Ola Landgren - Academia.edu (original) (raw)

Papers by Ola Landgren

Research paper thumbnail of CD34-selected allogeneic hematopoietic stem cell transplantation for patients with relapsed, high-risk multiple myeloma

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 29, 2015

We report results of a retrospective analysis of 44 patients with relapsed and high-risk multiple... more We report results of a retrospective analysis of 44 patients with relapsed and high-risk multiple myeloma (MM) undergoing allogeneic CD34-selected hematopoietic stem-cell transplantation (CD34-selected HSCT) from human leukocyte antigen (HLA)-compatible donors. Patients had multiply relapsed disease including relapse at <15 months after autologous transplant and most patients (28/44; 65%) also had high-risk cytogenetics. Before transplant, patients received busulfan (0.8 mg/kg X 10 doses), melphalan (70 mg/m(2) X 2 days), fludarabine (25 mg/m(2) X 5 days), and rabbit anti-thymocyte globulin (2.5 mg/kg X 2 days). Patients with 10/10 HLA- matched donors were treated prophylactically with low doses of donor lymphocyte infusions (0.5 to 1 X 10(6) CD3+/kg) starting at 4-6 months post CD34-selected HSCT. Acute (grade II-IV) graph-versus-host disease (GVHD) and transplant-related mortality at 12 months were 2% and 18%, respectively. Chronic GVHD was not observed in any patient. Overall ...

Research paper thumbnail of Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

eLife, 2015

Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction ... more Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance.

Research paper thumbnail of Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology

British Journal of Haematology

The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leu... more The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age-adjusted incidence rates (IRs) of CLL and SLL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age-standardized to the 2000 US population, overall IRs were 3.83 per 100 000 person-years for CLL (n = 15 676) and 1.31 for SLL (n = 5382) during 1993-2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1.98) than for SLL (1.67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal tr...

Research paper thumbnail of Etiology of Waldenström macroglobulinemia: genetic factors and immune-related conditions

Clinical lymphoma, myeloma & leukemia, 2013

Epidemiologic studies provide an insight into the etiology of lymphoplasmacytic lymphoma/Waldenst... more Epidemiologic studies provide an insight into the etiology of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, which indicates that repetitive immune stimulation and genetic factors play an important role. Here, the current understanding on the causes of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia are reviewed. Recent studies of the literature are discussed, and future population-based studies are proposed to further elucidate the molecular mechanisms that underlie these associations. Finally, the clinical implications of these data are outlined, and perspectives on clinical follow-up and counseling are provided.

Research paper thumbnail of Information for authors

Research paper thumbnail of Molecular Imaging in Myeloma Precursor Disease

Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy... more Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). By definition, precursor conditions do not exhibit end-organ disease (anemia, hypercalcemia, renal failure, skeletal lytic lesions, or a combination of these). However, new imaging methods are demonstrating that some patients in the MGUS or SMM category are exhibiting early signs of MM. Although MGUS/SMM patients are currently defined as low-risk versus high-risk based on clinical markers, we currently lack the ability to predict the individual patient&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;#39;s risk of progression from MGUS/SMM to MM. Given that the presence of gross lytic bone lesions is a hallmark of MM, it is reasonable to believe that less severe bone changes defined by more sensitive imaging may be predictive of MM progression. Indeed, since bone disease is such an essential aspect of MM, imaging techniques directed at the detection of early bone lesions, have the potential to become increasingly more useful in the setting of MGUS/SMM. Current guidelines for the radiological assessment of MM still recommend the traditional skeletal survey, although its limitations are well documented, especially in early phases of the disease when radiographs can significantly underestimate the extent of bone lesions and bone marrow involvement. Newer, more advanced imaging modalities, with higher sensitivities, including whole-body low-dose computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are being employed. Also various imaging techniques have been used to provide an assessment of bone involvement and identify extra-osseous disease. This review emphasizes the current state of the art and emerging imaging methods, which may help to better define high-risk versus low-risk MGUS/SMM. Ultimately, improved imaging could allow more tailored clinical management, and, most likely play an important role in the development of future treatment strategies for high-risk precursor disease.

Research paper thumbnail of Smoldering multiple myeloma: special considerations surrounding treatment on versus off clinical trials

Research paper thumbnail of Smoldering (Asymptomatic) Multiple Myeloma: Revisiting the Clinical Dilemma and Looking Into the Future

Clinical Lymphoma Myeloma and Leukemia, 2010

Research paper thumbnail of Minimal residual disease in multiple myeloma: bringing the bench to the bedside

Nature Reviews Clinical Oncology, 2015

Outcomes for patients with multiple myeloma (MM) have improved substantially in the past decade, ... more Outcomes for patients with multiple myeloma (MM) have improved substantially in the past decade, with improvements in both progression-free survival and overall survival. Many patients are now achieving a complete response to treatment, and consequently highly sensitive assays are needed for detection of minimal residual disease (MRD) in patients with MM. Results of multicolour flow cytometry and deep-sequencing studies suggest that among patients achieving a complete response, MRD-negative status is associated with significant improvements in progression-free survival and overall survival. Despite the increasing need for MRD testing in patients with MM, considerable heterogeneity in techniques for MRD detection hinders the clinical interpretation of their results. The criteria used to define MRD, strengths and weaknesses of the major types of tests (flow cytometry versus molecular testing), and the optimal sample type (bone marrow aspirate versus peripheral blood) are all unresolved dilemmas in MRD testing. This Review presents an overview of the various techniques for MRD detection in patients with MM. In addition, this article discusses challenges and opportunities for the routine use of MRD testing, possible future directions for clinical trials and implications for drug approval processes.

Research paper thumbnail of Flow cytometry detection of minimal residual disease in multiple myeloma: Lessons learned at FDA-NCI roundtable symposium

American Journal of Hematology, 2014

better, which significantly shorten hybridization time, increase reproducibility, and make it sui... more better, which significantly shorten hybridization time, increase reproducibility, and make it suitable for large scale production. Additionally, 23 mutations account for the majority (>98%) of thalassemia in Chinese population have been detected in the new assay, and the quantity of detection index can be easily expanded. Depending on the technical advantages of BBSAT, the new assay demonstrates outstanding extensibility for the requirement of various genetic mutations diagnosis. Furthermore, conventional molecular analysis of aand b-thalassemia usually utilizes two or three kinds of commercial kits, and the costs of which are comparatively high. The BBSAT can detect point mutations and deletions in parallel for the diagnosis of thalassemia, and contribute to reduce the costs for 20%.

Research paper thumbnail of International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

The Lancet. Oncology, 2014

This International Myeloma Working Group consensus updates the disease definition of multiple mye... more This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working...

Research paper thumbnail of Geriatric assessment predicts survival and toxicities in elderly myeloma: an International Myeloma Working Group report

Blood, Jan 27, 2015

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 pros... more We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective international trials. At diagnosis, a geriatric assessment had been performed to assess comorbidities, cognitive and physical status. An additive scoring system (range 0-5), based on age, comorbidities, cognitive and physical conditions, was developed to identify 3 groups: fit (score=0, 39%); intermediate-fitness (score=1, 31%), and frail (score≥2, 30%). The 3-year overall survival was 84% in fit patients, 76% in intermediate-fitness patients (HR 1.61, 95%CI 1.02-2.56, p=0.042) and 57% in frail patients (HR 3.57 CI 95% 2.37-5.39, p<0.001). The cumulative incidence of grade ≥3 non-hematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR 1.23, 95%CI 0.89-1.71; p 0.217) and 34.0% (HR 1.74, 95%CI 1.28-2.38; p<0.001) in frail patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fit...

Research paper thumbnail of The effects of cardiovascular disease on the clinical outcome of elderly patients with diffuse large B-cell lymphoma

Leukemia & lymphoma, Jan 15, 2014

We identified 3910 elderly (>65 yrs) patients with diffuse large B-cell lymphoma (DLBCL) who r... more We identified 3910 elderly (>65 yrs) patients with diffuse large B-cell lymphoma (DLBCL) who received doxorubicin-based (+/-rituximab) therapy and 77 347 cancer-free controls, and assessed cardiovascular events and survival in relation to preexisting cardiovascular comorbidities. Compared to controls, patients with DLBCL had a 3.4-fold (95%CI 3.0-3.9) and 2.5-fold (95%CI 2.3-2.7) increased risk of congestive heart failure (CHF)/cardiomyopathy (CM) within 6 months and 3 years of diagnosis, respectively. Risk of acute myocardial infarction (AMI) was similarly increased. The risk of CHF/CM and AMI was significantly higher in those patients with DLBCL (vs. controls) who did not report preexisting cardiovascular disease, compared to those who had preexisting cardiovascular disease; this was due to dose reductions of doxorubicin among patients with preexisting cardiovascular disease. Rituximab improved survival in patients with stage III-IV (but not I-II) disease (p-interaction = 0.000...

Research paper thumbnail of Flow cytometric sensitivity and characteristics of plasma cells in patients with multiple myeloma or its precursor disease: influence of biopsy site and anticoagulation method

Leukemia & Lymphoma, 2014

Flow cytometry (FC) has increasing relevance for prognosis in myeloma (MM) and precursor disease ... more Flow cytometry (FC) has increasing relevance for prognosis in myeloma (MM) and precursor disease (monoclonal gammopathy of unknown significance(MGUS)/smoldering myeloma(SMM)), yet it has been reported that plasma cell (PC) enumeration by FC varies depending on the quality of marrow aspirate and field biopsied in patchy disease. We demonstrated increased sensitivity of FC over immunohistochemistry in abnormal-PC detection in MGUS(n 59)/ SMM(n 87). We prospectively evaluated treatment-naïve SMM(n 9)/MM(n 11) patients for the percentage of abnormal PC/total plasma cell compartment(aPC/BMPC), PC viability, FC immunophenotype, and PC infiltration, depending on anticoagulant use, biopsy site and pull sequence in uni-and-bilateral bone marrow biopsies and aspirates. We found no statistical difference regarding aPC/BMPC, immunophenotype or number/distribution of plasma cells in marrow samples obtained from uni-and-bilateral bone marrow biopsies even when obtained by different sequence in aspirates, or anticoagulants (p 0.05). Our results show that PC enumeration and immunophenotyping by FC is consistent under different conditions in these populations.

Research paper thumbnail of Current Insight on Trends, Causes, and Mechanisms of Hodgkin’s Lymphoma

The Cancer Journal, 2009

Hodgkin's lymphoma (HL) has a unique and distinct history, epidemiology, treatment, and biology. ... more Hodgkin's lymphoma (HL) has a unique and distinct history, epidemiology, treatment, and biology. A viral agent or infectious agent has long been considered as the etiologic agent and Epstein-Barr virus is the main candidate for the infectious agent causing HL; however, Epstein-Barr virus genome is found within the tumor in only about 20% to 40% of HL cases with a prior diagnosis of infectious mononucleosis. Recently, autoimmune and related conditions have drawn attention to a potential role for immune-related and inflammatory conditions in the etiology and pathogenesis of the malignancy. Evidence from multiply-affected families, a twin study, a case-control study, and population-based registry studies implicate genetic factors. Data from Eastern Asia and among Chinese immigrants in North America indicate increasing incidence trends for HL being associated with westernization. These results emphasize an interaction between environmental and genetic risk factors in HL.

Research paper thumbnail of Molecular Imaging in Myeloma Precursor Disease

Seminars in Hematology, 2011

Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy... more Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). By definition, precursor conditions do not exhibit end-organ disease (anemia, hypercalcemia, renal failure, skeletal lytic lesions, or a combination of these). However, new imaging methods are demonstrating that some patients in the MGUS or SMM category are exhibiting early signs of MM. Although MGUS/SMM patients are currently defined as low-risk versus high-risk based on clinical markers, we currently lack the ability to predict the individual patient&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;#39;s risk of progression from MGUS/SMM to MM. Given that the presence of gross lytic bone lesions is a hallmark of MM, it is reasonable to believe that less severe bone changes defined by more sensitive imaging may be predictive of MM progression. Indeed, since bone disease is such an essential aspect of MM, imaging techniques directed at the detection of early bone lesions, have the potential to become increasingly more useful in the setting of MGUS/SMM. Current guidelines for the radiological assessment of MM still recommend the traditional skeletal survey, although its limitations are well documented, especially in early phases of the disease when radiographs can significantly underestimate the extent of bone lesions and bone marrow involvement. Newer, more advanced imaging modalities, with higher sensitivities, including whole-body low-dose computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are being employed. Also various imaging techniques have been used to provide an assessment of bone involvement and identify extra-osseous disease. This review emphasizes the current state of the art and emerging imaging methods, which may help to better define high-risk versus low-risk MGUS/SMM. Ultimately, improved imaging could allow more tailored clinical management, and, most likely play an important role in the development of future treatment strategies for high-risk precursor disease.

Research paper thumbnail of Mantle cell lymphomas with clonal immunoglobulin VH3–21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin VH genes

Modern Pathology, 2005

A preferential use of one particular immunoglobulin variable heavy chain gene, V H 3-21, has rece... more A preferential use of one particular immunoglobulin variable heavy chain gene, V H 3-21, has recently been reported in mantle cell lymphoma, where almost all of these V H 3-21 þ mantle cell lymphomas showed usage of the same light chain V k gene (V k 3-19) and also had a tendency towards improved prognosis. These findings suggested that V H 3-21 þ mantle cell lymphomas constitute a distinct subgroup, possibly with antigen stimulation involved in disease pathogenesis. In this study, we applied the comparative genomic hybridization (CGH) method on 37 mantle cell lymphoma tumors in order to investigate if the V H 3-21 þ tumors are different at the genomic level. Interestingly, V H 3-21 þ mantle cell lymphomas (n ¼ 14) showed significantly fewer genomic aberrations (mean 2.4) compared to non-V H 3-21 mantle cell lymphomas (n ¼ 23) (mean 4.9). The chromosomal aberrations identified in our study were generally in accordance with previous CGH studies of mantle cell lymphoma; the most frequent aberration was complete or partial loss of chromosome 13, followed by recurrent losses within 6q, 9p, 9q and 11q and frequent gains in 3q, 7p, 8q and 15q. Deletions within 8p and 9p as well as gains in 7p and 15q were found exclusively in the non-V H 3-21-utilizing tumors. In summary, V H 3-21 þ mantle cell lymphomas demonstrated both a lower number and a different spectrum of genomic aberrations than mantle cell lymphoma in general, thus supporting the hypothesis that V H 3-21 þ mantle cell lymphomas constitute a new subgroup. The findings presented in this report may explain the tendency for a better clinical outcome for patients whose tumors utilize V H 3-21.

Research paper thumbnail of Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases

Leukemia Research, 2014

Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognosticatio... more Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N = 34) and APC in a series of unselected PCD (N = 59). NPC subpopulations often demonstrated CD19(−), CD20(+), CD45(−) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N = 14), SMM (N = 35) and MM (N = 10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p = 0.0002).

Research paper thumbnail of Antigenic drift in relapsed extramedullary multiple myeloma: plasma cells without CD38 expression

Leukemia & Lymphoma, 2012

... Prashant Tembhare, MD1, Constance Yuan, MD, Ph.D.1, Neha Korde, MD2,3, Irina Maric, MD4, and ... more ... Prashant Tembhare, MD1, Constance Yuan, MD, Ph.D.1, Neha Korde, MD2,3, Irina Maric, MD4, and Ola Landgren, MD, PhD3 ... Given that MM patients live longer after the introduction of novel therapies 1, it seems reasonable to believe that this phenomenon will become ...

Research paper thumbnail of Lack of MYD88 L265P in non-immunoglobulin M lymphoplasmacytic lymphoma

Leukemia & Lymphoma, 2013

Research paper thumbnail of CD34-selected allogeneic hematopoietic stem cell transplantation for patients with relapsed, high-risk multiple myeloma

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 29, 2015

We report results of a retrospective analysis of 44 patients with relapsed and high-risk multiple... more We report results of a retrospective analysis of 44 patients with relapsed and high-risk multiple myeloma (MM) undergoing allogeneic CD34-selected hematopoietic stem-cell transplantation (CD34-selected HSCT) from human leukocyte antigen (HLA)-compatible donors. Patients had multiply relapsed disease including relapse at <15 months after autologous transplant and most patients (28/44; 65%) also had high-risk cytogenetics. Before transplant, patients received busulfan (0.8 mg/kg X 10 doses), melphalan (70 mg/m(2) X 2 days), fludarabine (25 mg/m(2) X 5 days), and rabbit anti-thymocyte globulin (2.5 mg/kg X 2 days). Patients with 10/10 HLA- matched donors were treated prophylactically with low doses of donor lymphocyte infusions (0.5 to 1 X 10(6) CD3+/kg) starting at 4-6 months post CD34-selected HSCT. Acute (grade II-IV) graph-versus-host disease (GVHD) and transplant-related mortality at 12 months were 2% and 18%, respectively. Chronic GVHD was not observed in any patient. Overall ...

Research paper thumbnail of Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

eLife, 2015

Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction ... more Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance.

Research paper thumbnail of Chronic lymphocytic leukaemia and small lymphocytic lymphoma: overview of the descriptive epidemiology

British Journal of Haematology

The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leu... more The 2001 World Health Organization classification scheme considers B-cell chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) in an aggregate category (CLL/SLL) because of shared clinicopathological features. We have estimated age-adjusted incidence rates (IRs) of CLL and SLL in the population-based Surveillance, Epidemiology and End Results Program in the United States to analyse patterns of CLL and SLL separately and jointly. Age-standardized to the 2000 US population, overall IRs were 3.83 per 100 000 person-years for CLL (n = 15 676) and 1.31 for SLL (n = 5382) during 1993-2004. Incidence of the combined entity, CLL/SLL, was 90% higher among males compared to females, and the male:female IR ratio was significantly higher for CLL (1.98) than for SLL (1.67). CLL/SLL IRs were 25% and 77% lower among Blacks and Asian/Pacific Islanders, respectively, compared to Whites. A significant reporting delay was evident for CLL but not for SLL, so that CLL/SLL temporal tr...

Research paper thumbnail of Etiology of Waldenström macroglobulinemia: genetic factors and immune-related conditions

Clinical lymphoma, myeloma & leukemia, 2013

Epidemiologic studies provide an insight into the etiology of lymphoplasmacytic lymphoma/Waldenst... more Epidemiologic studies provide an insight into the etiology of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, which indicates that repetitive immune stimulation and genetic factors play an important role. Here, the current understanding on the causes of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia are reviewed. Recent studies of the literature are discussed, and future population-based studies are proposed to further elucidate the molecular mechanisms that underlie these associations. Finally, the clinical implications of these data are outlined, and perspectives on clinical follow-up and counseling are provided.

Research paper thumbnail of Information for authors

Research paper thumbnail of Molecular Imaging in Myeloma Precursor Disease

Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy... more Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). By definition, precursor conditions do not exhibit end-organ disease (anemia, hypercalcemia, renal failure, skeletal lytic lesions, or a combination of these). However, new imaging methods are demonstrating that some patients in the MGUS or SMM category are exhibiting early signs of MM. Although MGUS/SMM patients are currently defined as low-risk versus high-risk based on clinical markers, we currently lack the ability to predict the individual patient&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;#39;s risk of progression from MGUS/SMM to MM. Given that the presence of gross lytic bone lesions is a hallmark of MM, it is reasonable to believe that less severe bone changes defined by more sensitive imaging may be predictive of MM progression. Indeed, since bone disease is such an essential aspect of MM, imaging techniques directed at the detection of early bone lesions, have the potential to become increasingly more useful in the setting of MGUS/SMM. Current guidelines for the radiological assessment of MM still recommend the traditional skeletal survey, although its limitations are well documented, especially in early phases of the disease when radiographs can significantly underestimate the extent of bone lesions and bone marrow involvement. Newer, more advanced imaging modalities, with higher sensitivities, including whole-body low-dose computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are being employed. Also various imaging techniques have been used to provide an assessment of bone involvement and identify extra-osseous disease. This review emphasizes the current state of the art and emerging imaging methods, which may help to better define high-risk versus low-risk MGUS/SMM. Ultimately, improved imaging could allow more tailored clinical management, and, most likely play an important role in the development of future treatment strategies for high-risk precursor disease.

Research paper thumbnail of Smoldering multiple myeloma: special considerations surrounding treatment on versus off clinical trials

Research paper thumbnail of Smoldering (Asymptomatic) Multiple Myeloma: Revisiting the Clinical Dilemma and Looking Into the Future

Clinical Lymphoma Myeloma and Leukemia, 2010

Research paper thumbnail of Minimal residual disease in multiple myeloma: bringing the bench to the bedside

Nature Reviews Clinical Oncology, 2015

Outcomes for patients with multiple myeloma (MM) have improved substantially in the past decade, ... more Outcomes for patients with multiple myeloma (MM) have improved substantially in the past decade, with improvements in both progression-free survival and overall survival. Many patients are now achieving a complete response to treatment, and consequently highly sensitive assays are needed for detection of minimal residual disease (MRD) in patients with MM. Results of multicolour flow cytometry and deep-sequencing studies suggest that among patients achieving a complete response, MRD-negative status is associated with significant improvements in progression-free survival and overall survival. Despite the increasing need for MRD testing in patients with MM, considerable heterogeneity in techniques for MRD detection hinders the clinical interpretation of their results. The criteria used to define MRD, strengths and weaknesses of the major types of tests (flow cytometry versus molecular testing), and the optimal sample type (bone marrow aspirate versus peripheral blood) are all unresolved dilemmas in MRD testing. This Review presents an overview of the various techniques for MRD detection in patients with MM. In addition, this article discusses challenges and opportunities for the routine use of MRD testing, possible future directions for clinical trials and implications for drug approval processes.

Research paper thumbnail of Flow cytometry detection of minimal residual disease in multiple myeloma: Lessons learned at FDA-NCI roundtable symposium

American Journal of Hematology, 2014

better, which significantly shorten hybridization time, increase reproducibility, and make it sui... more better, which significantly shorten hybridization time, increase reproducibility, and make it suitable for large scale production. Additionally, 23 mutations account for the majority (>98%) of thalassemia in Chinese population have been detected in the new assay, and the quantity of detection index can be easily expanded. Depending on the technical advantages of BBSAT, the new assay demonstrates outstanding extensibility for the requirement of various genetic mutations diagnosis. Furthermore, conventional molecular analysis of aand b-thalassemia usually utilizes two or three kinds of commercial kits, and the costs of which are comparatively high. The BBSAT can detect point mutations and deletions in parallel for the diagnosis of thalassemia, and contribute to reduce the costs for 20%.

Research paper thumbnail of International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

The Lancet. Oncology, 2014

This International Myeloma Working Group consensus updates the disease definition of multiple mye... more This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working...

Research paper thumbnail of Geriatric assessment predicts survival and toxicities in elderly myeloma: an International Myeloma Working Group report

Blood, Jan 27, 2015

We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 pros... more We conducted a pooled analysis of 869 individual newly diagnosed elderly patient data from 3 prospective international trials. At diagnosis, a geriatric assessment had been performed to assess comorbidities, cognitive and physical status. An additive scoring system (range 0-5), based on age, comorbidities, cognitive and physical conditions, was developed to identify 3 groups: fit (score=0, 39%); intermediate-fitness (score=1, 31%), and frail (score≥2, 30%). The 3-year overall survival was 84% in fit patients, 76% in intermediate-fitness patients (HR 1.61, 95%CI 1.02-2.56, p=0.042) and 57% in frail patients (HR 3.57 CI 95% 2.37-5.39, p<0.001). The cumulative incidence of grade ≥3 non-hematologic adverse events at 12 months was 22.2% in fit, 26.4% in intermediate-fitness (HR 1.23, 95%CI 0.89-1.71; p 0.217) and 34.0% (HR 1.74, 95%CI 1.28-2.38; p<0.001) in frail patients. The cumulative incidence of treatment discontinuation at 12 months was 16.5% in fit, 20.8% in intermediate-fit...

Research paper thumbnail of The effects of cardiovascular disease on the clinical outcome of elderly patients with diffuse large B-cell lymphoma

Leukemia & lymphoma, Jan 15, 2014

We identified 3910 elderly (>65 yrs) patients with diffuse large B-cell lymphoma (DLBCL) who r... more We identified 3910 elderly (>65 yrs) patients with diffuse large B-cell lymphoma (DLBCL) who received doxorubicin-based (+/-rituximab) therapy and 77 347 cancer-free controls, and assessed cardiovascular events and survival in relation to preexisting cardiovascular comorbidities. Compared to controls, patients with DLBCL had a 3.4-fold (95%CI 3.0-3.9) and 2.5-fold (95%CI 2.3-2.7) increased risk of congestive heart failure (CHF)/cardiomyopathy (CM) within 6 months and 3 years of diagnosis, respectively. Risk of acute myocardial infarction (AMI) was similarly increased. The risk of CHF/CM and AMI was significantly higher in those patients with DLBCL (vs. controls) who did not report preexisting cardiovascular disease, compared to those who had preexisting cardiovascular disease; this was due to dose reductions of doxorubicin among patients with preexisting cardiovascular disease. Rituximab improved survival in patients with stage III-IV (but not I-II) disease (p-interaction = 0.000...

Research paper thumbnail of Flow cytometric sensitivity and characteristics of plasma cells in patients with multiple myeloma or its precursor disease: influence of biopsy site and anticoagulation method

Leukemia & Lymphoma, 2014

Flow cytometry (FC) has increasing relevance for prognosis in myeloma (MM) and precursor disease ... more Flow cytometry (FC) has increasing relevance for prognosis in myeloma (MM) and precursor disease (monoclonal gammopathy of unknown significance(MGUS)/smoldering myeloma(SMM)), yet it has been reported that plasma cell (PC) enumeration by FC varies depending on the quality of marrow aspirate and field biopsied in patchy disease. We demonstrated increased sensitivity of FC over immunohistochemistry in abnormal-PC detection in MGUS(n 59)/ SMM(n 87). We prospectively evaluated treatment-naïve SMM(n 9)/MM(n 11) patients for the percentage of abnormal PC/total plasma cell compartment(aPC/BMPC), PC viability, FC immunophenotype, and PC infiltration, depending on anticoagulant use, biopsy site and pull sequence in uni-and-bilateral bone marrow biopsies and aspirates. We found no statistical difference regarding aPC/BMPC, immunophenotype or number/distribution of plasma cells in marrow samples obtained from uni-and-bilateral bone marrow biopsies even when obtained by different sequence in aspirates, or anticoagulants (p 0.05). Our results show that PC enumeration and immunophenotyping by FC is consistent under different conditions in these populations.

Research paper thumbnail of Current Insight on Trends, Causes, and Mechanisms of Hodgkin’s Lymphoma

The Cancer Journal, 2009

Hodgkin's lymphoma (HL) has a unique and distinct history, epidemiology, treatment, and biology. ... more Hodgkin's lymphoma (HL) has a unique and distinct history, epidemiology, treatment, and biology. A viral agent or infectious agent has long been considered as the etiologic agent and Epstein-Barr virus is the main candidate for the infectious agent causing HL; however, Epstein-Barr virus genome is found within the tumor in only about 20% to 40% of HL cases with a prior diagnosis of infectious mononucleosis. Recently, autoimmune and related conditions have drawn attention to a potential role for immune-related and inflammatory conditions in the etiology and pathogenesis of the malignancy. Evidence from multiply-affected families, a twin study, a case-control study, and population-based registry studies implicate genetic factors. Data from Eastern Asia and among Chinese immigrants in North America indicate increasing incidence trends for HL being associated with westernization. These results emphasize an interaction between environmental and genetic risk factors in HL.

Research paper thumbnail of Molecular Imaging in Myeloma Precursor Disease

Seminars in Hematology, 2011

Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy... more Multiple myeloma (MM) is consistently preceded by its pre-malignant states, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). By definition, precursor conditions do not exhibit end-organ disease (anemia, hypercalcemia, renal failure, skeletal lytic lesions, or a combination of these). However, new imaging methods are demonstrating that some patients in the MGUS or SMM category are exhibiting early signs of MM. Although MGUS/SMM patients are currently defined as low-risk versus high-risk based on clinical markers, we currently lack the ability to predict the individual patient&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;#39;s risk of progression from MGUS/SMM to MM. Given that the presence of gross lytic bone lesions is a hallmark of MM, it is reasonable to believe that less severe bone changes defined by more sensitive imaging may be predictive of MM progression. Indeed, since bone disease is such an essential aspect of MM, imaging techniques directed at the detection of early bone lesions, have the potential to become increasingly more useful in the setting of MGUS/SMM. Current guidelines for the radiological assessment of MM still recommend the traditional skeletal survey, although its limitations are well documented, especially in early phases of the disease when radiographs can significantly underestimate the extent of bone lesions and bone marrow involvement. Newer, more advanced imaging modalities, with higher sensitivities, including whole-body low-dose computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) are being employed. Also various imaging techniques have been used to provide an assessment of bone involvement and identify extra-osseous disease. This review emphasizes the current state of the art and emerging imaging methods, which may help to better define high-risk versus low-risk MGUS/SMM. Ultimately, improved imaging could allow more tailored clinical management, and, most likely play an important role in the development of future treatment strategies for high-risk precursor disease.

Research paper thumbnail of Mantle cell lymphomas with clonal immunoglobulin VH3–21 gene rearrangements exhibit fewer genomic imbalances than mantle cell lymphomas utilizing other immunoglobulin VH genes

Modern Pathology, 2005

A preferential use of one particular immunoglobulin variable heavy chain gene, V H 3-21, has rece... more A preferential use of one particular immunoglobulin variable heavy chain gene, V H 3-21, has recently been reported in mantle cell lymphoma, where almost all of these V H 3-21 þ mantle cell lymphomas showed usage of the same light chain V k gene (V k 3-19) and also had a tendency towards improved prognosis. These findings suggested that V H 3-21 þ mantle cell lymphomas constitute a distinct subgroup, possibly with antigen stimulation involved in disease pathogenesis. In this study, we applied the comparative genomic hybridization (CGH) method on 37 mantle cell lymphoma tumors in order to investigate if the V H 3-21 þ tumors are different at the genomic level. Interestingly, V H 3-21 þ mantle cell lymphomas (n ¼ 14) showed significantly fewer genomic aberrations (mean 2.4) compared to non-V H 3-21 mantle cell lymphomas (n ¼ 23) (mean 4.9). The chromosomal aberrations identified in our study were generally in accordance with previous CGH studies of mantle cell lymphoma; the most frequent aberration was complete or partial loss of chromosome 13, followed by recurrent losses within 6q, 9p, 9q and 11q and frequent gains in 3q, 7p, 8q and 15q. Deletions within 8p and 9p as well as gains in 7p and 15q were found exclusively in the non-V H 3-21-utilizing tumors. In summary, V H 3-21 þ mantle cell lymphomas demonstrated both a lower number and a different spectrum of genomic aberrations than mantle cell lymphoma in general, thus supporting the hypothesis that V H 3-21 þ mantle cell lymphomas constitute a new subgroup. The findings presented in this report may explain the tendency for a better clinical outcome for patients whose tumors utilize V H 3-21.

Research paper thumbnail of Flow cytometric differentiation of abnormal and normal plasma cells in the bone marrow in patients with multiple myeloma and its precursor diseases

Leukemia Research, 2014

Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognosticatio... more Flow cytometric (FC) enumeration of abnormal plasma cells (APCs) for diagnosis and prognostication of plasma cell dyscrasias (PCD) is challenging. We studied antigen expression in normal plasma cells (NPC) (N = 34) and APC in a series of unselected PCD (N = 59). NPC subpopulations often demonstrated CD19(−), CD20(+), CD45(−) or dim and CD56(+), an immunophenotype observed in PCD. However abnormal CD81 was only observed in APCs (APC detection sensitivity 95%; specificity 100%). We evaluated differences in antigen expression patterns among MGUS (N = 14), SMM (N = 35) and MM (N = 10), finding the combination of CD45 and CD56 helpful in differentiating MGUS from SMM and MM (p = 0.0002).

Research paper thumbnail of Antigenic drift in relapsed extramedullary multiple myeloma: plasma cells without CD38 expression

Leukemia & Lymphoma, 2012

... Prashant Tembhare, MD1, Constance Yuan, MD, Ph.D.1, Neha Korde, MD2,3, Irina Maric, MD4, and ... more ... Prashant Tembhare, MD1, Constance Yuan, MD, Ph.D.1, Neha Korde, MD2,3, Irina Maric, MD4, and Ola Landgren, MD, PhD3 ... Given that MM patients live longer after the introduction of novel therapies 1, it seems reasonable to believe that this phenomenon will become ...

Research paper thumbnail of Lack of MYD88 L265P in non-immunoglobulin M lymphoplasmacytic lymphoma

Leukemia & Lymphoma, 2013