Sidiqi, M Hasib

Abstract Frontline therapy for systemic amyloid light chain (AL) amyloidosis has evolved significantly with the approval of daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone, which has significantly improved rates of both hematologic and organ responses. Despite these advances, many patients eventually relapse, and there remains no established standard salvage regimen or optimal timing. In this review, we examine optimal timing of salvage regimens and currently available therapeutic options after daratumumab failure, including next-generation proteosome inhibitors or immunomodulatory drugs, autologous stem cell transplant, BCL-2 inhibitors, and emerging immunotherapeutic agents such as chimeric antigen receptor T-cell therapy and bispecific antibodies.

AbstractMultiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B‐cell lymphoma 2 (BCL‐2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut‐off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1–15) and 14% of patients had received ≥10 prior lines of therapy. Fifty‐three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9–10.3) months and median OS was 28.4 (95% CI 14.6‐not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily‐treated patients with relapsed/refractory MM, particularly the t(11;14) patient‐population.

AbstractIntroduction/AimsWe aimed to describe the clinical phenotype, histopathological findings and overall survival (OS) of the immune‐mediated neuromuscular complications of graft‐versus‐host disease (GVHD).MethodsWe conducted a retrospective chart review of adult patients presenting with immune‐mediated neuromuscular complications of GVHD to Mayo Clinic, between April 2013 and July 2018.We collected clinical and laboratory characteristics, histopathological findings, response to treatment and survival data.ResultsWe identified 20 patients with a mean age at presentation of 55 y. Mean time from transplant to neurological presentation was 14 mo. Myositis was the most common complication seen in 17 patients, manifesting with predominantly axial and/or proximal weakness. Eleven patients had a muscle biopsy showing diffuse perimysial, predominantly macrophagic infiltration in 10, 3 of them with perimysial perivascular lymphocytic collections, and endomysial and perimysial lymphocytic infiltration in 1. Only two patients had a neuropathic complication: one each with acute inflammatory demyelinating polyradiculoneuropathy and neuralgic amyotrophy. A single patient had a myasthenic syndrome presenting with fluctuating foot drop. Nineteen patients were treated and all responded to immunosuppressive agents; however, 11 had further GVHD flares requiring escalation of therapy. After a median follow‐up of 83 mo, seven (35%) patients died: five from progressive GVHD and two from infections. The 5‐y OS from time of transplant was 68%.DiscussionMyositis is the most common immune‐mediated neuromuscular complication of GVHD while peripheral neuropathy and myasthenic syndromes appear less common. The macrophage‐predominant infiltration on muscle biopsy deserves further study to better clarify the role of macrophages in GVHD pathogenesis.

Introduction: Cardiac involvement is one of the main predictors for survival in patients with light chain (AL) amyloidosis. Biomarkers such as Troponin T and N-terminal pro b-type natriuretic peptide (NT-proBNP) are used routinely for detecting cardiac involvement. In addition echocardiogram (ECHO) is used to determine septal and left ventricular wall thickness and strain. Most patients with AL present with preserved ejection fraction (EF) however, the outcomes of AL patients undergoing autologous stem cell transplantation (ASCT) with decreased EF are not very well described. Methods: We retrospectively reviewed patients who had a diagnosis of AL amyloidosis and received ASCT between March 1996 and September 2017. All patients had an ECHO done before ASCT and the EF was documented. In our practice, the threshold for performing ASCT is an EF >40%. We evaluated the outcomes of patients who had an EF <55% compared to patients with an EF ≥55%. The baseline characteristics were compared between patients with high and low EF. 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>65 vs. ≤65 years, Mayo 2012 stage 3/4 vs. 1/2, bone marrow plasma cell percentage (BMPC) ≥ 10% vs. <10%, organs involved >2 vs. ≤2, melphalan conditioning 200mg/m2 vs. 140 mg/m2 ,ASCT year >2010 vs. ≤2010, and EF <55% vs. ≥55%. Results: We identified 716 patients and 69 (10%) had an EF<55%, with most (n=63, 91%)having cardiac involvement . Compared to patients with EF ≥55%, patients with EF <55% were more likely to have Mayo 2012 stage 3/4 (58% vs. 22%, P<0.0001) and more likely to have thicker interventricular septum (median 14 vs. 12 mm, P<0.0001). The day 100 transplant related mortality (TRM) was higher in patients with EF <55% compared to EF ≥55% (19% vs. 6%, P=0.0006). In patients with Mayo 2012 stage 3/4, the day 100 TRM was higher in patients with an EF<55% compared to EF ≥55% (27% vs. 7%, P=0.004). Overall, PFS and OS were significantly shorter in patients with EF <55% compared to patients with EF ≥55% (Figure 1 A,B). Evaluating PFS and OS according to EF specifically in Mayo 2012 stage 3/4 patients is displayed in Figure 1 (C,D). Predictors for PFS included Mayo 2012 stage 3/4 vs. 1/2 (hazard ratio (HR): 1.4, P=0.006), BMPC ≥ 10% vs. <10% (HR: 1.5,P=0.0005), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.7, P=0.01), ASCT year >2010 vs. ≤2010 (HR: 0.7, P=0.01), and EF <55% vs. ≥55% (HR: 1.5, P=0.02). For OS, age >65 vs. ≤65 years (HR:1.4, P=0.04), Mayo 2012 stage 3/4 vs. 1/2 (HR: 1.96, P<0.0001), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.5, P<0.0001), BMPC ≥ 10% vs. <10% (HR: 1.8, P=0.03), ASCT year >2010 vs. ≤2010 (HR: 0.5, P<0.0001), and EF <55% vs. ≥55%(HR:1.9, P=0.003) were predictive. Conclusion: Having an EF <55% is associated with a higher day 100 TRM and is an independent predictor for PFS and OS in patients with AL amyloidosis undergoing ASCT. Disclosures Sidiqi: Janssen: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Other: Travel grant. Dingli:Alexion: Consultancy; Apellis: Consultancy; Sanofi-Genzyme: Consultancy; Millenium: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Janssen: Consultancy; Rigel: Consultancy. Kapoor:Janssen: Research Funding; GlaxoSmithKline: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Celgene: Honoraria; Takeda: Honoraria, Research Funding; Amgen: Research Funding. Dispenzieri:Janssen: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Kumar: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; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; 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; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Cellectar: Other; Carsgen: Other, Research Funding. Gertz:Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Sanofi: Other; Research to Practice: Other; Celgene: Other; Medscape: Other: personal fee, Speakers Bureau; Proclara: Other; DAVA oncology: Speakers Bureau; Alnylam: Other: personal fee; Johnson and Johnson: Speakers Bureau; Physicians Education Resource: Other: personal fee; Teva: Speakers Bureau; Ionis/Akcea: Other: personal fee; Amgen: Other: personal fee; Springer Publishing: Patents & Royalties; Aurora Bio: Other; Appellis: Other: personal fee; Abbvie: Other; Annexon: Other: personal fee; Prothena: Other: personal fee.

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>65 vs. ≤65 years, Mayo 2012 stage 3/4 vs. 1/2, BMPC ≥ 10% vs. <10%, organs involved >2 vs. ≤2, melphalan conditioning 200mg/m2 vs. 140 mg/m2 ,ASCT year >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. <10% (HR: 1.4,P=0.004), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.6, P=0.001), ASCT year >2010 vs. ≤2010 (HR: 0.8, P=0.03), and the presence vs. absence of a measurable serum M-spike (HR: 1.82, P<0.0001). For OS, Mayo 2012 stage 3/4 vs. 1/2 (HR: 2, P<0.0001), melphalan conditioning 200mg/m2 vs. 140 mg/m2 (HR:0.4, P<0.0001), ASCT year >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.

AbstractThree sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were independently developed for staging, progression and response criteria to predict renal survival in patients with AL amyloidosis. We evaluated these criteria using a cohort of 495 newly diagnosed AL amyloidosis patients with renal involvement using time to event competing risk analysis at baseline, 3, 6 and 12 months after treatment. Only Palladini and Kastritis had a staging system and both predicted a higher risk of end stage renal disease (ESRD) in the stage III vs stage I patients but only the Palladini model was predictive for stage II patients. At 3 months, risk of ESRD was significantly higher for Palladini and ISA renal progression (hazard ratio [HR] 2.8 [95% CI: 1.5–5.3, p = .001] and 2.5 [CI: 1.4–4.6, p = .004, respectively]), but renal response was not significantly protective; conversely, the risk of ESRD was not significantly higher for the Kastritis renal progression, but was significantly protective for the Kastritis renal responders (HR 0.38 [95% CI: 0.17–0.84], p = .017). Both progression and response with ISA, Palladini and Kastritis criteria were predictive of ESRD at 6 months and 12 months. While the Palladini staging criteria at baseline, and the ISA and Palladini criteria for progression at 3 months performed better than the Kastritis criteria at baseline and 3 months post‐treatment, the Kastritis criteria performed better for response 3 months after treatment. All three sets of criteria performed well at and after 6 months post‐treatment. These differences are important when choosing endpoints for clinical trials.

Background. Experience with sequential hematopoietic stem cell transplant (HSCT) and kidney transplant (KT) is limited. Methods. We conducted a retrospective observational study of adult patients who underwent both HSCT and KT at our center, with a median follow-up of 11 y. Results. In our 54 patients cohort (94% autologous HSCT), 36 (67%) patients received HSCT first followed by KT, while 18 (33%) received KT before HSCT. In both groups, AL amyloidosis represented 50% of hematologic diagnosis. Only 4 patients expired due to hematologic disease relapse (2 patients in each group) and only 3 allografts were lost due to hematologic disease recurrence (HSCT first n = 1 and KT first n = 2). Overall 1, 5, and 10 y death-censored graft survival rates were 94%, 94%, and 94%, respectively, for the HSCT first group and 89%, 89%, and 75%, respectively, for the KT first group. Overall 1, 5, and 10 y patients survival rates were 100%, 97% and 90%, respectively, for the HSCT first group and 100%, 76%, and 63%, respectively, for the KT first group. Conclusions. Our study supports safety of sequential KT and HSCT, with improved overall patient survival compared to recipients of HSCT remaining on dialysis and good long-term kidney allograft outcome.