and extramedullary plasmacytomas (EMPs), being the incidence of EMPs lower but with worse prognosis. Our aim has been to analyze the efficacy of the pomalidomide-dexamethasone combination in this patient profile. Method In the present study, the efficacy of pomalidomide and dexamethasone in 21 patients from nine hospitals of Catalonia (Spain), with relapsed or refractory MM and Ps, was analyzed. For this purpose, we describe the evolution of paraprotein in serum and urine and the size of plasmacytomas during treatment with pomalidomide-dexamethasone. Results While 34% of the patients achieved a paraprotein response, only two patients with PPs (9%) responded (RC and PR). There were no responses among patients with EMPs. The median progression-free survival from the start of treatment with pomalidomide/dexamethasone was only 1.7 months and the median overall survival of 4.5 months. Conclusion In conclusion, pomalidomide and dexamethasone has limited efficacy in patients with advanced MM and soft-tissue plasmacytomas.

OBJECTIVES Prognosis of immunoglobulin light-chain (AL) amyloidosis depends mainly on the presence of cardiac involvement and the disease burden. A higher bone marrow plasma cell (BMPC) burden has been recognized as an adverse prognostic factor. The aim of our study was to analyze the correlation between the BMPC infiltration, clinical features and outcomes in patients with AL amyloidosis. METHODS The clinical records of 79 patients with AL amyloidosis treated at a single institution. RESULTS Median BMPC infiltration at diagnosis was 11% and significantly correlated with the serum free light-chain difference (p

Purpose: A distinctive new group of polymorphisms is constituted by single-nucleotide polymorphism (SNP) in miRNA processing machinery in miRNA precursor molecules and in miRNA-binding sites, known as miRSNPs. The aim of this study was to ascertain the prognostic impact of six miRSNPs in patients with multiple myeloma and analyze the functional consequences. Experimental Design: One hundred and thirty-seven patients with chemosensitive multiple myeloma (73M/64F) intensified with autologous stem cell transplantation (ASCT) were studied. The median follow-up was 4 years. The genes and SNPs evaluated in genomic DNA by allelic discrimination were KRT81 (rs3660), AFF1 (rs17703261), FAM179b (rs1053667), and MIR196A2 (rs11614913) for miRNA target genes and TRBP (rs784567) and XPO5 (rs11077) for miRNA biogenesis pathway. Results: Overall survival (OS) was significantly longer in patients with KRT81 rs3660 C/C variant (P = 0.037). Functional analysis showed that the presence of C variant in KRT81 3′ untranslated region (UTR) is related with a reduction of the protein levels. Moreover, the reduction of KRT81 protein levels by siRNA in multiple myeloma cell lines is related to a decreased proliferation. On the other hand, OS was significantly longer in patients with C/C or A/C variant in XPO5 rs11077 (P = 0.012). There was also a significantly longer progression-free survival (PFS) for this SNP (P = 0.013). This SNP retained its prognostic impact on PFS and OS in a multivariate regression analysis (P = 0.028 and P = 0.014, respectively). Conclusion: This is the first report that relates miRSNPs with prognosis in multiple myeloma either in a keratin gene (KRT81), target of diverse miRNA multiple myeloma clusters, or in the miRNA biogenesis pathway–related protein exportin-5. Clin Cancer Res; 18(13); 3697–704. ©2012 AACR.

Autologous stem cell transplantation (ASCT) is the therapy of choice in systemic light-chain (AL) amyloidosis, a disease in which the kidney is involved in more than two-thirds of patients at diagn...

Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.

Abstract 4041 Background: Thalidomide was the first of the so-called new drugs incorporated in the treatment of multiple myeloma (MM). In this era of emerging novel agents, there is a real need for increased knowledge of the pre-treatment genetic profile of patients who will potentially benefit from each drug. The analysis of polymorphisms in drug metabolism pathways and in immune system genes can help to identify patients with possible different treatment response and outcome. Single nucleotide polymorphisms (SNPs) are the most frequent type of genomic polymorphisms and are involved in chemotherapy response in different tumors, including MM. We examined SNPs in 12 genes and correlated our findings with response, toxicity and overall survival (OS) to thalidomide in patients with relapsed MM. Methods: Twenty-eight patients (13M/15F; median age 59 years, range 40 to 82 years) with relapsed or refractory MM from November 1999 to December 2003 were treated with single agent thalidomide at a single institution. The median duration of thalidomide treatment was 4 months and the median dose was 400 mg/day. Median follow-up for alive patients was 103 months (range 86 to 112). Genomic DNA was isolated from bone marrow slides using a commercial assay (Qiagen). SNPs were analyzed by TaqMan assay in an ABI Prism 7500 Sequence Detection system (Applied Biosystems). The genes explored were those related to multidrug resistance (ABCB1 [rs3842, rs1045642]), drug metabolic pathways (NR1I2 [rs1523130, rs1523127], GSTT1 [rs4630], SULT1C2 [rs1402467]), DNA repair systems (XPA [rs1800975], ERCC1 [rs735482], ERCC2 [rs13181], ERCC5 [rs17655, rs1047768], XRCC1 [rs25487], XRCC5 [rs1051677, rs1051685], TOP2A [rs13695]) and cytokines (VEGFA [rs10434, rs2010963]). Results: Partial response (PR) was attained in 17.9% (5/28) and minimal response (MR) in 28.6% (8/28), while 3 (10.7%) and 12 (42.9%) patients showed no response (NR) or progressive disease (PD), respectively. The response rate (PR+MR vs. NR+PD) to thalidomide was higher (66.7%) in patients with hetero- (AC) or homozygous (CC) SNPs in ERCC1 (rs735482) than in those with wild type (AA) (33.3%) (p=0.006). Patients with the ERCC5 heterozygous SNP rs17655 (CG) had a higher response rate (77.8%) than those with the homozygous SNP (GG) or wild type (CC) (31.6%) (p=0.04). Patients with heterozygous XRCC5 (AG) polymorphism rs1051685 showed a higher response rate (100%) than those with wild type (AA) (34.8%) (p=0.013). Longer OS was associated with the homo- and the heterozygous SNP in ERCC1 (AC + CC vs. AA; p=0.005) and with the heterozygous SNP in XRCC5 (rs1051685) (AG vs. AA; p=0.02) (Figures 1 and 2). A trend to longer OS was also observed in patients with polymorphisms in XRCC1 (p=0.06). The heterozygous polymorphism in GSTT1 (CT vs. TT) was associated with a lower frequency of thalidomide-induced peripheral neuropathy (p=0.04). Conclusion: SNPs in ERCC1 and XRCC5 were strongly associated with higher response rate and longer OS to thalidomide in patients with relapsed/refractory MM. SNPs in ERCC5 were also associated with greater response rate. Since the polymorphism in XRCC1 was not related to a better response to thalidomide, it can be speculated that the trend to prolonged OS could be related to other molecular mechanisms. Our findings could be useful to identify patients with MM who are more likely to benefit from thalidomide-based therapies. Disclosures: Cibeira: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosiñol:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blade:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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 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. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

INTRODUCTION: Multiple myeloma (MM) is the second most common blood cancer, with estimated 5-year overall survival (OS) rate of 50%. Survival rates have steadily increased over last decades due to the introduction of high-dose melphalan with autologous stem cell transplantation (ASCT) and newer drugs (thalidomide, lenalidomide and bortezomib). Nevertheless, most studies in MM do not reflect the true real-world population. The aims of the present study were to analyze the survival outcomes, as well as to determine the incidence and causes of early mortality and time to next therapy (TTNT) over time, in patients diagnosed with MM, treated and followed at a single institution. METHODS: We reviewed the clinical records of patients with MM diagnosed at a single institution from January 1970 to December 2015. One thousand one hundred sixty-one patients (591 [50.9%] male; median age at diagnosis 64 years) was the final study population. Median follow-up for alive patients was 5.4 years (range, 0.5-34.4 years). The diagnosis of MM was based on international criteria established during the different periods analyzed. Baseline demographics, clinical and laboratory data, treatment and follow-up were collected. The population was divided into three periods, which included: group A (1970 to 1985), group B (1986 to 1999) and group C (2000 to 2015) (Table 1). The Ethics Committee of the Hospital Clínic of Barcelona approved the study. RESULTS: The median OS (mOS) of all patients was 3.6 years (95% CI: 3.2-3.8). We observed an improvement in mOS during follow-up (Group A: 1.7 years [95% CI: 1.23-2.06]; Group B: 2.92 years [95% CI: 2.44-3.32]; Group C: 5.01 years [95% CI: 4.31-5.52]; p75 years old (Group A: 1.1 years [95% CI: 0.12-2.13]; Group B: 1.8 years [95% CI: 1.30-2.74]; Group C: 2.8 years [95% CI: 1.99-3.24]; p The early mortality rate (first 60 days after diagnosis) was 5.7%; 17.1% in the Group A, 5.7% in Group B, and 2.7% in Group C; p In terms of time elapse between the start of front-line treatment until the beginning of the subsequent line, the median time to second line treatment in the group A, B and C, were 10.5 months (95% CI: 8.8-14.2), 18.6 months (95% CI: 15.9-21.8), and 26.6 months (95% CI: 23.5-30.7), respectively (p75 years old: 15 months [95% CI: 9.4-18.5]; p CONCLUSIONS: This study shows that the survival outcome have significantly improved over the last decades in all age groups, including the elderly, due to ASCT and novel drugs. The incidence of early mortality is low, being the most frequent MM progression and infectious complications. Finally, the time to second line treatment has increased, specifically during the period from 2000 to 2015, with no differences in subsequent lines. Disclosures Bladé: Janssen: Honoraria. Rosinol:Janssen, Celgene, Amgen, Takeda: Honoraria.

Introduction: As in multiple myeloma, Waldenström macroglobulinemia (WM) is preceded by an asymptomatic phase, mainly as monoclonal gammopathy of undetermined significance (MGUS) or by a smoldering WM (SWM) phase. It has recently been reported that patients with IgM MGUS have a higher risk of progression in comparison to those with other MGUS isotypes. Moreover, it has been described that if the IgM MGUS is associated with adverse factors such as abnormal serum free light chains ratio and more than 15 g /L serum M-spike, the risk of progression at 20 years is as high as 55%. The aim of this study was to evaluate the risk of progression of asymptomatic IgM monoclonal gammopathies, using bone marrow aspiration as the main criteria for classification between SWM and IgM MGUS. Methods: We reviewed retrospectively the medical records of 206 patients with asymptomatic IgM monoclonal gammopathies, 143 (69.4%) with IgM MGUS and 63 (30.6%) with SWM diagnosed in our institution from May 1982 to December 2017. In the absence of clinical manifestations, IgM MGUS was defined as the presence of less than 30 g/L of serum IgM monoclonal protein and less than 10% lymphoplasmacytic bone marrow (BM) infiltration. The diagnosis of SWM required the presence of any size IgM M spike associated with ≥10% lymphoplasmacytic bone marrow infiltration with no target organ involvement, constitutional symptoms, hyperviscosity, lymphadenopathies or peripheral neuropathy. Progression to WM was defined according to the 2014 International Consensus. Results: The median age of the series was 70 years (range, 29 to 98) and the male/female distribution was 106/100. SWM group had a significantly higher median serum M spike than the MGUS group (9.2 vs. 4.6 g/L; p Only 6 (2.9%) of the patients had more than 30 g/L of serum M protein. For this reason, diagnosis of SWM was mainly based on results of BM aspiration. Median BM infiltration by plasma cells and lymphocytes was significantly higher in patients with SWM when compared to patients with MGUS (4 vs. 3%, p=0.027; 24 vs. 9%, p < 0.001, respectively), being the lymphocyte infiltration the most relevant difference. Thus, serum M protein correlated significantly with BM lymphocyte percentage (p=0.011) but not reaching significance when plasma cell infiltration (p=0.071) was analyzed. Median time of follow up was of 3.3 years for living patients. The evolving pattern of the M-spike was identified in 21 patients (10.2%). This paraprotein behavior was associated with a shorter progression to symptomatic WM (p=0.026), but mainly due to its higher frequency in the SWM group than in the MGUS one (19% vs. 6.3%, p=0.005). Diagnosis of SWM impacted negatively the prognosis of the patients, with a higher rate of progression to symptomatic disease at 3 years (15% vs. 2%). Thus, the risk of progression of SWM was 11 times greater than those with IgM MGUS (HR 11.7, p < 0.001; 95% CI 3.3-41.3) (Figure 1). There was also a significant difference on survival between both groups of patients (median overall survival 20 vs. 13 years; p=0.027). Conclusions: In our series, the progression rate from IgM MGUS to symptomatic WM was clearly inferior to that reported in other historical series and quite similar to the progression rate of IgG MGUS (1% per year), being also significantly higher for patients with SWM. Evolving pattern is rare in IgM MGUS but it was identified in 19% of patients with SWM. These findings suggest that bone marrow evaluation is crucial in the prognosis of asymptomatic IgM monoclonal gammopathies. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

Introduction: Smoldering multiple myeloma (SMM) is an asymptomatic and biologically heterogeneous clonal plasma cell disorder. A number of prognostic factors to identify patients at a higher risk of progression have been described, such as the size of the M protein, proportion of abnormal bone marrow plasma cells (BMPCs), immunoparesis and serum free light chain (FLC) k/l ratio. More recently, isotype-specific uninvolved heavy and light chain (HLC) pair suppression measured with the Hevylite assay was also associated with an increased risk of progression. Recent studies have evaluated the key prognostic impact of an increase in M-protein levels during follow-up ("evolving" pattern). However, an important limitation could be the evaluation of M-protein level variations based on serum protein electrophoresis (SPE) in patients with a small size M-spike. The aim of this study was to prospectively analyze the changes in M-protein according to SPE and HLC measurements, as well as other risk factors for progression, in patients with SMM. Methods: Thirty patients newly diagnosed with SMM at a single institution from January 2014 through September 2017 were prospectively included in the study. For each patient, baseline levels of known prognostic factors (serum M-protein, serum and urine immunofixation, clonal BMPCs percentage, total immunoglobulins, involved/uninvolved FLC and involved/uninvolved HLC pairs) were recorded. During the follow up, M-protein level, FLC and isotype specific HLC pairs were also analyzed. Evolving change in M-protein level according to SPE was defined as ³ 10% increase within the first 6 months of diagnosis (if M-protein was ³ 30 g/L) and/or ³ 25% increase within the first 12 months (for any level of M-protein); evolving change according to HLC was defined as a ³ 10% increase in the involved pair. A sequential increase in each of three or more consecutive measurements from diagnosis was considered an evolving change regardless of its magnitude. Results: The clinical characteristics of the total of patients, as well as of the patients with evolving changes in M-protein according to HLC are summarized in Table 1. During the study period, 5/30 (17%) of patients demonstrated an evolving behavior of the M-protein according to SPE. Four of these patients (4/5) also showed a progressive increase in the M-protein in the HLC measurements. One patient showed stable HLC levels even though both the M-protein and the involved FLC progressively increased. This patient was of intermediate and low risk according to Mayo Clinic and PETHEMA scores, respectively. On follow up, no progressive suppression of the isotype-specific uninvolved HLC pair or increase in the FLC ratio was noted, and there have been no signs of progression after a follow up of 3 years. According to involved HLC-pair levels, 12/30 (40%) of patients demonstrated an evolving behavior. Five out of 7 patients that were not classified as evolving by SPE, were IgA isotype. Eight out of 12 patients showed severe isotype-specific suppression of the uninvolved HLC-pair (> 50% below lower level of normal) as well as a highly abnormal FLC ratio (8). Three out of the 4 remaining patients showed either severe isotype-specific HLC pair suppression or highly abnormal FLC ratio in follow up measurements. Compared to patients with no "HLC-evolving pattern", evolving patients were more likely to have highly abnormal FLC ratios (90 vs. 33%, p=0.009), severe suppression of the other isotypes (64 vs. 19%, p=0,024), highly abnormal isotype-specific HLC ratios (67 vs. 33%, p=NS), severe isotype-specific HLC-pair suppression (75 vs. 50%, p=NS), and immunoparesis (67 vs. 39%p=NS). Five patients progressed to symptomatic multiple myeloma during follow up; 4 of them showed a progressive increase in the involved HLC pair from diagnosis. The remaining patient demonstrated a progressive increase in the involved HLC pair that started 19 months prior to progression, followed 4 months later with an increase in M-protein as measured by SPE. Conclusions: In our series, the Hevylite assay allowed us to identify patients with a progressive increase in M-protein (clonal heavy/light chain pair) that was not evident with SPE measurements. This "HLC evolving pattern" was associated with other risk factors for progression to symptomatic disease and with worsening of other prognostic parameters during follow up. Disclosures Rosinol: Janssen, Celgene, Amgen, Takeda: Honoraria. Bladé:Janssen: Honoraria.

Background: The randomized PETHEMA/GEM phase III trial GEM05menos65 (www.clinicaltrials.gov NCT00461747) demonstrated that pretransplant induction therapy with VTD resulted in a significantly higher CR rate both, pretransplant and postransplant and in a significantly longer progression-free survival (PFS) when compared with thalidomide/dexamethasone (TD) and combination chemotherapy plus bortezomib (VBMCP/VBAD/B) (Rosiñol et al, Blood 2012). We report here the definitive results of the trial, ten years after the last patient was included. Methods: From April 6, 2006 to August 5, 2009, 386 patients younger than 65 years with newly diagnosed symptomatic multiple myeloma (MM) were randomized to receive three different induction regimens: six 4-week cycles of TD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12) vs. six 4-week cycles of VTD (TD at identical doses plus i.v. bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) vs. combination chemotherapy plus bortezomib (4 cycles of alternating VBMCP and VBAD chemotherapy followed by two cycles of i.v. bortezomib at the usual dose of 1.3 mg/m2 on days 1,4,8,11 every 3 weeks). The duration of the induction therapy was 24 weeks in all arms. All patients were planned to undergo ASCT with high-dose melphalan at 200 mg/m2 followed by maintenance therapy with thalidomide/bortezomib (TV) vs. thalidomide (T) vs. alfa-2b-interferon (alfa2-IFN) for 3 years. One-hundred and thirty patients were allocated to VTD, 127 to TD and 129 to VBMCP/VBAD/B. Seventy out of the 330 patients (21%) with cytogenetic studies had high-risk cytogenetics [t(4;14), t(14;16) and/or 17p deletion]. Patient characteristics at diagnosis and prognostic factors such as ISS, cytogenetics and maintenance arm were similarly distributed in the 3 arms. Results: After a median follow-up of 115 months for alive patients, VTD resulted in a significantly longer PFS when compared with TD and VBMCP/VBAD/B (52 vs 28 vs 32 months, p=0.01) (Figure 1). The median overall survival (OS) was 128 vs 99 vs 93 months, respectively, with no significant differences among the 3 arms. In the overall series, the PFS was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk (15 vs. 42 months, p=0.001). In the TD and in the VBMCP/VBAD/B arm patients with high-risk cytogenetics had a significantly shorter PFS than patients with standard-risk (7 vs 32 months, p=0.029 in TD group; 13 vs. 38 months, p=0.027 in VBMCP/VBAD/B group). However, there was no significant difference in the VTD arm (23 vs 52 months, p=0.125). Patients with high-risk cytogenetics had a significantly shorter OS in the overall series (median 38 months vs 114, p=0.0001) and this was observed in the three treatment arms: VTD median 36 months vs not reached (p=0.0001), TD median 52 months vs 113 (p=0.017), VBMCP/VBAD/B median 29 months vs 93 (p=0.01). The achievement of a negative MRD after transplant was associated with a longer PFS and OS. Thus, on an intention to treat basis, patients who had MRD negative after transplant had a significantly longer PFS (59 vs 38 months, p=0.0001) and OS (median not reached vs 102 months, p=0.001) than those who remained MRD positive after ASCT. Of interest, there are no significant differences in PFS (41 months vs 60 months, p=0.367) or OS (114 moths vs not reached, p=0.329) between patients with high-risk or standard risk cytogenetics who achieved negative MRD after transplant. By contrast, in patients with MRD positive after transplant, the PFS ( 16 months vs 38 months, p=0.006) and OS (29 months vs 113 months, p=0.001) was significantly shorter in patients with high-risk cytogenetics compared with patients with standard-risk cytogenetics. Conclusions: Our long-term results confirm that induction with VTD results in a significantly longer PFS when compared with TD and VBMCP/VBAD/B. Patients with high-risk cytogenetics who achieved postransplant MRD negative had a similar outcome than patients with standard-risk cytogenetics, while patients with high-risk cytogenetics who remain MRD positive had a dismal prognosis. Finally, the PFS of 52 months achieved with VTD is the longest ever reported in the first line treatment of younger patients with MM elegible for ASCT and support the use of VTD as the standard of care for pretransplant induction therapy. Figure 1. Figure 1. Disclosures Rosinol Dachs: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Oriol:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, 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, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Blanchard:Janssen: Honoraria. Granell:Janssen: Honoraria; Celgene: Honoraria. Mateos:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinez-Lopez:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Vivia: Honoraria; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding. Alegre:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. San-Miguel:BMS: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Blade:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

A 44-yr-old man with IgG-lambda multiple myeloma reached a complete response after induction chemotherapy and autologous stem cell transplantation and maintenance therapy with interferon α2b and prednisone 4 yr later, he presented an increase in the M-protein plus extramedullary myeloma involvement with sacrum and clivus plasmacytomas. Treatment with bortezomib, cyclophosphamide and dexamethasone plus local radiotherapy was initiated. The patient developed a bilateral humeral pathological fracture. Surgical osteosynthesis of both humeri was performed with no immediate complications. Two months later, he developed a prominent swelling in both deltoid areas with fever and high serum LDH levels. X-ray examination showed a displacement of bone fragments of both humeri. Humerus CT scan showed a bilateral fracture in proximal diaphysis with posterior displacement. A magnetic resonance of right scapular region revealed a very extensive infiltration originated in the humerus. A fine-needle punction showed a diffuse plasmablastic infiltration. This case illustrates an atypical presentation of extramedullary myeloma with extensive soft-tissue involvement, originated at the fractured lytic lesions, which was likely triggered by bone surgery. This direct mechanism of myeloma spread has been observed in experimental myeloma mouse models.

El sindrome de POEMS (polineuropatia, organomegalia, endocrinopatia, banda monoclonal y alteraciones cutaneas) es una entidad infrecuente, que se caracteriza por una proliferacion clonal de celulas plasmaticas que da lugar a un componente monoclonal, por lo general poco abundante y con restriccion de la cadena lambda. Clinicamente cursa con afectacion multisistemica, dentro de la cual predomina la polineuropatia periferica. No existe un tratamiento especifico para esta enfermedad. Se presentan 4 casos de sindrome de POEMS tratados mediante trasplante autologo de progenitors hematopoyeticos en nuestro centro. Todos ellos mejoraron de sus manifestaciones neurologicas y sistemicas, al tiempo que presentaron una disminucion o desaparicion del componente monoclonal y de las lesiones oseas. En conclusion, el trasplante autologo de progenitores hematopoyeticos constituye una opcion terapeutica util en el sindrome de POEMS.

Bortezomib is a potent and selective proteasome inhibitor recently introduced in the treatment of multiple myeloma (MM). This drug produces significant responses in about one-third of patients with relapsed/refractory disease. We first recognized the lack of efficacy of thalidomide in soft-tissue plasmacytomas. There is little information on the effect of bortezomib on extramedullary myeloma. Four of 23 patients treated with bortezomib at our institution had extramedullary involvement at the time of relapse. In three of these patients large soft-tissue plasmacytomas disappeared. This indicates that bortezomib may be useful in clinical situations of extramedullary disease in which other agents, such as thalidomide, may not be effective.

Immunomodulatory drugs have been shown to be of benefit in relapsed/refractory immunoglobulin light-chain (AL) amyloidosis. We designed a prospective, multicentre phase II trial of lenalidomide, dexamethasone and cyclophosphamide for newly diagnosed patients with AL amyloidosis not eligible for autologous stem-cell transplantation. Twenty-eight patients were included in the study. Cardiac involvement was present in 23 patients; 14 of them had cardiac stage III. The overall haematological response rate was 46%, including complete and very good partial responses in 25% and 18% of patients respectively. Haematological response was mainly associated with absence of cardiac stage III and lower tumour burden. Organ response was observed in 46% of patients. After a median follow-up of 24 months, median progression-free and overall survival have not been reached, both being significantly longer in responders (P < 0·001 and P = 0·001 respectively). Seventeen patients have discontinued treatment, mostly due to amyloid-related death, disease progression or lack of response. Only 14% of the patients discontinued treatment due to therapy-related adverse events. Our results support the efficacy of this regimen, with high quality responses and prolonged survival, as well as its tolerability, in patients with AL amyloidosis not eligible for stem cell transplant and without advanced cardiac involvement (clinicaltrials.gov identifier: NCT01194791).

The prevalence of an abnormal serum free light chain (FLC) ratio in 34 patients with multiple myeloma in complete response (CR) after hematopoietic stem cell transplantation was studied. Fourteen of 34 patients (41.2%) showed an abnormal FLC ratio. The frequency of abnormal FLC ratio in patients with or without oligoclonal bands was 72.7% versus 26%, respectively (P = .023). The median value of FLC ratio was 2.55 (95% confidence interval, 1.89-3.20) in patients with oligoclonal bands versus 0.87 (95% confidence interval, 0.70-1.04) for those with no oligoclonal bands (P = .011). This is the first report showing that the presence of oligoclonal bands in patients with multiple myeloma in CR frequently results in an abnormal FLC ratio. Because an oligoclonal immune response is associated with a good outcome, our results question the current definition of stringent CR and support that the prognostic impact of oligoclonal bands should be also assessed on multivariate analysis.

A 73-year-old woman complaining of bone pain and weight loss was suspected to have a malignant disease, and extensive laboratory investigations were carried out. She was diagnosed with multiple myeloma; however, because of the finding of extremely high serum levels of CA125 and CA15.3 and focal liver lesions, a concomitant solid tumor was suspected, which was then excluded with the appropriate tests, including an ultrasound-guided liver biopsy. While being diagnosed, the patient developed a rapidly evolving plasma cell leukemia with a simultaneous increase in CA125 and CA15.3. After treatment with cyclophosphamide and dexamethasone, the peripheral blood plasma cells disappeared and there was a dramatic decrease in the CA125 and CA15.3 tumor markers. High levels of the latter can be observed in patients with aggressive plasma cell dyscrasias, an observation that is crucial in order to avoid unnecessary tests that can result in treatment delay.

Although splenic rupture is a recognized complication of primary amyloidosis, very few cases have been reported in the context of stem cell transplantation. A patient with systemic primary amyloidosis with renal and cardiac involvement and factor X deficiency, who developed a splenic rupture 24 h after the peripheral blood stem cells infusion during autologous transplantation, is described. This complication has been reported during stem cell mobilization and after post-transplant hematopoietic recovery, but we have not found a previous report of splenic rupture in the immediate postinfusion period. This case illustrates that splenic rupture can occur at any time during the transplant procedure. Need for close monitoring, particularly in patients with factor X deficiency after receiving granulocyte colony stimulating factor, two recently recognized risk factors for splenic hemorrhage, is highlighted.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare clinical entity where tumor cell embolisms in pulmonary circulation induce thrombotic microangiopathy (TMA), respiratory failure, and subacute cor pulmonale. We describe 3 cases of PTTM that presented as the initial manifestation of metastatic gastric adenocarcinoma with TMA and pulmonary infiltrates. All 3 cases had similar clinical and laboratory features, which included moderate thrombocytopenia without renal failure, hemolysis with extremely high serum lactate dehydrogenase levels, leukoerythroblastosis in peripheral blood smear, altered coagulation tests, lymphadenopathies, and interstitial pulmonary infiltrates. All patients died within 2 weeks of diagnosis. Two cases were initially misdiagnosed as idiopathic thrombotic thrombocytopenic purpura and treated with plasma exchange with no response. One patient had bone marrow infiltration by malignant cells. Autopsies revealed PTTM associated with gastric disseminated adenocarcinoma (signet-ring cell type in 2 patients and poorly differentiated type in 1). PTTM should be considered in the differential diagnosis of patients with fulminant microangiopathic hemolytic anemia, such as atypical thrombotic thrombocytopenic purpura, mainly those with pulmonary infiltrates, disseminated intravascular coagulation, or Trousseau syndrome.

Adult-acquired Fanconi syndrome (FS) is a rare kidneycomplication of monoclonal plasma cell disorderscharacterized by dysfunction of the proximal renaltubule, resulting in metabolic changes, bone disease,and progressive renal failure. There are limited data inthe literature, mainly isolated cases reports or smallcase series.We describe our single-institution experience with 4patients diagnosed with FS associated with mono-clonal gammopathy (2 women and 2 men) fromJanuary 2001 to December 2011.The patients had a mean age of 63.5 years at diag-nosis. In 1 patient, diagnosis of monoclonal gamm-opathy and FS was simultaneous, whereas in theremaining 3 patients, FS was recognized during thefollow-up of monoclonal gammopathy.

Abstract 132 Background: There is increasing evidence on the importance of epigenetic mechanisms such as DNA methylation and acetylation in the pathogenesis of multiple myeloma (MM). A global DNA hypomethylation pattern with selective genes hypermethylated has been described in myeloma plasma cells when compared with normal plasma cells. This fact could constitute a potential target for the use of demethylating agents. The response to bortezomib, a widely used agent against myeloma cells through proteasome inhibition, is particularly variable in patients with relapsed or refractory disease. We examined both, the global DNA methylation pattern and methylation state in 30 genes, in DNA from bone marrow cells and correlated our findings with response, progression (PFS) and overall-survival (OS) to bortezomib in patients with relapsed myeloma. Methods: Seventy-five patients (37M/38F; median age 65 years, range 29 to 80) with relapsed MM were treated from December 2002 to March 2010 with bortezomib-based regimens at our institution. Median follow-up for patients alive was 31 months (range 6 to 45). Genomic DNA was isolated from bone marrow slides with plasma cell infiltration at the time of relapse using a commercial kit (Qiagen). Global methylation was determined in all patients by ELISA (Epigentek), obtaining the percentage of 5-methylcytosine (5-mC) present in total DNA. CpG island DNA methylation profile of 30 genes was determined in 42 patients by a DNA methylation PCR system based on methylation sensitive and/or dependent restriction enzymes digestion (Qiagen). These genes were selected based on either their potential impact on prognosis in previous reports, or on the pathogenesis of MM, involving several cellular pathways such as innate immune response (CD40, EP300, MIF, CBP, TGFB1, TGFBR2), cytokine receptors (CXCR4, CXCL12, IL6R, IL17RA), transcription factors (NFKB1, NFKBIB, IRF4), cytokine stimulus response (SOCS3), apoptosis (TNFRSF13C, TNFRSF21, TNFRSF25, BCL2L11), tumor suppression (TP53, BRCA1, DAPK1, CDH1, RASD1), cellular cycle control (CCNB1, CCND1, CCNA2, CCNE1, CDKN2A, CDKN1A) and efflux transporter (ABCG2). Results: Overall response (OR) was achieved in 62% of the patients (complete remission 6.7%, partial response 44% and minor response 10.7%), while 9 (12%) and 20 (26.7%) showed no response (NR) or progressive disease (PD), respectively. The median PFS and OS after bortezomib therapy were 6 and 19.6 months, respectively. A low global methylation status was observed (median 4.68% of 5-mC, range 0.02 to 13.6) and patients with more than 3.95% of total DNA methylated achieved better OS than patients with more unmethylated DNA (median 30 versus 15 months) (p=0.004; Figure 1). Concerning methylation on specific-genes, a methylation status lower than 3.97% in CXCR4 was correlated with a longer PFS after bortezomib treatment (p=0.009; Figure 2). Clustering analysis with methylation status for these genes, showed that NFkB presented a differential profile according to response to bortezomib (p=0.037). A relative low methylation percentage (lower than 6.7%) in this gene was also associated with longer OS after bortezomib treatment (p=0.015; Figure 3). A positive correlation was observed with high methylation status in NFkB and other genes involved in the same cellular pathway (NFKBIB, EP300, CBP, CCNA2, CCNB1) (p Conclusion: In our study, a low methylation grade in the overall DNA was observed. A relative high methylation status in the global genome and low in NFkB were associated with longer OS after bortezomib therapy in patients with relapsed or refractory myeloma. These results could be explained through the potential cell effect mediated by bortezomib in the NFkb pathway. Finally, a subgroup of patients with an ominous prognosis associated with DNA methylation at relapse in spite of bortezomib treatment was identified. Disclosures: Fernández de Larrea: Novartis: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

Here we report the efficacy, safety and health-related quality-of-life (HRQoL) associated with long-term lenalidomide and dexamethasone (Len + Dex) treatment in patients with relapsed or refractory multiple myeloma (RRMM) enrolled in the Spanish cohort of the MM-018 study. In this open-label, multicenter, single-arm expanded access study, 63 patients received Len + Dex until disease progression. The overall response rate was 78%, with 21% of the patients achieving a complete response. The quality of response improved with continuous treatment. The median duration of response was 18.4 months. Median time-to-progression and progression-free survival was 13.3 months for both; median overall survival was not reached. Len + Dex had a manageable safety profile consistent with previously reported phase III studies. HRQoL assessments (n = 42) at baseline and 6 months using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ MY-20 questionnaires revealed that patients with RRMM treated with long-term lenalidomide reported clinically relevant improvements in certain QoL and symptoms scores regardless of treatment response (ClinicalTrials.gov: NCT00420849).

The Spanish Myeloma Group conducted a trial to compare bortezomib/thalidomide/dexamethasone (VTD) versus thalidomide/dexamethasone (TD) versus vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, doxorubicin, dexamethasone/bortezomib (VBMCP/VBAD/B) in patients aged 65 years or younger with multiple myeloma. The primary endpoint was complete response (CR) rate postinduction and post–autologous stem cell transplantation (ASCT). Three hundred eighty-six patients were allocated to VTD (130), TD (127), or VBMCP/VBAD/B (129). The CR rate was significantly higher with VTD than with TD (35% vs 14%, P = .001) or with VBMCP/VBAD/B (35% vs 21%, P = .01). The median progression-free survival (PFS) was significantly longer with VTD (56.2 vs 28.2 vs 35.5 months, P = .01). In an intention-to-treat analysis, the post-ASCT CR rate was higher with VTD than with TD (46% vs 24%, P = .004) or with VBMCP/VBAD/B (46% vs 38%, P = .1). Patients with high-risk cytogenetics had a shorter PFS and overall survival in the overall series and in all treatment groups. In conclusion, VTD resulted in a higher pre- and posttransplantation CR rate and in a significantly longer PFS although it was not able to overcome the poor prognosis of high-risk cytogenetics. Our results support the use of VTD as a highly effective induction regimen prior to ASCT. The study was registered with http://www.clinicaltrials.gov (NCT00461747) and Eudra CT (no. 2005-001110-41).

We provide an overview on soft-tissue extramedullary plasmacytomas (EMPs) in multiple myeloma (MM). We reviewed the incidence of EMPs in MM, myeloma bone marrow homing, possible mechanisms of extramedullary spread, and prognosis and response to therapy. The incidence of EMPs is 7% to 18% at MM diagnosis and up to 20% at relapse. The current notion that EMPs are more frequent after treatment with novel agents remains to be proven, especially considering that different patterns of disease recurrence can emerge as patients live longer in the era of novel drugs. Bone marrow genetic abnormalities are not associated with extramedullary spread per se, which also suggests that microenvironmental interactions are key. Possible mechanisms of extramedullary spread include decreased adhesion molecule expression and downregulation of chemokine receptors. EMPs usually show plasmablastic morphology with negative CD56 expression. High-dose therapy with autologous stem-cell transplantation (ASCT) can overcome the negative prognostic impact of extramedullary disease in younger selected patients. EMPs do not typically respond to thalidomide alone, but in contrast, responses to bortezomib have been reported. The incidence of EMPs in patients with MM is high and is associated with poor outcome in patients treated conventionally. A potential first-line treatment option seems to be a bortezomib-containing regimen followed by ASCT, whenever possible. Experimental studies on the mechanisms of myeloma cell adhesion, myeloma growth at extramedullary sites, and drug sensitivity are priorities for this area of continuing therapeutic challenge.

A 44-yr-old man with IgG-lambda multiple myeloma reached a complete response after induction chemotherapy and autologous stem cell transplantation and maintenance therapy with interferon α2b and prednisone 4 yr later, he presented an increase in the M-protein plus extramedullary myeloma involvement with sacrum and clivus plasmacytomas. Treatment with bortezomib, cyclophosphamide and dexamethasone plus local radiotherapy was initiated. The patient developed a bilateral humeral pathological fracture. Surgical osteosynthesis of both humeri was performed with no immediate complications. Two months later, he developed a prominent swelling in both deltoid areas with fever and high serum LDH levels. X-ray examination showed a displacement of bone fragments of both humeri. Humerus CT scan showed a bilateral fracture in proximal diaphysis with posterior displacement. A magnetic resonance of right scapular region revealed a very extensive infiltration originated in the humerus. A fine-needle punction showed a diffuse plasmablastic infiltration. This case illustrates an atypical presentation of extramedullary myeloma with extensive soft-tissue involvement, originated at the fractured lytic lesions, which was likely triggered by bone surgery. This direct mechanism of myeloma spread has been observed in experimental myeloma mouse models.

The emergence of oligoclonal bands is associated with a favorable outcome after autologous stem cell transplantation in multiple myeloma. The aim of this study was to determine the prevalence of immunoglobulin oligoclonality in 33 patients with multiple myeloma in complete remission achieved with primary therapy with either cytotoxic agents (n = 18, 54.5%) or new induction regimens incorporating novel drugs (n = 15, 45.4%). Eleven patients (33.3%) developed oligoclonal bands. In the group treated with novel agents, this oligoclonal immune response was observed in 60% (9 of 15) of the patients versus only 11.1% (2 of 18) of those given cytotoxic therapy (P = 0.003). This is the first report showing a different frequency of oligoclonal humoral response in patients in complete remission achieved after conventional cytotoxic therapy versus induction incorporating novel agents. This difference could be due to a higher antitumor effect associated with the use of novel drugs, a stronger immune reconstitution, or both.

The current definition of complete remission (CR) in multiple myeloma (MM) requires a negative serum and urine immunofixation (IFE) and 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.