Citations

Background: Two-stage exchange arthroplasty with a high-dose antibiotic-loaded bone cement (ALBC) spacer and intravenous or oral antibiotics is the most common method of managing a periprosthetic joint infection (PJI) after a total knee arthroplasty (TKA). However, little is known about the contemporary incidence, the risk factors, and the outcomes of acute kidney injuries (AKIs) in this cohort. Methods: We identified 424 patients who had been treated with 455 ALBC spacers after resection of a PJI following a primary TKA from 2000 to 2017. The mean age at resection was 67 years, the mean body mass index (BMI) was 33 kg/m 2 , 47% of the patients were women, and 15% had preexisting chronic kidney disease (CKD). The spacers (87% nonarticulating) contained a mean of 8 g of vancomycin and 9 g of an aminoglycoside per construct (in situ for a mean of 11 weeks). Eighty-six spacers also had amphotericin B (mean, 412 mg). All of the patients were concomitantly treated with systemic antibiotics for a mean of 6 weeks. An AKI was defined as a creatinine level of ≥1.5 times the baseline or an increase of ≥0.3 mg/dL within any 48-hour period. The mean follow-up was 6 years (range, 2 to 17 years). Results: Fifty-four AKIs occurred in 52 (14%) of the 359 patients without preexisting CKD versus 32 AKIs in 29 (45%) of the 65 patients with CKD (odds ratio [OR], 5; p = 0.0001); none required acute dialysis. Overall, when the vancomycin concentration or aminoglycoside concentration was >3.6 g/batch of cement, the risk of AKI increased (OR, 1.9 and 1.8, respectively; p = 0.02 for both). Hypertension (β = 0.17; p = 0.002), perioperative hypovolemia (β = 0.28; p = 0.0001), and acute atrial fibrillation (β = 0.13; p = 0.009) were independent predictors for AKI in patients without preexisting CKD. At the last follow-up, 8 patients who had sustained an AKI had progressed to CKD, 4 of whom received dialysis. Conclusions: In our study, the largest series to date that we are aware of regarding this issue, AKI occurred in 14% of patients with normal renal function at baseline, and 2% developed CKD after undergoing a 2-stage exchange arthroplasty for a PJI after TKA. However, the risk of AKI was fivefold greater in those with preexisting CKD. The causes of acute renal blood flow impairment were independent predictors for AKI. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Significance Statement Treatment of proliferative GN with monoclonal Ig deposition (PGNMID), in which direct deposition of the monoclonal proteins damages the kidney, is not established. Daratumumab, a monoclonal anti-CD38 antibody, has shown effectiveness as multiple myeloma therapy. In an open-label, phase 2 study, the authors evaluated safety and efficacy of a 6-month course of intravenous daratumumab in 11 patients with PGNMID and one with C3 glomerulopathy with monoclonal gammopathy. Five episodes of serious adverse events (two of which were infection related) occurred. All ten patients with PGNMID who received at least one daratumumab dose experienced a significant reduction in proteinuria at 6 months, which was sustained in seven patients by 12 months. Overall, in this pilot study, daratumumab’s acceptable toxicity profile and significant improvement in proteinuria, while stabilizing kidney function, suggest further investigation is warranted. Background Treatment of proliferative GN with monoclonal Ig deposits (PGNMID) is not established. A monoclonal anti-CD38 antibody (daratumumab) is effective in treating multiple myeloma. Abnormal plasma cell clones may play a role in the pathogenesis of PGNMID. Methods We evaluated daratumumab’s safety and efficacy in an open-label, phase 2 trial in 11 adults with PGNMID and one with C3 glomerulopathy (C3G) with monoclonal gammopathy. Patients had an eGFR >20 ml/min per 1.73 m 2 and proteinuria >1 g/d. They received daratumumab intravenously (16 mg/kg) once weekly for 8 weeks, and then every other week for eight additional doses. Primary outcome was safety, defined as major infections, grade 3 or 4 anemia, leukopenia, or thrombocytopenia. Secondary outcomes were rate of complete remission (proteinuria <500 mg/d with <15% decline in baseline eGFR) or partial remission (>50% reduction in 24-hour proteinuria with <30% decline in eGFR) and proteinuria at 6 and 12 months. Results One patient with C3G had GN unrelated to the monoclonal gammopathy, and one with PGNMID did not complete the first infusion. Five serious adverse events occurred. During the 12 months of the trial, six of the ten patients with PGNMID who received at least one dose of daratumumab had a partial response, and four had a complete response (an overall response rate of 100%). Three patients experienced relapse, two of whom re-entered partial remission after resuming daratumumab therapy. Proteinuria declined significantly, from a median of 4346 mg/d to 1264 mg/d by 12 months. Conclusions Daratumumab demonstrated an acceptable safety profile and resulted in significant improvement in proteinuria while stabilizing kidney function in patients with PGNMID, suggesting the drug merits further investigation. Clinical Trial registry name and registration number: Daratumumab in Treatment of PGNMID and C3 GN, NCT03095118

Abstract The utility of systemic light chain (AL) amyloidosis staging systems has been validated for newly diagnosed patients, but their role in restaging after treatment has not been explored. We designed this study to evaluate whether the currently used systems are of prognostic value at 3 and 6 months of starting first-line treatment, and whether stage migration from diagnosis impacts survival. This is a retrospective study including Mayo Clinic patients with AL amyloidosis diagnosed between 1 January 2006 and 30 June 2019; 536 and 204 patients had restaging data for at least 1 system at 3 and 6 months, respectively. Using modified Mayo 2004 staging at 3 months, median overall survival (OSs) were 11.8, 10.8, 4.6, and 1.1 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, median OSs were 11.8, 9.0, 5.2, and 0.8 years for stage I, II, III, and IV, respectively. Using modified Mayo 2004 staging at 6 months, median OSs were not reached (NR), NR, 5.4, and 0.9 years for stage I, II, IIIa, and IIIb, respectively. Using Mayo 2012, OSs were NR, NR, 4.6, and 0.9 years for stage I, II, III, and IV, respectively. Worsening stage at 3 or 6 months was associated with worse survival than retaining baseline stage. In conclusion, the current staging systems can be used for restaging at 3 and 6 months from treatment initiation. Migration to higher stage predicts poor prognosis.

Background: Bortezomib, a proteasome inhibitor, has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and the combination of bortezomib, cyclophosphamide and dexamethasone is a commonly used regimen in AL. Ixazomib is the first oral proteasome inhibitor to be approved, and the combination of ixazomib with cyclophosphamide and dexamethasone is an all oral effective regimen for the treatment of multiple myeloma. This phase 2 trial was designed to evaluate the efficacy of this regimen in patients with AL, who have not received any therapy. Patients and methods: Newly diagnosed patients with biopsy proven AL amyloidosis, with organ involvement requiring therapy, were enrolled if they had measurable disease (Serum immunoglobulin free light chain ≥5 mg/dL AND abnormal serum free light chain ratio) and adequate organ function. Patients with severe organ involvement were excluded (Alkaline phosphatase &gt;750 U/L, creatinine clearance &lt;30 mL/min or NT-ProBNP ≥ 7500 ng/dL). Treatment consisted of ixazomib 4 mg days 1, 8, 15; cyclophosphamide 500 mg PO weekly and dexamethasone 40 mg, weekly for twelve 28-day cycles, followed by ixazomib maintenance (days 1, 8, 15) at the last tolerated dose till progression. The primary objective was to determine the hematologic response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated AL. A one-stage binomial design was utilized to test the null hypothesis that the hematologic response rate is at most 30% against the alternative hypothesis that it is at least 50%, with 85% power and 9% type I error. Results: Thirty-five patients were enrolled, median age was 67 (range 38-78) years; 69% were male. Organ involvement included cardiac in 23 (65.7%), renal in 19 (54.3%), and nervous system involvement in 5 (14.3%). At data cutoff 8 patients still remain on study with a median follow up of 4.4 months for those who are alive. Across the trial a median of 4 cycles (range 0-23) of treatment have been completed; the most common reason for going off study was institution of alternate therapy in 17 patients (63%). The overall hematologic response was 57% (20/35) and included amyloid CR in 5 (14%), VGPR in 9 (26%) and a PR in 6 (17%) patients. Confirmed organ responses have been observed in 5 patients so far, 2 each for cardiac and renal and 1 hepatic. The median PFS and OS have not been reached; 4 patients had hematological progression; 6 patients (17%) have died. Across 193 cycles of treatment administered, dose modification was required in 5, 3, and 10 patients, respectively, for ixazomib, cyclophosphamide and dexamethasone. A grade 3 or higher adverse event (AE), at least possibly attributed to the study drugs, was observed in 41% of patients. The figure shows the maximum grade of adverse events for individual patients seen in more than one patient across the study. Conclusions: The all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone is active in patients with previously untreated AL amyloidosis with hematologic responses observed in 57% of patients, including complete responses. Organ response has been observed but will likely need longer follow up for accurate assessment, given the delay in organ responses in this disease. Further evaluation of this combination is warranted. Disclosures Gertz: Alnylam: Consultancy; Ionis/Akcea: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy. Kapoor:Celgene: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Larsen:Janssen Oncology: 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. Dingli:Apellis: Consultancy; Janssen: Consultancy; Sanofi-Genzyme: Consultancy; Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Alexion: Consultancy; Millenium: Consultancy. Dispenzieri:Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Kumar:Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; AbbVie: 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; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; 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; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; MedImmune: Research Funding.

Background: Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. FDG PET/CT has been shown to be predictive of patient outcomes throughout the disease course, with several studies demonstrating that PET/CT is an independent prognostic factor for progression free survival and overall survival (OS). We sought to corroborate these findings by specifically examining the prognostic impact of PET/CT in the post-transplant setting. We retrospectively analyzed PET/CT in MM patients after consolidation therapy with autologous stem cell transplant (ASCT) and correlated these findings with time to progression (TTP) and OS to assess the impact of day 100 PET/CT findings as an independent prognostic factor. Methods: A retrospective cohort study was conducted on 231 myeloma patients who underwent ASCT between 2003-2016 and had a FDG PET/CT exam available for analysis at an average of day 104 post-transplant. We recorded the findings on PET/CT prior to transplant, where available. PET/CT without evidence of active/residual disease (PET-) was defined per IMWG guidelines (disappearance of every area of increased tracer uptake found on preceding PET/CT, or uptake &lt; mediastinal blood pool, or decrease &lt; surrounding normal tissue). PET/CT indicating active disease (PET+) was defined as any abnormal uptake or incompletely resolved uptake from previous exam. A Kaplan-Meier model was used to estimate median TTP and OS and the 2-sided log-rank test to compare groups. TTP and OS were calculated from the date of ASCT to the date of confirmed disease progression or death, respectively. Outcomes were then compared among patients with a PET/CT versus those without a PET/CT post-ASCT to assess for the presence of selection bias. A proportional hazards fit model was used for multivariate analysis. Results: The median length of follow-up for the entire cohort was 49 months (range: 43-58 mo), median TTP was 18.5 months (95% CI; 15.4-21.8), and median OS was 61.5 months (95% CI; 49-75). Among the entire cohort (n=231), 150 (65%) patients had a positive PET/CT exam at day 100 post-ASCT while 81 (35%) had a negative PET exam. There were 195 (84%) patients with a PET/CT exam prior to ASCT available for comparison, of which 161 (85%) were PET+ and 29 (15%) were PET-. Median time between PET/CT exams was 4.1 months (range 1.4-55). Median TTP among PET+ patients near day 100 was 12.4 months vs. 24 months PET- patients (p&lt;.0001, Fig 1, panel A). Median OS in the PET+ group was 46 months compared to 99 months in the PET- group (p&lt;.0001, Fig 1, panel B). Among patients with a prior PET/CT (195, 84%), median TTP was longer in patients with both exams negative compared to those who were day 100 PET- and previously PET+ (42.6 mo vs. 21.1 mo respectively; p&lt;.0001). TTP was shorter in those who were day 100 PET+ and previously PET- compared to those with persistently PET+ on both exams (4.5 vs. 12.3 mo; p&lt;.0001, Figure 2). Since PET/CT was not routinely ordered post ASCT, we also compared the outcomes between patients getting a PET/CT (n=231) and remaining patients undergoing ASCT (n=1764). Among patients with a day 100 PET/CT vs. those without a PET/CT exam, there was a slightly longer median TTP and OS in the group who did not have a post-ASCT PET/CT. Hazard ratios (HR) after adjusting for disease response (CR at day 100 vs. non-CR) were as follows: TTP PET+ HR 1.76 (1.2-2.4; p=0.003), OS PET+ HR 1.8 (1.2-2.6; p=.0016). Conclusions: MM is a heterogeneous disease that relies on different assessments for determining response, activity, and prognosis. Among these, PET/CT has shown promise in predicting prognosis, independent of disease state and conventional prognostic factors. Our study confirms these findings, demonstrating that an abnormal PET/CT near day 100 post-transplant is predictive of shorter TTP and OS. This prognostic significance remained even after adjusting for disease response (CR vs. non-CR), which could be explained by the sometimes patchy distribution of myeloma in the bone marrow, and identification of extramedullary disease by PET/CT. Taken together, these results demonstrate a possible role for incorporating PET/CT in the post-transplant setting as an independent prognostic variable in stratifying disease risk. Disclosures Dingli: Apellis: Consultancy; Janssen: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Karyopharm Therapeutics: Research Funding; Sanofi-Genzyme: Consultancy; Bristol Myers Squibb: Research Funding; Alexion: Consultancy. Gertz:NCI SPORE MM: Research Funding; International Waldenstrom Foundation: Research Funding; Amyloidosis Foundation: Research Funding; Springer Publishing: Patents & Royalties; i3Health: Consultancy; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; DAVA oncology: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Physicians Education Resource: Consultancy; Medscape: Consultancy, Speakers Bureau; Amgen: Consultancy; Appellis: Consultancy; Annexon: Consultancy; Spectrum: Consultancy, Research Funding; Janssen: Consultancy; Sanofi: Consultancy; Prothena: Consultancy; Alnylam: Consultancy; Ionis/Akcea: Consultancy. Dispenzieri:Janssen: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Intellia: Research Funding; Takeda: Research Funding. Kapoor:Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; GlaxoSmithKline: Research Funding. Lin:Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Kumar:Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; 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; Cellectar: Other; Tenebio: Other, Research Funding; Sanofi: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Genecentrix: Consultancy; MedImmune: Research Funding; BMS: Consultancy, Research Funding.

Background: The absence of residual monoclonal protein in the serum and urine by IFE using specific antibodies to individual heavy and light chains has been an important part of response assessment and is required for categorizing patients as in complete response. MASS FIX has been shown to be more sensitive in picking up small amounts of monoclonal protein and represents an advancement in the field. Ongoing studies are examining the clinical significance of this increased sensitivity. We designed the following study using clinically obtained test results to examine this question. Patients and methods: The clinical laboratory at Mayo Clinic changed the process from IFE to MASS FIX in July 2018. We identified patients who had sequential testing before and after this date and collected test results from the last IFE prior to the date of transition and the first MASS FIX after the date of transition. Patients were grouped based on the paired results and outcomes compared between groups. Time to next therapy (TTNT) was defined as the time from the first MASS FIX date to the start of next therapy. Survival was estimated by the Kaplan-Meier method and these curves were compared using log rank test. Results: Overall, 739 patients with MM, who had a MASS FIX within 12 months of the IFE were studied; 380 (51%) patients had a negative IFE prior to implementation of MASS FIX. These patients had a MASS FIX test performed at a median of 3.7 (0.03-12) months from the last available IFE. The gap between IFE and MASS FIX was &lt;6 months and &lt; 3 months in 71% and 54% of the patients. Among the patients with a negative IFE, 130 (34%) tested positive on the subsequent MASS FIX. Limiting the analysis to those with a MASS FIX within 6 and 3 months yielded 32% in each group that turned positive from previous negative IFE. The median TTNT from the MASS FIX date was significantly shorter for those who became positive on MASSFIX; median was not reached for either group (P=0.002) (Figure). We then limited the analysis to those patients with a gap of &lt;6 months and &lt;3 months between the tests. The results were consistent: P= 0.012 for those with a gap of &lt; 6 months and P=0.01 for those with a gap &lt; 3 months. Conclusion: The results suggest that the additional sensitivity offered by MASS FIX have clinical significance in patients with MM, given that patients with residual disease identified by MASS FIX have an earlier relapse. The data supports the use of the more sensitive MASS FIX in the laboratory compared to the conventional IFE approaches. The study has the disadvantage that the samples were not tested simultaneously and some of the samples turning positive may reflect an early evidence of relapse, but the relative consistency of the finding irrespective of the gap between the tests argues against that. Ongoing studies are examining MASS FIX on the samples that were called to be negative by IFE initially. Figure Disclosures Murray: The Binding Site: Patents & Royalties: Patent Use of Mass Spec to identify monoclonal proteins licensed to The Binding Site. Dispenzieri:Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Intellia: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding. Kapoor:Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Amgen: Research Funding. Gertz:Janssen: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Springer Publishing: Patents & Royalties; Abbvie: Other; Appellis: Other: personal fee; Annexon: Other: personal fee; Celgene: Other; Amgen: Other: personal fee; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Research to Practice: Other; Sanofi: Other; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Proclara: Other; Aurora Bio: Other; Prothena: Other: personal fee; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee. Dingli:Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy; Alexion: Consultancy; Janssen: Consultancy; Apellis: Consultancy. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy. Kumar:Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; Tenebio: Other, Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy, Research Funding; Sanofi: Research Funding; Takeda: 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; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; MedImmune: Research Funding; Cellectar: Other; Genecentrix: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Novartis: Research Funding.

Introduction: Light chain deposition disease (LCDD) is a rare complication of monoclonal gammopathies, defined by non-amyloid linear monoclonal light chain (most commonly kappa) deposits in the kidney and other organs. The rarity of LCDD has hampered clinical studies and staging systems and response criteria are lacking. The International Kidney Myeloma Working Group (IKMG) started a clinical data collection from all participating centers in order to define the natural history of LCDD, and to establish prognostic factors and response criteria in a large, international, unselected patient population. Methods: Eight referral centers have yet participated in the data collection at the data lock of July 31, 2020. Patient inclusion is ongoing and expected accrual is 500 patients. The diagnosis of LCDD had to be biopsy-proven. The patients were diagnosed between 1992 to 2020. Response was assessed 6 months after treatment initiation according to the criteria used in light chain (AL) amyloidosis. Renal survival (RS) was defined as time from diagnosis to dialysis or last follow-up. Patients who died without requiring dialysis were censored at the time of death. The analysis of factors predicting RS was performed in patients whose baseline estimated glomerular filtration rate (eGFR) was &gt;15 mL/min. The cutoffs of baseline variables, as well as the cutoffs measured at the time of response, best predicting RS or OS at 12 months were identified by means of Receiver Operator Characteristics (ROC) analyses. All patients gave written informed consent for their clinical data to be used for research purposes. Results: Overall, 359 patients have been included in this first analysis. Sixteen (4%) subjects had concomitant cast nephropathy. The main clinical characteristics are reported in the Table. Median overall survival (OS) was 13 years and RS was 12 years (Figure1 A and 1B) and median survival of living patients is 4.5 years. At univariate analysis the only baseline variables predicting RS were proteinuria [best cutoff 2.5 g/24h, HR 2.25 (95%CI 1.13-4.60), P=0.02], and eGFR [best cutoff &gt;30 mL/min, HR 0.50 (95%CI 0.26-0.96) P=0.037], but at multivariate analysis only proteinuria predicted RS [HR 2.17 (95% CI 1.08, 4.33), P=0.027]. At univariate analysis, a higher bone marrow plasma cell infiltrate (best cutoff ≥20%) at diagnosis was associated with a significantly lower OS [HR 1.96 (95% CI 1.23-3.13) P=0.004], as was having end stage renal disease (ESRD) defined as an eGFR &lt;15 mL/min [HR 1.81 (95%CI 1.11-2.92) P=0.015]. We then tested the ability of the hematologic response criteria for AL amyloidosis to discriminate groups with different survival after treatment in a 6 months landmark analysis. Our choice of adopting the amyloidosis response criteria was corroborated by the results of the ROC analysis showing that the difference between involved and uninvolved free light chains (dFLC) cutoff (40 mg/L) used in AL amyloidosis to define very good partial response (VGPR) had 87% sensitivity and 65% specificity in identifying patients who needed dialysis within 12 months. Partial response (PR, 19% requiring dialysis at 3 years) was not associated with a RS benefit over no-response (29% requiring dialysis at 3 years, P=0.511). However, VGPR conferred a significant RS advantage (10% requiring dialysis at 3 years) over PR (P=0.002). No significant difference in RS was seen between complete response (CR, 0% requiring dialysis at 3 years) and VGPR (P=0.178). Thus, achieving VGPR or CR by amyloidosis response criteria [post-treatment dFLC&lt;40 mg/L (VGPR by AL criteria), with or without negative serum and urine immunofixation and normal FLC-ratio (CR by AL criteria)] was adopted as a provisional criterion for hematologic response in LCDD (Figure 1D). LCDD response was also associated with prolonged OS (Figure 1C). Conclusions: Almost one-third of patients with LCDD are diagnosed when they already have ESRD resulting in shorter OS. The degree of proteinuria and of bone marrow plasma cell infiltration predict RS and OS, respectively. Achievement of post treatment dFLC &lt;40 mg/L or negative serum and urine immunofixation at 6 months is proposed as a provisional criterion for hematologic response, being able to predict both improved RS and OS. Planned expanded recruitment might allow a validation analysis of the results, the analysis of organ response data and the evaluation of different time-points for response assessment. Disclosures Milani: Celgene: Other: Travel support; Janssen: Other: Speaker honoraria; Pfizer: Other: Speaker honoraria. Kastritis:Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Bridoux:Baxter: Consultancy; Janssen: Honoraria; Celgene: Honoraria. Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Oncopeptides: Consultancy; Amgen: Research Funding; Caelum: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Research Funding; Roche: Research Funding; Karyopharm: Honoraria, Research Funding. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. Palladini:Jannsen Cilag: Honoraria, Other; Celgene: Other: Travel support. Wechalekar:Celgene: Honoraria; Caelum: Other: Advisory; Janssen: Honoraria, Other: Advisory; Takeda: Honoraria, Other: Travel.

Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab (Dara), a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to PI or IMiD. Ixazomib, lenalidomide and dexamethasone (IRd) is an effective, all oral, induction regimen that has been studied in phase 2 and 3 trials. We designed this trial to examine the feasibility and efficacy of adding daratumumab to the IRd regimen as well as early discontinuation of dexamethasone in two sequential cohorts of patients. Patients and Methods: Patients with previously untreated MM who had measurable disease and adequate organ function were enrolled, irrespective of their autologous stem cell transplant eligibility. The primary objective was to determine the rate of complete response to IRD-Dara combination. A one-stage binomial design was utilized in each cohort independently to test the null hypothesis that the complete response rate is at most 25% against the alternative hypothesis that it is at least 45%, with 89% power and 9% type I error. Treatment involved 28-day cycles consisting of ixazomib 4 mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and Dara 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks thereafter during induction (12-cyles) followed by Dara-ixazomib maintenance (maximum 24 cycles). Cohorts A (n=38) and B (N=40) comprised the study population, with dexamethasone discontinued after two cycles in Cohort B. Results: Baseline demographics and patient disposition are outlined in the table. Among those who have gone off study, 9 and 5 patients, respectively in Cohort A and B went off for progression, while 11 and 8 patients in the respective arms discontinued treatment for an alternative therapy, most frequently a transplant. Responses were rapid and deepened over the duration of treatment as shown in the figure; 32% of patients in Cohort A and 28% of patients in Cohort B achieved a complete response; 29% and 23%, respectively, achieved a marrow minimal residual disease (MRD) negative status. After a median follow up was 31.4 months for Cohort A and 18.2 months for Cohort B, median PFS has not been reached in either cohort. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 58% of patients in Cohort A (hematologic in 47% and non-hematologic in 26%) and 50% of patients in Cohort B (hematologic 43%, non-hematologic 20%). The most common toxicities included fatigue, neutropenia, lymphopenia, peripheral neuropathy and nausea. Stem cells were collected in 30 and 31 patients in Cohorts A and B respectively; median (range) of CD34 cells/kg were 8.5 (2.8, 15.9) x 106and 7.0 (2.9, 12.1) x 106, with plerixafor used in 83% and 94% of patients, respectively, in Cohorts A and B as per our standard of care "on-demand" approach based on blood CD34 count. Conclusion: Dara-IRd is an active regimen in newly diagnosed MM, with high overall rates of response and deep responses that improved over time with therapy. Early discontinuation of dexamethasone does not appear to impact the depth, rate or kinetics of response. The toxicities were manageable, with dose modifications. All patients were able to collect stem cells when required, though majority needed plerixafor. Disclosures Kumar: Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Kite Pharma: Consultancy, Research Funding; Carsgen: Other, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Dr. Reddy's Laboratories: Honoraria; Takeda: 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; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Tenebio: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Sanofi: Research Funding; Novartis: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding. Kapoor:GlaxoSmithKline: Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Dingli:Apellis: Consultancy; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Bristol Myers Squibb: Research Funding; Alexion: Consultancy; Rigel: Consultancy; Millenium: Consultancy; Sanofi-Genzyme: Consultancy. Dispenzieri:Pfizer: Research Funding; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Intellia: Research Funding. Gertz:Abbvie: Other; Sanofi: Other; Celgene: Other; Research to Practice: Other; Physicians Education Resource: Other: personal fee; Amgen: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau; Appellis: Other: personal fee; Annexon: Other: personal fee; Alnylam: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Teva: Speakers Bureau; Aurora Bio: Other; Springer Publishing: Patents & Royalties; Proclara: Other; DAVA oncology: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Ionis/Akcea: Other: personal fee; Prothena: Other: personal fee.

Background: Newly diagnosed patients with AL Amyloidosis are a heterogeneous population, ranging from incidentally found nephrotic syndrome to delayed advanced cardiac disease. For the purposes of trials, patients with the highest-risk disease are often excluded from trial participation. An NT-proBNP of 8500 or higher is the criterion most often used for exclusion from clinical trials due to high rates of early death. It is well documented that overall survival is improving over time, in part due to earlier diagnosis and in part due to more effective therapies. It is our aim to describe outcomes of patients with very high (NT-proBNP &gt;=8500) and advanced stage amyloidosis excluding very high (VH) NT-proBNP. Methods: To address this need, we examined the outcomes of AL patients diagnosed between 1/2012 and 7/2020 and seen at our institution within 90 days of diagnosis. Of the 1290 patients, 291 were seen beyond the 90 day threshold and were thus excluded. Another 170 patients were excluded due to missing biomarkers to calculate stage, leaving 829 patients for our analysis. Thresholds for troponins and BNPs were used according to Muchtar Blood 133(7):2019 to correct for assay used. The vast majority of patients had troponin T measured, and for them the 0.025 mcg/L and the 0.035 mcg/L cut-points were used for the 2012 and 2004 staging systems. A minority of patients did not have troponin T, but rather high sensitivity troponin T (n=129) or troponin I (n=23). For patients with high sensitivity troponin T, cut-points of 41 and 50 ng/L were used, respectively, for the 2012 and 2004 systems, and for patients with troponin I only, a cut-point of 0.1 mcg/L was used for both systems. In the 3 patients with no NT-proBNP but with BNP, 400 and 81 ng/L were used respectively for the 2012 and 2004 systems; otherwise, the 1800 ng/L and 332 ng/L cut-offs were used. A BNP of &gt; 700 ng/L was considered equivalent to NT-proBNP greater than or equal to 8500 ng/L. For the 2012 system, the dFLC of 18 mg/dL was used as a cut-off. Survival estimates were done using the method of Kaplan-Meier, and differences in survival were by determined by Log-Rank. Results: The median age of patients was 65 (range 29, 89), and 65% were male. 148 (17%) of these newly diagnosed patients had a VH (&gt;=8500) NT-proBNP. Patients with VH NT-proBNP were older (67 versus 64 years, p=0.004). Only 4% of the VH NT-proBNP patients received an ASCT in contrast to 34% without VH NT-proBNP. With a median follow-up of 30 months for surviving patients, median OS for VH NT-proBNP patients was 3.3 months in contrast to patients without VH NT-proBNP at 68.4 months (Figure). Breakdown of early death for patients with VH NT-proBNP by stage is shown in Table. Of Mayo 2012 patients staged I, II, III, and IV, the percent of patients with VH NT-proBNP was 0, 3, 20, and 45%. In contrast, for the European modification of the Mayo 2004 system, the percent with VH NT-proBNP by stage was 0, 6, 0, 100 for stages I, II, IIIa, and IIIb, respectively. Among the VH NT-proBNP patients, there was stage discrimination using the Mayo 2012 system (6-month death rates were 17, 45, and 66% for patients with stages II, III, and IV, respectively, p=0.02). In contrast, using the Mayo 2004 system in the patients with VH NT-proBNP, 6-month death rates were 45 and 60% for stage II and IIIb patients, respectively (p= 0.12). Among patients without VH NT-proBNP, rates of death in the first year were 21% including stage I patients whose death rates were well under 10%. Patients without VH NT-proBNP but Mayo 2012 Stage III and IV had 1-year mortalities of 28 and 43% respectively. Using the modified Mayo 2004 system, excluding the VH NT-proBNP 1-year mortality was 19 and 37% for patients with stage II and IIIa, respectively. Discussion: Establishing expected outcomes for the sickest AL amyloidosis patients is a means by which trials can be designed for these patients with an unmet need. Patients with VH NT-proBNP should be considered for specially designed trials, and patients without VH NT-proBNP and advanced stage should be included in trials for newly diagnosed patients regardless of stage as long as there is appropriate stratification. Disclosures Dispenzieri: Janssen: Research Funding; Pfizer: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Kumar:AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Carsgen: Other, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Merck: Consultancy, Research Funding; Takeda: 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; Adaptive Biotechnologies: Consultancy; Dr. Reddy's Laboratories: Honoraria; Novartis: Research Funding; MedImmune: Research Funding; Genecentrix: Consultancy; Kite Pharma: Consultancy, Research Funding; Cellectar: Other; Karyopharm: Consultancy; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments. Dingli:Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Millenium: Consultancy; Janssen: Consultancy; Alexion: Consultancy; Rigel: Consultancy; Apellis: Consultancy; Sanofi-Genzyme: Consultancy. Kapoor:Celgene: Honoraria; Cellectar: Consultancy; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Gertz:Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy.