Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy

<b><i>Introduction:</i></b> B-cell depletion has been shown to be an effective strategy for the majority of patients with membranous nephropathy (MN), and in PLA2R-positive MN, immunologic remission (improvement or elimination of measurable serum anti-PLA2R antibodies) precedes renal remission. Yet, cases exist of patients who do not achieve immunologic remission despite achieving peripheral B-cell depletion. This has led to the hypothesis that some patients have plasma cells that are responsible for producing anti-PLA2R antibodies. <b><i>Case Presentation:</i></b> A 66-year-old man with a past medical history of hypertension, hyperlipidemia, and cerebrovascular disease presented with nephrotic syndrome and was diagnosed with PLA2R-positive MN on kidney biopsy. He was refractory to multiple therapies including tacrolimus, and was resistant to rituximab despite having achieved B-cell depletion. He also did not enter into remission with plasmapharesis and cyclophosphamide. He then achieved immediate immunologic remission after treatment with the proteasome inhibitor bortezomib, which is used as first-line therapy for multiple myeloma. <b><i>Discussion/Conclusion:</i></b> This case suggests that considering the source of PLA2R antibody production could lead to individualized and targeted therapies for MN.

Presence of a Measurable M-Spike before Autologous Stem Cell Transplantation Is Associated with Shorter Survival in Patients with Light Chain Amyloidosis

Introduction: The bone marrow plasma cell (BMPC) clone burden is typically low in light chain (AL) amyloidosis and some patients do not have a detectable serum monoclonal spike (M-spike). Increased BMPC% and serum free light chain (FLC) are associated with poorer outcomes. However, the outcomes of patients with AL amyloidosis based on the presence or an absence of a measurable serum M-spike before autologous stem cell transplantation (ASCT) has not been explored. Methods: This was a retrospective review of patients who had a diagnosis of AL amyloidosis and received ASCT between March 1996 and September 2017. The serum M-spike was recorded before ASCT and patients were divided according to the presence or absence of a measurable serum M-spike. Progression-free survival (PFS) was defined as time from ASCT to disease progression, relapse or death of any cause. Overall survival (OS) was calculated from time of ASCT to death of any cause. Univariate and multivariate analysis for PFS and OS were done using the following variables: age&gt;65 vs. ≤65 years, Mayo 2012 stage 3/4 vs. 1/2, BMPC ≥ 10% vs. &lt;10%, organs involved &gt;2 vs. ≤2, melphalan conditioning 200mg/m2 vs. 140 mg/m2 ,ASCT year &gt;2010 vs. ≤2010, and presence vs. absence of a measurable serum M-spike. Results: Seven-hundred and sixteen patients were identified and 521 (73%) had a measurable serum M-spike. Patients who had a measurable serum M-spike were more likely to have BMPC≥ 10% than patients without a measurable serum M-spike (46% vs. 34%, P=0.002) and they were more likely to have a difference in FLC ≥18 mg/dl (47% vs. 29%, P=0.0001). Overall, PFS and OS were significantly shorter in patients who had a measurable serum M-spike compared to patients without a measurable serum M-spike (Figure 1 A,B). The shorter survival was irrespective of the administration of induction therapy before ASCT. We also evaluated the difference in survival in patients with Mayo 2012 stage 3/4 based on the presence or absence of a measurable serum M-spike. The PFS and OS were also significantly different in these patients (Figure 1 C,D). Predictors for PFS included Mayo 2012 stage 3/4 vs. 1/2 (hazard ratio (HR): 1.5, P=0.003), BMPC ≥ 10% vs. &lt;10% (HR: 1.4,P=0.004), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.6, P=0.001), ASCT year &gt;2010 vs. ≤2010 (HR: 0.8, P=0.03), and the presence vs. absence of a measurable serum M-spike (HR: 1.82, P&lt;0.0001). For OS, Mayo 2012 stage 3/4 vs. 1/2 (HR: 2, P&lt;0.0001), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.4, P&lt;0.0001), ASCT year &gt;2010 vs. ≤2010 (HR: 0.6, P=0.002), and the presence vs. absence of a measurable serum M-spike (HR:1.9, P=0.003) were predictive. Conclusion: The presence of a measurable serum M-spike before ASCT is a negative independent predictor for PFS and OS in AL amyloidosis. Figure 1 Disclosures Sidiqi: Amgen: Honoraria; Celgene: Honoraria, Other: Travel grant; Janssen: Honoraria. Dingli:Karyopharm Therapeutics: Research Funding; Apellis: Consultancy; Alexion: Consultancy; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Amgen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; GlaxoSmithKline: Research Funding. Dispenzieri:Intellia: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Kumar:Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; Genecentrix: Consultancy; MedImmune: Research Funding; Cellectar: Other; Dr. Reddy's Laboratories: Honoraria; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Novartis: Research Funding; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Carsgen: Other, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding. Gertz:Proclara: Other; Abbvie: Other; DAVA oncology: Speakers Bureau; Aurora Bio: Other; Prothena: Other: personal fee; Teva: Speakers Bureau; Physicians Education Resource: Other: personal fee; Annexon: Other: personal fee; Ionis/Akcea: Other: personal fee; Sanofi: Other; Appellis: Other: personal fee; Amgen: Other: personal fee; Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Medscape: Other: personal fee, Speakers Bureau; Research to Practice: Other; Alnylam: Other: personal fee; Johnson and Johnson: Speakers Bureau; Springer Publishing: Patents & Royalties; Celgene: Other.

Serum concentration of bisphenol A in elderly cats and its association with clinicopathological findings

Objectives Bisphenol A (BPA) has been mentioned as a possible factor contributing to feline hyperthyroidism. Nevertheless, there are no previous studies reporting on the concentration of BPA in feline serum and its association with thyroid function. The objectives of this study were to measure serum BPA concentration in cats aged ⩾7 years, considered as healthy by their owners, and to compare the results with clinicopathological findings. Methods Sixty-nine cats aged ⩾7 years considered as healthy by their owners were enrolled in the study. The concentration of BPA in feline serum was measured using liquid chromatography–tandem mass spectrometry. In all cats, signalment, living environment, diet history, and the results of haematological and biochemical analysis, including thyroxine levels, were available. Results The mean serum BPA concentration in feline serum was 1.06 ± 0.908 ng/ml. Significant correlation was found between BPA concentration and haemoglobin ( r = 0.3397; P = 0.0043), haematocrit ( r = 0.3245; P = 0.0065) and the number of red blood cells ( r = 0.2916; P = 0.0151), concentration of total protein ( r = 0.2383; P = 0.0486), concentration of calcium ( r = 0.3915; P = 0.0009) and level of bilirubin ( r = 0.3848; P = 0.0011). No other significant correlations were found. Significant differences ( P <0.01) were found between mature (1.28 ± 0.994 ng/ml) and geriatric cats (0.420 ± 0.240 ng/ml), between strictly indoor cats (1.27 ± 0.992 ng/ml) and cats with outdoor access (0.660 ± 0.529 ng/ml), and between cats fed canned food (1.23 ± 0.935 ng/ml) and cats fed non-canned food (0.774 ± 0.795 ng/ml). Conclusions and relevance Measurable serum BPA levels were found in all examined samples. The age of the cats was revealed as a significant factor affecting BPA concentration and mature cats had the highest levels. A significantly higher concentration of BPA was found in cats living strictly indoors and in cats fed canned food. No association was found between BPA and thyroid function. Further studies are needed that focus on hyperthyroid cats for better evaluation of this relationship.

Prognostic factors for COVID-19 pneumonia progression to severe symptom based on the earlier clinical features: a retrospective analysis

Approximately 15-20% of COVID-19 patients will develop severe pneumonia, about 10 % of which will die if not properly managed. Earlier discrimination of the potential severe patients basing on routine clinical and laboratory changes and commencement of prophylactical management will not only save their lives but also mitigate the otherwise overwhelmed health care burden. In this retrospective investigation, the clinical and laboratory features were collected from 125 COVID-19 patients, who were classified into mild (93 cases) or severe (32 cases) groups according to their clinical outcomes after 3 to 7-days post-admission. The subsequent analysis with single-factor and multivariate logistic regression methods indicated that 17 factors on admission differed significantly between mild and severe groups, but that only comorbid with underlying diseases, increased respiratory rate (>24/min), elevated C-reactive protein (CRP >10mg/liter), and lactate dehydrogenase (LDH >250U/liter), were independently associated with the later disease development. Finally, we evaluated their prognostic values with the receiver operating characteristic curve (ROC) analysis and found that the above four factors could not confidently predict the occurrence of severe pneumonia individually, but that a combination of fast respiratory rate and elevated LDH significantly increased the predictive confidence (AUC= 0.944, sensitivity= 0.941, and specificity= 0.902). A combination consisting of 3- or 4-factors could further increase the prognostic value. Additionally, measurable serum viral RNA post-admission independently predicted the severe illness occurrence. In conclusion, a combination of general clinical characteristics and laboratory tests could provide high confident prognostic value for identifying potential severe COVID-19 pneumonia patients.SummaryWith our successful experience of treating COVID-19 patients, we retrospectively found that routine clinical features could reliably predict severe pneumonia development, thus provide quick and affordable references for physicians to save the otherwise fatal patients with the limited medical resource.

Interpretation and Application of the International Myeloma Working Group (IMWG) Criteria: Proposal for Uniform Assessment and Reporting in Clinical Trials Based on the First Study Independent Response Adjudication Committee (IRAC) Experience

Background: In multiple myeloma (MM), reproducible criteria of disease response and progression are critical to ensuring consistency in trial analysis and reporting. Regulatory Agencies responsible for drug approval often require clinical trials use objective endpoints that are evaluated by Independent Response Adjudication Committees (IRACs). The International Myeloma Working Group (IMWG) has developed objective criteria to define disease evaluability, response, and progression (Durie, Leukemia 2006). However, there are scenarios were IMWG criteria are ambiguous, potentially leading to inconsistency amongst IRAC members or between different IRACs when interpreting response data. To address these practical issues, we developed rules for applying IMWG response criteria to the FIRST trial, the largest study in newly-diagnosed MM (Facon, Blood 2013). Patients and Methods: FIRST is a pivotal phase III trial for previously untreated patients with MM not eligible for ASCT that enrolled 1623 patients; the primary endpoint was progression-free survival (PFS). At 12 in-person meetings between 2010-2013, the IRAC assessed eligibility, evaluability and response status of all patients after each cycle until PD or study discontinuation. These evaluations were used in the trial’s primary analysis. Response was based on central laboratory values and assessed using IMWG criteria. For circumstances where IMWG criteria were ambiguous, rules were developed through unanimous consensus of IRAC members and then applied uniformly throughout the study. Results: Rules addressing identified issues on evaluability, response and progressive disease are shown in tables 1-3. Common situations posing a need for rules concerned to measurability, missing laboratory values, timing of BM exam to assess CR, discrepancies between screening and baseline lab values or measurements in the size of extramedullary plasmacytomas Conclusions: These recommendations provide explicit descriptions of response assessment of the FIRST trial, can be used for a more uniform evaluation and reporting in future clinical studies and can assist investigators’ adherence to clinical trial requirements. Table 1. Rules for Use of Data for Evaluation Issue Recommendation Light chain (Bence-Jones) myeloma with “non-measurable” serum light chain Use only 24 hour urine M-spike value for response evaluation, except for complete response (CR) IgG, IgA or IgD myeloma with “non-measurable” serum M-spike values and measurable urine M-spike Use only urine values for response evaluation except for CR or PD Disease with “measurable” values at screening but “non-measurable” at baseline (cycle 1, day 1) All assessments not meeting CR or PD should be “non-evaluable (NE)” Missing data for 2 or more consecutive cycles Consider “NE” for the specific missing cycle assessments M-spike reported as “too small to quantitate” in responding patient Assign value of 0 to allow subsequent calculation of absolute increase to determine PD Plasmacytoma given prior radiation therapy or located only in bone Not used for response assessment, except for potential PD Table 2. Rules for Response Assessment Issue Recommendation Absence of 2 consecutive negative IFE and simultaneous <5% BMPCs CR not assigned, assess as VGPR Extramedullary plasmacytomas (EMPs) - Visits until first EMP assessment Assess as NE - Two consecutive missing EMP assessments Assess as NE - EMPs not assessed as per protocol Assess as NE (consider a sensitivity analysis (ignoring EMPs)) - Patients in serologic VGPR, with ³ 50% decrease in EMP, but still present Assess as PR, until EMPs have disappeared Table 3. Rules for Determining Progressive Disease Issue Recommendation Increase in a previously existing EMP or bone lesion as only source of PD Request verification of radiologist reports before PD is assigned Initiation of a new antimyeloma therapy before documented PD Censor at the time of last assessment before starting the new therapy PD only based on the BMPCs Determine reason for BM exam (anemia? bone pain?) before assigning PD Radiation therapy not for pre-planned reasons Assess as PD PD based on M-protein measurements with no confirmation Censor unless that PD is considered unequivocal by unanimous agreement of IRAC Disclosures Blade: Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Knop:Celgene: Honoraria. Cohen:Celgene: Honoraria. Shah:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Meyer:Celgene: Honoraria.

Unmeasurable Serum M-Protein Multiple Myeloma Benefit Less from Bortezomib Than Measurable Myeloma

Background: According to international uniform response criteria for multiple myeloma(MM), unmeasurable disease is defined as serum M-protein level of less than 1 g/dl and urine M-protein level less than 200 mg/d. The anti-tumor activity of bortezomib partly depended on degradation of misfolded or unfolded proteins through ubiquitin-proteasome pathway. We postulate that bortezomib may not able to induce sufficient apoptosis in unmeasurable serum M-protein myeloma comparing with measurable group. The goal of this study is to determine whether the level of serumM-protein expression act as a validated surrogate marker to predict the prognosis in the bortezomib-based therapy. Materials and Methods: Between 2004 and 2013, a retrospective study was carried out of 630 patients with new diagnosis MM (NDMM) excluding light chain MM, who underwent bortezomib-based therapy or thalidomide-based therapy and for whom had complete data on clinical characteristics, molecular cytogenetics variety, treatment and overall survival (OS) time. According to the level of M-protein, they were devided into two groups: unmeasurable (serum M-protein<1g/dl) and measurable (serum M-protein>1g/dl) M-protein MM. Results: 1) 92 patients were defined asunmeasurable M-protein MM and were 14.60% of the 630 cases cohort. 2) Compared with measurable M-protein MM, unmeasurable M-protein MM were characterized by younger age(54.89 vs.58.85, p<0.001), lower frequency of IgG and IgA M-protein type (IgG, 14.13% vs. 68.96%; IgA, 21.74% vs. 30.86%; p<0.001), higher incidence of IgD M-protein type (IgD, 36.96% vs. 0.19%; p<0.001), lower frequency of kappa light chain involved (kappa, 26.09% vs. 53.72% p<0.001), higher level of albumin (44.44 vs.32.34, p<0.001) and higher median of LDH (265.29 vs.168.99, p<0.001), higher incidence of renal dysfunction (33.70% vs 16.54%, p<0.001 ) and less advanced ISS stage (Ⅰ, 34.09% vs. 17.30%; Ⅱ, 21.69% vs. 42.54%; Ⅲ, 44.32% vs.40.16%; p<0.001). In addition, unmeasurable M-protein patients had higher incidence of del(17p) ( 15.49% vs. 5.45%; p=0.001) and t(11;14) ( 35.85% vs. 13.99%; p<0.001). However, the incidence of del(13q), 1q21 gains and t(4;14), t(14;16) had no statistically significance (p>0.05). 3) Furthermore, we analyzed OS in these two groups with thalidomide-based or bortezomib-based chemotherapy. In thalidomide-based therapy, the median OS of unmeasurable and measurable M-protein MM were 32.0 (95% CI: 14.3-49.7) and 40.0 (95% CI: 34.3-45.7) months respectively (p=0.124).In bortezomib-based group, the median OS of unmeasurable and measurable M-protein MM were 29.5 (95% CI: 15.4-43.6) and 58.0 (95% CI: 46.1-70.0) months respectively. The unmeasurable M-protein MM had a remarkably shorter OS (P=0.034). Secondly, patients were stratified according to level of M-protein (unmeasurable and measurable), then compared according to treatment. In unmeasurable M-protein MM, the median OS of bortezomib group and thalidomide groupwere 29.5 (95% CI: 15.4-43.6) and 32.0 (95% CI: 14.3-49.7) months respectively(p=0.498). In measurable M-protein MM with bortezomib and thalidomide-based chemotherapy, the median OS were 58.0 (95% CI: 46.1-70.0) and 40.0 (95% CI: 34.3-45.7) months respectively (p=0.004). Conclusion: In conclusion, unmeasurable serum M-protein myeloma had shorter OS than measurable group, especially in the bortezomib-based therapy. In unmeasurable group, the difference of OS was not significant between thalidomide-based and bortezomib-based therapy. Our findings suggested that the level of serum M-protein was capable of predicting different survival groups to bortezomib and unmeasurable myeloma might benefit less than measurable group from bortezomib. Disclosures No relevant conflicts of interest to declare.

Dietary vitamin D2 – a potentially underestimated contributor to vitamin D nutritional status of adults?

It has been suggested that vitamin D2 is not very prevalent in the human food chain. However, data from a number of recent intervention studies suggest that the majority of subjects had measurable serum 25-hydroxyvitamin D2 (25(OH)D2) concentrations. Serum 25(OH)D2, unlike 25(OH)D3, is not directly influenced by exposure of skin to sun and thus has dietary origins; however, quantifying dietary vitamin D2 is difficult due to the limitations of food composition data. Therefore, the present study aimed to characterise serum 25(OH)D2 concentrations in the participants of the National Adult Nutrition Survey (NANS) in Ireland, and to use these serum concentrations to estimate the intake of vitamin D2 using a mathematical modelling approach. Serum 25(OH)D2 concentration was measured by a liquid chromatography–tandem MS method, and information on diet as well as subject characteristics was obtained from the NANS. Of these participants, 78·7 % (n 884) had serum 25(OH)D2 concentrations above the limit of quantification, and the mean, maximum, 10th, 50th (median) and 90th percentile values of serum 25(OH)D2 concentrations were 3·69, 27·6, 1·71, 2·96 and 6·36 nmol/l, respectively. To approximate the intake of vitamin D2 from these serum 25(OH)D2 concentrations, we used recently published data on the relationship between vitamin D intake and the responses of serum 25(OH)D concentrations. The projected 5th to 95th percentile intakes of vitamin D2 for adults were in the range of 0·9–1·2 and 5–6 μg/d, respectively, and the median intake ranged from 1·7 to 2·3 μg/d. In conclusion, the present data demonstrate that 25(OH)D2 concentrations are present in the sera of adults from this nationally representative sample. Vitamin D2 may have an impact on nutritional adequacy at a population level and thus warrants further investigation.

Long-Term Biological Variation of Serum Protein Electrophoresis M-Spike, Urine M-Spike, and Monoclonal Serum Free Light Chain Quantification: Implications for Monitoring Monoclonal Gammopathies

BACKGROUND We analyzed serial data in patients with clinically stable monoclonal gammopathy to determine the total variation of serum M-spikes [measured with serum protein electrophoresis (SPEP)], urine M-spikes [measured with urine protein electrophoresis (UPEP)], and monoclonal serum free light chain (FLC) concentrations measured with immunoassay. METHODS Patients to be studied were identified by (a) no treatment during the study interval, (b) no change in diagnosis and &lt;5 g/L change in serum M-spike over the course of observation; (c) performance of all 3 tests (SPEP, UPEP, FLC immunoassay) in at least 3 serial samples that were obtained 9 months to 5 years apart; (d) serum M-spike ≥10 g/L, urine M-spike ≥200 mg/24 h, or clonal FLC ≥100 mg/L. The total CV was calculated for each method. RESULTS Among the cohort of 158 patients, 90 had measurable serum M-spikes, 25 had urine M-spikes, and 52 had measurable serum FLC abnormalities. The CVs were calculated for serial SPEP M-spikes (8.1%), UPEP M-spikes (35.8%), and serum FLC concentrations (28.4%). Combining these CVs and the interassay analytical CVs, we calculated the biological CV for the serum M-spike (7.8%), urine M-spike (35.5%), and serum FLC concentration (27.8%). CONCLUSIONS The variations in urine M-spike and serum FLC measurements during patient monitoring are similar and are larger than those for serum M-spikes. In addition, in this group of stable patients, a measurable serum FLC concentration was available twice as often as a measurable urine M-spike.

Patterns of Myeloma (MM) Progression After Autologous Transplant (AHCT) – Biochemical Progression Vs. Clinical Relapse

Abstract 5097 Background: The uniform response criteria for MM suggest that in clinical practice early biochemical progression (EBP) of MM and clinical relapse (clinREL) be distinguished to identify symptomatic patients requiring therapy. The interval between EBP and clinREL in MM is not well characterized. Biochemical progression in those with intact immunoglobulin MM (IIM) could involve serum free light chain (SFLC) progression or monoclonal component (M spike) progression by serum protein electrophoresis (SPE) or both. ClinREL could precede, be concurrent with or follow tumor marker elevation. Methods: We studied EBP and clinREL in 221 consecutive AHCT recipients for MM between 2005 and 2010. Patients with IIM and measurable M spike and SFLC elevation at diagnosis were analyzed. Patients were uniformly monitored at a single institution with SFLC and SPE every 8–12 weeks. Biochemical progression and clinREL were defined by standard IMWG criteria (Durie el al, Leukemia 2006). ClinREL was defined by new/progressive bone lesion or plasmacytoma, hypercalcemia (>11.5 mg/dl), decrease in hemoglobin ≥ 2 g/dl, rise in creatinine ≥ 2 mg/dl, or indication for new myeloma therapy. Results: 76 patients had clinREL after AHCT, 24 were excluded due to light chain predominant or oligosecretory disease, subsequent AlloHCT or other preemptive treatment. Among 52 evaluable patients, median age was 57 years (42–74), 72% had DSS stage III, 40% ISS stage III, 40% high-risk (HR) MM based on t(4;14), t(14;16), 17q del or karyotypic 13 q abnormality. Median time from AHCT to relapse was 484 days (76–1631). Three temporal patterns of MM recurrence were identified: EBP where SFLC/M spike elevation (or both) preceded clinREL (n=28, 54%); concurrent clinREL and SFLC/M spike elevation (n=22, 42%) or isolated clinREL (4%). The proportion of HR MM was similar among groups. The EBP cohort had superior OS compared to concurrent relapse cohort (log rank p <0.0001). Additionally in the EBP cohort, SFLC elevation alone (39%), M spike progression alone (22%) or concurrent SFLC and M spike (39%) progression could be the initial relapse marker. After isolated SFLC progression, median time to M spike progression was 112 days and to clinREL was 200 days. After isolated M spike progression median time to clinREL was 254 days. After simultaneous SFLC and M spike progression median time to clinREL was 234 days. In these 3 groups, overall time to clinREL after AHCT was longest for patients with M spike progression alone (17.8, 20.5 and 36.8 months, respectively; p=0.05). This was due to HR MM being more common in the first 2 groups (45% for isolated SFLC and 37% in the simultaneous SFLC/M spike group). Discussion: In this cohort of relapsed MM after transplant, 54% had isolated early biochemical progression prior to clinREL and this pattern predicted for superior survival. The category of clinREL may not be detected in advance in about one half of patients and predicts for more aggressive relapse. Present guidelines do not recommend SFLC monitoring for relapse in IIM patients with measurable serum M spike. Based on the above data early SFLC progression was seen in 20% of relapses and identified a higher risk subgroup within those with biochemical progression preceding clinREL. Disclosures: No relevant conflicts of interest to declare.

Thyrotropinomas

Thyrotropinomas are rare tumours, accounting for no more than 1% of all secreting or nonsecreting pituitary adenomas (1, 2). Since the prevalence of pituitary tumours in the general population is about 0.03%, 1–3 thyrotropinomas are expected to be seen per million people. The number of reported thyrotropinomas increased exponentially in the past years, as a consequence of the introduction of ultrasensitive immunometric assays for thyroid-stimulating hormone (TSH) as first-line test for evaluating thyroid function (1). Based on the finding of measurable serum TSH levels in the presence of elevated thyroid hormone concentrations, many patients previously thought to be affected with Graves’ disease or toxic nodular goitre could be correctly diagnosed as patients with central hyperthyroidism. In our opinion, this latter term is preferable to ‘inappropriate secretion of TSH’, as it more precisely reflects the pathophysiological events underlying such an unusual disorder, where the thyroid hormone negative feedback mechanism is clearly disrupted and TSH itself is responsible for the hyperstimulation of the thyroid gland and the consequent hypersecretion of thyroid hormones (Fig. 2.3.13.1). Central hyperthyroidism is mainly due to autonomous TSH hypersecretion from a thyrotropinoma. However, signs and symptoms of hyperthyroidism along with biochemical findings similar to those found in thyrotropinoma, may be recorded in the minority of patients with resistance to thyroid hormones (RTH) (3, 4). This form of RTH is called pituitary RTH (PRTH), as the resistance to thyroid hormone action appears more severe at the pituitary than at the peripheral tissue level (see Fig. 2.3.13.1). The clinical importance of these rare entities is based on the diagnostic and therapeutic challenges they present. Failure to recognize these different disorders may result in undesirable consequences, such as improper thyroid ablation in patients with central hyperthyroidism or unnecessary pituitary surgery in patients with RTH. Conversely, early diagnosis and correct treatment of thyrotropinomas may prevent the occurrence of complications (visual defects by compression of the optic chiasm, hypopituitarism, etc.) and should improve the rate of cure.