Hasib Sidiqi - Academia.edu (original) (raw)

Papers by Hasib Sidiqi

Research paper thumbnail of Differences in clinical presentation and outcome in different countries for Takayasuʼs arteritis

Current Opinion in Rheumatology, 1997

Research paper thumbnail of Prognostic role of beta-2 microglobulin in patients with light chain amyloidosis treated with autologous stem cell transplantation

Journal of Clinical Oncology, 2020

e20506 Background: Autologous stem cell transplantation (ASCT) prolongs survival in patients with... more e20506 Background: Autologous stem cell transplantation (ASCT) prolongs survival in patients with light chain (AL) amyloidosis. Mayo 2012 stage and increased plasma cell percentage (%PC) are known predictors for survival. Increased beta-2 microglobulin (B2M) predicts survival in patients with multiple myeloma. However, its prognostic effect in patients with AL amyloidosis undergoing ASCT is not known. Methods: We retrospectively reviewed patients who had a diagnosis of AL amyloidosis and were treated with ASCT between July-1996 and September-2017. Patients with creatinine > 1.2 mg/dL were excluded, as that affects B2M levels. The receiver operator curve was used to determine the best cutoff for B2M in predicting survival and was 2.5 mcg/mL. Baseline characteristics were compared between patients with B2M > 2.5 and ≤2.5. Progression-free survival (PFS) was defined as time from ASCT to relapse or death, whichever occurred first. Overall survival (OS) was calculated from ASCT to ...

Research paper thumbnail of Utility and prognostic value of 18F-FDG PET/CT scan in patients with newly diagnosed multiple myeloma

Journal of Clinical Oncology, 2018

8023Background: Positron emission tomography–Computed tomography (PET/CT) can identify bony lesio... more 8023Background: Positron emission tomography–Computed tomography (PET/CT) can identify bony lesions, assess disease burden and detect extramedullary disease in patients with newly diagnosed multipl...

Research paper thumbnail of The role of bone marrow biopsy in patients with plasma cell disorders; should all patients with a monoclonal protein be biopsied?

Clinical Lymphoma Myeloma and Leukemia, 2019

We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), ... more We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) patients seen at Mayo Clinic to determine whether a bone marrow biopsy (BM) is necessary in all patients diagnosed with a monoclonal protein. A total of 2254 MM, 397 SMM, and 5836 MGUS patients were included in the study. A total of 29 (1.3%) MM patients "without CRAB/FLC" were identified where BM or advanced imaging was critical for diagnosis, 8 (0.3% MM cohort) of whom were diagnosed with MM solely on BM findings (plasma cells > 60%). Without BM or advanced imaging none of these patients would be classified low-risk MGUS. A total of 314 (79%) MGUS-like SMM patients were identified where classification of SMM was based on BM findings. Without BM 97 would be classified as low/low-intermediate-risk MGUS and 151 intermediate or high-risk MGUS; 66 had missing information precluding classification. Only three (<1% SMM cohort) were low-risk MGUS without abnormalities in hemoglobin, calcium, and renal function. In patients presenting with low-risk MGUS and normal hemoglobin, calcium, and renal function, the risk of missing a diagnosis of SMM and MM by omitting BM is <1%. BM should be deferred in these patients in preference to clinical and laboratory monitoring.

Research paper thumbnail of Impact of Minimal Residual Negativity on Outcomes in Light Chain Amyloidosis

Clinical Lymphoma Myeloma and Leukemia, 2019

Research paper thumbnail of A Hematopoietic Score Predicts Survival in Newly Diagnosed Multiple Myeloma Patients

Clinical Lymphoma Myeloma and Leukemia, 2019

CD45, CD19), as well as the CD24 antibody. We analyzed CD24 expression in 84 newly diagnosed MM p... more CD45, CD19), as well as the CD24 antibody. We analyzed CD24 expression in 84 newly diagnosed MM patients using immunohistochemistry with CD138 and CD24 antibodies. Transcriptional factor activation assay and gene expression profiles were performed on CD24+ and CD24e MM cells. Results: We have identified that the cell surface protein CD24 is a TIC biomarker in MM. CD24+ MM cells show increased clonogenicity, drug resistance, and tumorigenicity as few as 10 CD24+ MM cells were required to develop plasmacytomas in mice. In complete remission (CR) MM patients with minimal residual disease (MRD), CD24+ MM cells were enriched after chemotherapy thus exhibiting increased drug resistance. The induced pluripotent or embryonic stem cell genes, such as NANOG, OCT4, KLF4, and SOX2, were significantly upregulated in CD24+ MM cells. We also discovered that nucleosomal remodeling by pioneer transcription factors facilitates STAT3 to mediate TIC features in MM. Targeting of CD24+ MM cells prevented tumor progression in vivo. Conclusion: The studies presented here demonstrate that CD24 maintains the feature of self-renewal and drug resistance in MM. Improved understanding of myeloma tumor-initiating cell biology will lead to the development of novel therapeutic targets and drugs that will be tested pre-clinically and in the clinic. The evidence from clinical trials and correlative studies should also provide valuable information about how inhibition of TIC cells leads to improvement in long-term clinical outcome.

Research paper thumbnail of Plasma Cell Disorders in Patients with Age-Related Transthyretin (ATTRwt) Amyloidosis

Blood, 2018

ATTRwt (formerly known as senile) amyloidosis and plasma cell disorders share a common demographi... more ATTRwt (formerly known as senile) amyloidosis and plasma cell disorders share a common demographic of occurrence with increasing prevalence with age. We aimed to identify the prevalence of plasma cell disorders in patients diagnosed with ATTRwt. We retrospectively reviewed all patients seen at Mayo Clinic Rochester between 1st January 2009 and 31st of December 2017 who were diagnosed with ATTRwt. The start date of the study was chosen to coincide with routine clinical availability of laser microdissection mass spectrometry (LCMS) for subtyping of amyloidosis. 492 patients with ATTRwt were evaluated during the study period. Serum immunofixation electrophoresis (SIFE), urine immunofixation electrophoresis (UIFE) and serum free light chain (FLC) assay testing was performed in 74% (n=362), 53% (n=261) and 79% (n=386) respectively. Of the 492 ATTRwt seen during this period, 139 (28%) had abnormal monoclonal protein studies, the vast majority (92%, n=128) of which were monoclonal gammopat...

Research paper thumbnail of Three Decades of Autologous Stem Cell Transplantation for Myeloma; Trends in Early Mortality and Survival

Blood, 2018

Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to t... more Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to the availability of newer more effective therapies. Autologous stem cell transplantation (ASCT) has been used for over three decades to treat multiple myeloma. We aimed to evaluate the outcome of patients receiving ASCT at our institution between 1990 and 2015. Patients and Methods: A total of 2025 patients received ASCT at Mayo Clinic Rochester between 1st January 1990 and 31st December 2015. The patients were divided in to three cohorts of approximately equal time period, Cohort 1 (1990-1999, n=144), Cohort 2 (2000-2009, n=909) and Cohort 3 (2010-2015, n=972). Outcomes of interest were early mortality, progression free survival (PFS) and overall survival (OS). Disease characteristics were documented from time of diagnosis and PFS and OS were calculated from date of ASCT unless otherwise stated. Results: Median age for the whole cohort was 60 years (range 24-77) and increased over time (...

Research paper thumbnail of Impact of consolidation therapy post autologous stem cell transplant in patients with light chain amyloidosis

American Journal of Hematology, 2019

Research paper thumbnail of Comparison of different techniques to identify cardiac involvement in immunoglobulin light chain (AL) amyloidosis

Blood Advances, 2019

We retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT... more We retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and transthoracic echocardiogram (TTE) in diagnosing cardiac involvement in patients with biopsy-proven systemic immunoglobulin light chain amyloidosis seen at the Mayo Clinic between 1 January 2006 and 30 December 2015. We analyzed 2 cohorts: patients undergoing endomyocardial biopsy for suspicion of cardiac involvement (cohort 1) and patients who had serum NT-proBNP and comprehensive echocardiographic evaluation at diagnosis (cohort 2). Of 179 patients undergoing endomyocardial biopsy (cohort 1), 173 (97%) had evidence of amyloid deposition, with 159 having NT-proBNP performed at the time of the procedure. The NT-proBNP was elevated (>300 pg/mL) in all 159 patients (sensitivity, 100%; median NT-proBNP, 4917 pg/mL; range, 355-69 541). The left ventricular ejection fraction, interventricular septal thickness, and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/...

Research paper thumbnail of Impact of Allogeneic Stem Cell Transplant on Outcomes of Patients with Acute Myeloid Leukemia Based on NPM1 and FLT3 Mutational Status

Biology of Blood and Marrow Transplantation, 2019

Research paper thumbnail of Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: Results from a matched pair analysis

American Journal of Hematology, 2008

High-dose therapy and autologous stem cell transplant (HDT) have been shown to prolong survival i... more High-dose therapy and autologous stem cell transplant (HDT) have been shown to prolong survival in multiple myeloma (MM) in randomized trials, but only included patients of 65 years or younger. Given the median age at diagnosis of 66 years, it is important to have a better understanding of the outcome of transplantation in the older patients. We identified 33 patients with MM, who were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =70 years at the time of their HDT. We matched them to a group of 60 patients, 65 years or younger, (two controls for each patient), based on time to transplant, disease status at transplant, Durie-Salmon stage, labeling index, presence of cytogenetic abnormalities, and presence of circulating plasma cells. The median age of the two groups were 55.6 (range, 37.3-64.9) and 71.7 (range 70-75.8) years at transplant. Although more of the older patients received dose reduced melphalan, the overall response rate was similar (97% vs. 98%) as was the median time to progression (28.5 months vs. 17.8 months, P = 0.7) for the elderly group compared to the younger patients. The median overall survival from transplant was not reached for the elderly patient group compared to 53.2 months for the younger patients, P = 0.7. HDT is feasible in selected patients with multiple myeloma over 70 years. The toxicity of transplant as well as the outcome appears comparable to younger patients. Patients with MM should not be excluded from HDT solely on the basis of their chronological age.

Research paper thumbnail of Monoclonal gammopathy plus positive amyloid biopsy does not always equal AL amyloidosis

American Journal of Hematology, 2019

Research paper thumbnail of Checkpoint Inhibitors in Multiple Myeloma: Intriguing Potential and Unfulfilled Promises

Cancers, 2021

Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to ... more Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment.

Research paper thumbnail of Decreased Cardiac Ejection Fraction Is Associated with Worse Survival in Patients with Light Chain Amyloidosis Treated with Autologous Stem Cell Transplantation

Blood, 2020

Introduction: Cardiac involvement is one of the main predictors for survival in patients with lig... more 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 com...

Research paper thumbnail of Comparison of the current renal staging, progression and response criteria to predict renal survival in AL amyloidosis using a Mayo cohort

American Journal of Hematology, 2021

Three sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were... more Three 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.

Research paper thumbnail of Optimal Therapy for Relapsed AL Amyloidosis Post Autologous Stem Cell Transplant

Blood, 2019

Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosi... more Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma. Methods: We conducted a retrospective review of patients who relapsed after receiving autologous stem cell transplant at Mayo Clinic. Patients treated for first relapse between January 2004 and December 2018 were included. Results: Three hundred and twenty-one patients were seen for relapsed AL amyloidosis post ASCT during the study period. Baseline characteristics were typical for a cohort with AL amyloidosis and are listed in Table1. 39% received therapy prior to transplant, conditioning in the majority (75%) was melphalan 200mg/m2. The median progression free survival from transplant (PFS1) was 30.7 months. Of the 321 patients 294 received treatment for relapsed disease. We categorized treatment regimens according to commonly used combinations and drug classes to further analyze outcomes. 34 patients...

Research paper thumbnail of Fifteen year overall survival rates after autologous stem cell transplantation for AL amyloidosis

American Journal of Hematology, 2019

In appropriately selected patients with AL amyloidosis, autologous stem cell transplant (ASCT) is... more In appropriately selected patients with AL amyloidosis, autologous stem cell transplant (ASCT) is an established treatment modality with excellent outcomes and decreasing transplant related mortality (TRM) over time. We report on 15‐year overall survival (OS) in 159 patients undergoing ASCT from 1996 to 2003, with median follow up of 17.1 years. Day 100 TRM was 13.2% (n = 21). The OS of ≥15 years was observed in 30% (47/159) of patients. Patients surviving ≥15 years were younger (53 vs 56 years, P = .02), less likely to have lambda as the involved light chain (62% vs 78%, P = .03) and were less likely to have heart involvement (32% vs 56%, P = .005). Median OS of patients with heart involvement vs not was 4.0 vs 11.1 years, P = .006 and actuarial 15‐year OS was 23% vs 43%, respectively. A higher proportion of patients with OS ≥15 years received full‐dose melphalan conditioning (81% vs 61%, P = .01), and achieved day 100 complete response (CR) (64% vs 24%, P < .001). Median OS amongst patients who achieved CR vs not was 19.3 vs 5.4 years, P < .001. Heart involvement, receiving full‐dose melphalan and achieving CR remained independent predictors of OS. AL amyloidosis and related complications were the cause of death in 52% of patients overall (1‐5 years post‐transplant: 81%; 5‐10 years: 62% and 10‐15 years: 55%). These results reinforce the key role of ASCT in AL amyloidosis. With improvements in TRM and more options for relapsed disease, we expect the long‐term survival post‐transplant to improve significantly in the future.

Research paper thumbnail of Plasma cell proliferative index is an independent predictor of progression in smoldering multiple myeloma

Blood Advances, 2018

The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry,... more The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry, detects cells in the S phase of the cell cycle and is a useful prognostic tool in patients with plasma cell disorders such as multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic effect of PCPI in 306 patients with smoldering multiple myeloma (SMM). Seventy-nine (26%) patients had an elevated PCPI (>0.5). An elevated PCPI predicted an inferior time to progression (median, 3.0 vs 7.1 years for those with a low PCPI; P = .0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI (49% vs. 20%; P < .0001). PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow-up and consideration of early intervention trials.

Research paper thumbnail of Daratumumab for the treatment of AL amyloidosis

Leukemia & Lymphoma, 2018

Autologous stem cell transplantation (ASCT) has been used as treatment for immunoglobulin light c... more Autologous stem cell transplantation (ASCT) has been used as treatment for immunoglobulin light chain (AL) amyloidosis for over two decades with improving outcomes; however the majority of patients are not candidates for this therapy at diagnosis. Novel agents such as immunomodulatory drugs, proteasome inhibitors and immunotherapy with monoclonal antibodies targeting CD38 have been adopted from the multiple myeloma sphere with encouraging results. Herein we discuss the role of daratumumab, a monoclonal antibody to CD38, in the treatment of AL amyloidosis. We focus on its mechanism of action, tolerability and the current published data on its use in AL amyloidosis. Early data from phase I and phase II studies show that daratumumab is tolerated well in this population and induces rapid and deep responses. Phase III trials are currently accruing and we envision daratumumab becoming a key component in the treatment of AL amyloidosis in the future.

Research paper thumbnail of Differences in clinical presentation and outcome in different countries for Takayasuʼs arteritis

Current Opinion in Rheumatology, 1997

Research paper thumbnail of Prognostic role of beta-2 microglobulin in patients with light chain amyloidosis treated with autologous stem cell transplantation

Journal of Clinical Oncology, 2020

e20506 Background: Autologous stem cell transplantation (ASCT) prolongs survival in patients with... more e20506 Background: Autologous stem cell transplantation (ASCT) prolongs survival in patients with light chain (AL) amyloidosis. Mayo 2012 stage and increased plasma cell percentage (%PC) are known predictors for survival. Increased beta-2 microglobulin (B2M) predicts survival in patients with multiple myeloma. However, its prognostic effect in patients with AL amyloidosis undergoing ASCT is not known. Methods: We retrospectively reviewed patients who had a diagnosis of AL amyloidosis and were treated with ASCT between July-1996 and September-2017. Patients with creatinine > 1.2 mg/dL were excluded, as that affects B2M levels. The receiver operator curve was used to determine the best cutoff for B2M in predicting survival and was 2.5 mcg/mL. Baseline characteristics were compared between patients with B2M > 2.5 and ≤2.5. Progression-free survival (PFS) was defined as time from ASCT to relapse or death, whichever occurred first. Overall survival (OS) was calculated from ASCT to ...

Research paper thumbnail of Utility and prognostic value of 18F-FDG PET/CT scan in patients with newly diagnosed multiple myeloma

Journal of Clinical Oncology, 2018

8023Background: Positron emission tomography–Computed tomography (PET/CT) can identify bony lesio... more 8023Background: Positron emission tomography–Computed tomography (PET/CT) can identify bony lesions, assess disease burden and detect extramedullary disease in patients with newly diagnosed multipl...

Research paper thumbnail of The role of bone marrow biopsy in patients with plasma cell disorders; should all patients with a monoclonal protein be biopsied?

Clinical Lymphoma Myeloma and Leukemia, 2019

We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), ... more We conducted a retrospective review of multiple myeloma (MM), smoldering multiple myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) patients seen at Mayo Clinic to determine whether a bone marrow biopsy (BM) is necessary in all patients diagnosed with a monoclonal protein. A total of 2254 MM, 397 SMM, and 5836 MGUS patients were included in the study. A total of 29 (1.3%) MM patients "without CRAB/FLC" were identified where BM or advanced imaging was critical for diagnosis, 8 (0.3% MM cohort) of whom were diagnosed with MM solely on BM findings (plasma cells > 60%). Without BM or advanced imaging none of these patients would be classified low-risk MGUS. A total of 314 (79%) MGUS-like SMM patients were identified where classification of SMM was based on BM findings. Without BM 97 would be classified as low/low-intermediate-risk MGUS and 151 intermediate or high-risk MGUS; 66 had missing information precluding classification. Only three (<1% SMM cohort) were low-risk MGUS without abnormalities in hemoglobin, calcium, and renal function. In patients presenting with low-risk MGUS and normal hemoglobin, calcium, and renal function, the risk of missing a diagnosis of SMM and MM by omitting BM is <1%. BM should be deferred in these patients in preference to clinical and laboratory monitoring.

Research paper thumbnail of Impact of Minimal Residual Negativity on Outcomes in Light Chain Amyloidosis

Clinical Lymphoma Myeloma and Leukemia, 2019

Research paper thumbnail of A Hematopoietic Score Predicts Survival in Newly Diagnosed Multiple Myeloma Patients

Clinical Lymphoma Myeloma and Leukemia, 2019

CD45, CD19), as well as the CD24 antibody. We analyzed CD24 expression in 84 newly diagnosed MM p... more CD45, CD19), as well as the CD24 antibody. We analyzed CD24 expression in 84 newly diagnosed MM patients using immunohistochemistry with CD138 and CD24 antibodies. Transcriptional factor activation assay and gene expression profiles were performed on CD24+ and CD24e MM cells. Results: We have identified that the cell surface protein CD24 is a TIC biomarker in MM. CD24+ MM cells show increased clonogenicity, drug resistance, and tumorigenicity as few as 10 CD24+ MM cells were required to develop plasmacytomas in mice. In complete remission (CR) MM patients with minimal residual disease (MRD), CD24+ MM cells were enriched after chemotherapy thus exhibiting increased drug resistance. The induced pluripotent or embryonic stem cell genes, such as NANOG, OCT4, KLF4, and SOX2, were significantly upregulated in CD24+ MM cells. We also discovered that nucleosomal remodeling by pioneer transcription factors facilitates STAT3 to mediate TIC features in MM. Targeting of CD24+ MM cells prevented tumor progression in vivo. Conclusion: The studies presented here demonstrate that CD24 maintains the feature of self-renewal and drug resistance in MM. Improved understanding of myeloma tumor-initiating cell biology will lead to the development of novel therapeutic targets and drugs that will be tested pre-clinically and in the clinic. The evidence from clinical trials and correlative studies should also provide valuable information about how inhibition of TIC cells leads to improvement in long-term clinical outcome.

Research paper thumbnail of Plasma Cell Disorders in Patients with Age-Related Transthyretin (ATTRwt) Amyloidosis

Blood, 2018

ATTRwt (formerly known as senile) amyloidosis and plasma cell disorders share a common demographi... more ATTRwt (formerly known as senile) amyloidosis and plasma cell disorders share a common demographic of occurrence with increasing prevalence with age. We aimed to identify the prevalence of plasma cell disorders in patients diagnosed with ATTRwt. We retrospectively reviewed all patients seen at Mayo Clinic Rochester between 1st January 2009 and 31st of December 2017 who were diagnosed with ATTRwt. The start date of the study was chosen to coincide with routine clinical availability of laser microdissection mass spectrometry (LCMS) for subtyping of amyloidosis. 492 patients with ATTRwt were evaluated during the study period. Serum immunofixation electrophoresis (SIFE), urine immunofixation electrophoresis (UIFE) and serum free light chain (FLC) assay testing was performed in 74% (n=362), 53% (n=261) and 79% (n=386) respectively. Of the 492 ATTRwt seen during this period, 139 (28%) had abnormal monoclonal protein studies, the vast majority (92%, n=128) of which were monoclonal gammopat...

Research paper thumbnail of Three Decades of Autologous Stem Cell Transplantation for Myeloma; Trends in Early Mortality and Survival

Blood, 2018

Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to t... more Introduction: Outcomes in multiple myeloma have significantly improved in recent times owing to the availability of newer more effective therapies. Autologous stem cell transplantation (ASCT) has been used for over three decades to treat multiple myeloma. We aimed to evaluate the outcome of patients receiving ASCT at our institution between 1990 and 2015. Patients and Methods: A total of 2025 patients received ASCT at Mayo Clinic Rochester between 1st January 1990 and 31st December 2015. The patients were divided in to three cohorts of approximately equal time period, Cohort 1 (1990-1999, n=144), Cohort 2 (2000-2009, n=909) and Cohort 3 (2010-2015, n=972). Outcomes of interest were early mortality, progression free survival (PFS) and overall survival (OS). Disease characteristics were documented from time of diagnosis and PFS and OS were calculated from date of ASCT unless otherwise stated. Results: Median age for the whole cohort was 60 years (range 24-77) and increased over time (...

Research paper thumbnail of Impact of consolidation therapy post autologous stem cell transplant in patients with light chain amyloidosis

American Journal of Hematology, 2019

Research paper thumbnail of Comparison of different techniques to identify cardiac involvement in immunoglobulin light chain (AL) amyloidosis

Blood Advances, 2019

We retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT... more We retrospectively reviewed the utility of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and transthoracic echocardiogram (TTE) in diagnosing cardiac involvement in patients with biopsy-proven systemic immunoglobulin light chain amyloidosis seen at the Mayo Clinic between 1 January 2006 and 30 December 2015. We analyzed 2 cohorts: patients undergoing endomyocardial biopsy for suspicion of cardiac involvement (cohort 1) and patients who had serum NT-proBNP and comprehensive echocardiographic evaluation at diagnosis (cohort 2). Of 179 patients undergoing endomyocardial biopsy (cohort 1), 173 (97%) had evidence of amyloid deposition, with 159 having NT-proBNP performed at the time of the procedure. The NT-proBNP was elevated (>300 pg/mL) in all 159 patients (sensitivity, 100%; median NT-proBNP, 4917 pg/mL; range, 355-69 541). The left ventricular ejection fraction, interventricular septal thickness, and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/...

Research paper thumbnail of Impact of Allogeneic Stem Cell Transplant on Outcomes of Patients with Acute Myeloid Leukemia Based on NPM1 and FLT3 Mutational Status

Biology of Blood and Marrow Transplantation, 2019

Research paper thumbnail of Autologous stem cell transplantation in patients of 70 years and older with multiple myeloma: Results from a matched pair analysis

American Journal of Hematology, 2008

High-dose therapy and autologous stem cell transplant (HDT) have been shown to prolong survival i... more High-dose therapy and autologous stem cell transplant (HDT) have been shown to prolong survival in multiple myeloma (MM) in randomized trials, but only included patients of 65 years or younger. Given the median age at diagnosis of 66 years, it is important to have a better understanding of the outcome of transplantation in the older patients. We identified 33 patients with MM, who were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; or =70 years at the time of their HDT. We matched them to a group of 60 patients, 65 years or younger, (two controls for each patient), based on time to transplant, disease status at transplant, Durie-Salmon stage, labeling index, presence of cytogenetic abnormalities, and presence of circulating plasma cells. The median age of the two groups were 55.6 (range, 37.3-64.9) and 71.7 (range 70-75.8) years at transplant. Although more of the older patients received dose reduced melphalan, the overall response rate was similar (97% vs. 98%) as was the median time to progression (28.5 months vs. 17.8 months, P = 0.7) for the elderly group compared to the younger patients. The median overall survival from transplant was not reached for the elderly patient group compared to 53.2 months for the younger patients, P = 0.7. HDT is feasible in selected patients with multiple myeloma over 70 years. The toxicity of transplant as well as the outcome appears comparable to younger patients. Patients with MM should not be excluded from HDT solely on the basis of their chronological age.

Research paper thumbnail of Monoclonal gammopathy plus positive amyloid biopsy does not always equal AL amyloidosis

American Journal of Hematology, 2019

Research paper thumbnail of Checkpoint Inhibitors in Multiple Myeloma: Intriguing Potential and Unfulfilled Promises

Cancers, 2021

Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to ... more Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment.

Research paper thumbnail of Decreased Cardiac Ejection Fraction Is Associated with Worse Survival in Patients with Light Chain Amyloidosis Treated with Autologous Stem Cell Transplantation

Blood, 2020

Introduction: Cardiac involvement is one of the main predictors for survival in patients with lig... more 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 com...

Research paper thumbnail of Comparison of the current renal staging, progression and response criteria to predict renal survival in AL amyloidosis using a Mayo cohort

American Journal of Hematology, 2021

Three sets of criteria (International Society of Amyloidosis [ISA], Palladini and Kastritis) were... more Three 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.

Research paper thumbnail of Optimal Therapy for Relapsed AL Amyloidosis Post Autologous Stem Cell Transplant

Blood, 2019

Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosi... more Introduction: There is a paucity of randomized trials to guide therapy for relapsed AL amyloidosis with treatment regimens generally extrapolated from experience in multiple myeloma. Methods: We conducted a retrospective review of patients who relapsed after receiving autologous stem cell transplant at Mayo Clinic. Patients treated for first relapse between January 2004 and December 2018 were included. Results: Three hundred and twenty-one patients were seen for relapsed AL amyloidosis post ASCT during the study period. Baseline characteristics were typical for a cohort with AL amyloidosis and are listed in Table1. 39% received therapy prior to transplant, conditioning in the majority (75%) was melphalan 200mg/m2. The median progression free survival from transplant (PFS1) was 30.7 months. Of the 321 patients 294 received treatment for relapsed disease. We categorized treatment regimens according to commonly used combinations and drug classes to further analyze outcomes. 34 patients...

Research paper thumbnail of Fifteen year overall survival rates after autologous stem cell transplantation for AL amyloidosis

American Journal of Hematology, 2019

In appropriately selected patients with AL amyloidosis, autologous stem cell transplant (ASCT) is... more In appropriately selected patients with AL amyloidosis, autologous stem cell transplant (ASCT) is an established treatment modality with excellent outcomes and decreasing transplant related mortality (TRM) over time. We report on 15‐year overall survival (OS) in 159 patients undergoing ASCT from 1996 to 2003, with median follow up of 17.1 years. Day 100 TRM was 13.2% (n = 21). The OS of ≥15 years was observed in 30% (47/159) of patients. Patients surviving ≥15 years were younger (53 vs 56 years, P = .02), less likely to have lambda as the involved light chain (62% vs 78%, P = .03) and were less likely to have heart involvement (32% vs 56%, P = .005). Median OS of patients with heart involvement vs not was 4.0 vs 11.1 years, P = .006 and actuarial 15‐year OS was 23% vs 43%, respectively. A higher proportion of patients with OS ≥15 years received full‐dose melphalan conditioning (81% vs 61%, P = .01), and achieved day 100 complete response (CR) (64% vs 24%, P < .001). Median OS amongst patients who achieved CR vs not was 19.3 vs 5.4 years, P < .001. Heart involvement, receiving full‐dose melphalan and achieving CR remained independent predictors of OS. AL amyloidosis and related complications were the cause of death in 52% of patients overall (1‐5 years post‐transplant: 81%; 5‐10 years: 62% and 10‐15 years: 55%). These results reinforce the key role of ASCT in AL amyloidosis. With improvements in TRM and more options for relapsed disease, we expect the long‐term survival post‐transplant to improve significantly in the future.

Research paper thumbnail of Plasma cell proliferative index is an independent predictor of progression in smoldering multiple myeloma

Blood Advances, 2018

The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry,... more The plasma cell proliferative index (PCPI), determined by a slide technique or by flow cytometry, detects cells in the S phase of the cell cycle and is a useful prognostic tool in patients with plasma cell disorders such as multiple myeloma and amyloidosis. We conducted a retrospective review analyzing the prognostic effect of PCPI in 306 patients with smoldering multiple myeloma (SMM). Seventy-nine (26%) patients had an elevated PCPI (>0.5). An elevated PCPI predicted an inferior time to progression (median, 3.0 vs 7.1 years for those with a low PCPI; P = .0004). Within 24 months, the progression rate was significantly higher for patients with an elevated PCPI (49% vs. 20%; P < .0001). PCPI is a valuable tool in risk stratifying patients with SMM and identifies patients with earlier progression who may benefit from closer follow-up and consideration of early intervention trials.

Research paper thumbnail of Daratumumab for the treatment of AL amyloidosis

Leukemia & Lymphoma, 2018

Autologous stem cell transplantation (ASCT) has been used as treatment for immunoglobulin light c... more Autologous stem cell transplantation (ASCT) has been used as treatment for immunoglobulin light chain (AL) amyloidosis for over two decades with improving outcomes; however the majority of patients are not candidates for this therapy at diagnosis. Novel agents such as immunomodulatory drugs, proteasome inhibitors and immunotherapy with monoclonal antibodies targeting CD38 have been adopted from the multiple myeloma sphere with encouraging results. Herein we discuss the role of daratumumab, a monoclonal antibody to CD38, in the treatment of AL amyloidosis. We focus on its mechanism of action, tolerability and the current published data on its use in AL amyloidosis. Early data from phase I and phase II studies show that daratumumab is tolerated well in this population and induces rapid and deep responses. Phase III trials are currently accruing and we envision daratumumab becoming a key component in the treatment of AL amyloidosis in the future.