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Malignancies of the B-lymphocyte lineage are among the most diagnosed haematological malignancies in clinical practice. In our community, multiple myeloma (MM) and its precursor condition monoclonal gammopathy of undetermined significance are the commonest, accounting for ~12% of diagnoses, followed by chronic lymphocytic leukaemia (CLL) and its precursor condition monoclonal B lymphocytosis, ~9%. Along with diffuse large B cell lymphoma, follicular lymphoma and marginal zone lymphoma, these conditions comprise around a third of all haematological malignancies diagnosed. Infection remains an important cause of mortality and morbidity in the management of patients with these conditions. This is in part treatment-related but also reflective of disease-related immune dysfunction. Infectious complications account for up to 50% of early mortality in patients with myeloma and up to 50% of all mortality in patients with CLL. A variety of strategies are available to decrease the morbidity and mortality of infectious complications; however, practices vary between countries and often between treating physicians. Treatment options have evolved significantly over the last decade, with the introduction of monoclonal antibodies, small molecule inhibitors, second- and third-generation immunomodulatory agents and CAR-T cell therapy. Much of the data that inform clinical practice in infection management predates current therapeutic approaches. This is in part because of the rapid development of new therapies but also reflective of the long natural history of many of these diseases and the need for prolonged periods of observation. In this article, we review the aspects of disease and treatment that contribute to immune dysfunction in MM, CLL and B-cell non-Hodgkin lymphoma and review the current strategies used to manage immune dysfunction and infection., (© 2023 Royal Australasian College of Physicians.)

Waldenström macroglobulinaemia (WM) is an indolent B-cell malignancy characterised by the presence of IgM paraprotein, bone marrow infiltration by clonal small B lymphocytes with plasmacytic differentiation and the MYD88 L265P mutation in >90% of cases. Traditionally, WM has been treated with chemoimmunotherapy. Recent trials have demonstrated the efficacy and safety of Bruton tyrosine kinase inhibitors in WM, both as monotherapy and in combination with other drugs. There is emerging evidence on the use of other agents including B-cell lymphoma 2 inhibitors and on the treatment of rare presentations of WM. In this update, the Medical and Scientific Advisory Group of Myeloma Australia reviews the available evidence on the treatment of WM since the last publication in 2017 and provides specific recommendations to assist Australian clinicians in the management of this disease., (© 2022 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Aim: To evaluate the accuracy of melphalan test dose pharmacokinetic (PK) predictions of the subsequent high dose (HDM) area under the concentration-versus-time curve (AUC) and to identify sources of prediction error (PE)., Methods: A prospective multicentre PK study was conducted in 40 myeloma patients of median age 60 (range:35-71) years using a 20 mg/m 2 test dose administered 1-3 days prior to HDM (predominantly 180 mg/m 2 ). PK data were collected post the test and high doses to compare predicted versus actual AUCs determined using the trapezoidal rule. Test and high dose infusion concentration, volume and duration and the time from preparation to infusion were compared using the paired Wilcoxin rank sign test. The impact of Melphalan administration parameters on PE was evaluated using the Mann-Whitney test. The predictive capacity of a previously published population PK (PopPK) model was also examined., Results: Predicted HDM AUC was within 15% of the observed values in only 63% of patients when analysed using the trapezoidal rule and 70% of patients using PopPK. Test dose infusion concentration, volume, duration and time from preparation to infusion were significantly lower than for HDM (p < 0.005). Test dose administration within 15 min of reconstitution (n = 5) was associated with significantly lower PE than administration times of 16-60 min (n = 22), p < 0.05. Test and HDM infusion concentrations were lower in patients with large PE (> ± 15%), but the differences were not significant (p = 0.078, 0.228, respectively)., Conclusion: Test dose PK has the potential to predict subsequent HDM exposure to achieve a target AUC once melphalan administration parameters are optimised to account for stability issues in the formulation., (© 2022. Crown.)

Imaging modalities for multiple myeloma (MM) have evolved to enable earlier detection of disease. Furthermore, the diagnosis of MM requiring therapy has recently changed to include disease prior to bone destruction, specifically the detection of focal bone lesions. Focal lesions are early, abnormal areas in the bone marrow, which may signal the development of subsequent lytic lesions that typically occur within the next 18-24 months. Cross-sectional imaging modalities are more sensitive for the detection and monitoring of bone and bone marrow disease and are now included in the International Myeloma Working Group current consensus criteria for initial diagnosis and treatment response assessment. The aim of this consensus practice statement is to review the evidence supporting these modalities. A more detailed Position Statement can be found on the Myeloma Australia website., (© 2021 Royal Australasian College of Physicians.)

The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4 + regulatory T cells (Treg) and cytotoxic CD8 + T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8 + T cells (T TE ). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8 + T TE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8 + T TE cells and BM-residency of CD8 + T TE cells in MGUS and newly diagnosed multiple myeloma patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Joshua, Vuckovic, Favaloro, Lau, Yang, Bryant, Gibson and Ho.)

CD8+CD57+ terminal effector T (TTE) cells are a component of marrow-infiltrating lymphocytes and may contribute to the altered immune responses in multiple myeloma (MM) patients. We analyzed TTE cells in the bone marrow (BM) and peripheral blood (PB) of age-matched controls and patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering MM (SMM), and newly diagnosed (ND) MM using flow cytometry, mass cytometry, and FlowSOM clustering. TTE cells are heterogeneous in all subjects, with BM containing both CD69- and CD69+ subsets, while only CD69- cells are found in PB. Within the BM-TTE compartment, CD69- and CD69+ cells are found in comparable proportions in controls, while CD69- cells are dominant in MGUS and SMM and predominantly either CD69- or CD69+ cells in NDMM. A positive relationship between CD69+TTE and CD69-TTE cells is observed in the BM of controls, lost in MGUS, and converted to an inverse relationship in NDMM. CD69-TTE cells include multiple oligoclonal expansions of T-cell receptor/Vβ families shared between BM and PB of NDMM. Oligoclonal expanded CD69-TTE cells from the PB include myeloma-reactive cells capable of killing autologous CD38hi plasma cells in vitro, involving degranulation and high expression of perforin and granzyme. In contrast to CD69-TTE cells, oligoclonal expansions are not evident within CD69+TTE cells, which possess low perforin and granzyme expression and high inhibitory checkpoint expression and resemble T resident memory cells. Both CD69-TTE and CD69+TTE cells from the BM of NDMM produce large amounts of the inflammatory cytokines interferon-γ and tumor necrosis factor α. The balance between CD69- and CD69+ cells within the BM-TTE compartment may regulate immune responses in NDMM and contribute to the clinical heterogeneity of the disease., (© 2020 by The American Society of Hematology.)

Multiple Myeloma (MM) is preceded by the clinically stable condition monoclonal gammopathy of undetermined significance (MGUS). Critical immune events that discriminate MGUS from newly diagnosed MM (ND)MM patients remain unknown, but may involve changes in the regulatory T cell (Treg) compartment that favor myeloma growth. To address this possibility, we used mass cytometry and the unsupervised clustering algorithm Flow self-organizing map (FlowSOM) to interrogate the distribution of multiple subsets within CD25 + CD127 low/neg Treg in matched bone marrow (BM) and peripheral blood (PB) of MGUS and NDMM patients. Both mass cytometry and flow cytometry confirmed a trend toward prevalence of CD39 - Treg within the Treg compartment in BM and PB of NDMM patients compared to CD39 - Treg in MGUS patients. FlowSOM clustering displayed a phenotypic organization of Treg into 25 metaclusters that confirmed Treg heterogeneity. It identified two subsets which emerged within CD39 - Treg of NDMM patients that were negligible or absent in CD39 - Treg of MGUS patients. One subset was found in both BM and PB which phenotypically resembled activated Treg based on CD45RO, CD49d, and CD62L expression; another subset resembled BM-resident Treg based on its tissue-resident CD69 + CD62L - CD49d - phenotype and restricted location within the BM. Both subsets co-expressed PD-1 and TIGIT, but PD-1 was expressed at higher levels on BM-resident Treg than on activated Treg. Within BM, both subsets had limited Perforin and Granzyme B production, whilst activated Treg in PB acquired high Perforin and Granzyme B production. In conclusion, the use of mass cytometry and FlowSOM clustering discovered two discrete subsets of CD39 - Treg which are discordant in MGUS and NDMM patients and may be permissive of myeloma growth which warrants further study. Understanding the regulatory properties of these subsets may also advance MGUS and MM diagnosis, prognosis, and therapeutic implications for MM patients.

Genetic sequencing of the myeloma genome has not revealed a specific disease-determining genetic alteration. Multiple disease subclones exist at diagnosis and vary in clinical importance with time and drug sensitivity. New diagnostic criteria have identified indications for early introduction of therapy. Autologous stem cell transplantation remains an essential component of therapy in young and fit patients. The use of continual suppressive (maintenance) therapy has been established as an important component in therapy. Immune therapies and the harnessing of the innate immune system offer great promise for future treatments. Since 2005, quality of life, supportive therapies, and survival have dramatically improved over a decade of remarkable progress. The common manifestations of multiple myeloma, such as bone pain, fatigue and weight loss, may be non-specific and are often initially ignored or missed by patients and medical practitioners., (© 2019 AMPCo Pty Ltd.)

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal proliferation of plasma cells in the bone marrow. More than 80% of patients with MM display evidence of myeloma bone disease (MBD), characterised by the formation of osteolytic lesions throughout the axial and appendicular skeleton. MBD significantly increases the risk of skeletal-related events such as pathologic fracture, spinal cord compression and hypercalcaemia. MBD is the result of MM plasma cells-mediated activation of osteoclast activity and suppression of osteoblast activity. Bisphosphonates (BP), pyrophosphate analogues with high bone affinity, are the only pharmacological agents currently recommended for the treatment and prevention of MBD and remain the standard of care. Pamidronate and zoledronic acid are the most commonly used BP to treat MBD. Although generally safe, frequent high doses of BP are associated with adverse events such as renal toxicity and osteonecrosis of the jaw. As such, optimal duration and dosing of BP therapy is required in order to minimise BP-associated adverse events. The following guidelines provide currently available evidence for the adoption of a tailored approach when using BP for the management of MBD., (© 2017 Royal Australasian College of Physicians.)

An active role for the immune system in controlling the malignant plasma cell clone in myeloma has been postulated for many years. The clinical states of monoclonal gammopathy of undetermined significance, plateau phase disease, and smoldering myeloma all suggest that a significant host-tumor interaction is taking place. The fundamental role of the cytotoxic T cell in tumor elimination and control has been exemplified by the dramatic efficacy of adoptive T-cell therapies in many hemopoietic malignancies. However, tumor-host cross-talk results in suppression of the endogenous cytotoxic T-cell response against the malignant plasma cell. Whereas patients with myeloma do not clinically exhibit a T-cell immunodeficiency state, with, for example, increased mycobacterial infections, a number of abnormalities of T-cell function are evident. The major abnormalities of T cells include clonal expansions and associated immunosenescence, alterations of regulatory T cells/T helper 17 cells (Treg/Th17 ratio) and acquired membrane abnormalities, due to trogocytosis, which result in acquired Treg cells. Dendritic cell dysfunction associated with impaired antigen processing and presentation caused by abnormalities of the bone marrow microenvironment plays an additional role. In this perspective, we examine the T-cell abnormalities in myeloma and postulate that, whereas cytotoxic T cells interacting with the tumor are dysfunctional, residual T cells still function adequately against external pathogens and thus protect patients from the infections normally associated with a generalized T-cell immunodeficiency state. The so-called 3 E's of host-tumor interaction (elimination, equilibrium, and escape) are clearly reflected in the immune landscape and clinical behavior of myeloma., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells that have been implicated as inhibitors of lymphopoiesis in patients with malignancies. They have a consensus phenotype of CD33+/CD11b+/HLA-DRlo/- and can be further divided into CD15 + granulocytic (G-MDSC) and CD14 + monocytic (M-MDSC) subsets. We characterized MDSCs in patients with multiple myeloma (MM) and found a significant increase in G-MDSCs in the blood of patients with progressive MM. Flow-sorted MDSCs from patients with MM induced the generation of regulatory T cells (Treg). MDSCs from both patients with MM and aged-matched controls demonstrated a dose-dependent inhibition of lymphocyte proliferation in carboxyfluorescein succinimidyl ester (CFSE)-tracking experiments. Granulocyte colony stimulating factor (G-CSF) administered to induce stem cell mobilization caused an increase in the number of MDSCs in the peripheral blood of patients with MM and a concentration of these immune-suppressive cells in peripheral blood stem cell collections. MDSCs are likely to cause immune dysfunction in patients with MM.

Autologous hematopoietic cell transplantation (AHCT) for plasma cell myeloma is performed less often in people >70 years old than in people ≤70 years old. We analyzed 11,430 AHCT recipients for plasma cell myeloma prospectively reported to the Center for International Blood and Marrow Transplant Research between 2008 and 2011, representing the majority of US AHCT activity during this period. Survival (OS) was compared in 3 cohorts: ages 18 to 59 years (n = 5818), 60 to 69 years (n = 4666), and >70 years (n = 946). Median OS was not reached for any cohort. In multivariate analysis, increasing age was associated with mortality (P = .0006). Myeloma-specific mortality was similar among cohorts at 12%, indicating an age-related effect on nonmyeloma mortality. Analyses were performed in a representative subgroup comparing relapse rate, progression-free survival (PFS), and nonrelapse mortality (NRM). One-year NRM was 0% for age >70 years and 2% for other ages (P = not significant). The three-year relapse rate was 56% in age 18 to 59 years, 61% in age 60 to 69 years, and 63% age >70 (P = not significant). Three-year PFS was similar at 42% in age 18 to 59 years, 38% in age 60 to 69 years, and 33% in age >70 years (P = not significant). Postrelapse survival was significantly worse for the older cohort (P = .03). Older subjects selected for AHCT derived similar antimyeloma benefit without worse NRM, relapse rate, or PFS., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Abstract Discrepancies in the literature between regulatory T cell (Treg) and pro-inflammatory T helper 17 (Th17) numbers in multiple myeloma (MM) can be largely explained by technical differences in methodology and patient selection. In this study, Treg cells were defined as CD3(+)CD4(+)CD25(++)CD127(lo) cells. Patients with MM (n = 20) had a significant imbalance in Treg/Th17 ratio when compared with either aged-matched controls (n = 28) or other monoclonal gammopathies, and this was associated with a significantly worse survival. The percent Treg in bone marrow of patients with MM was higher than that in matched peripheral blood samples (p = 0.02), although FOXP3 expression within bone marrow T cells was lower (p = 0.02). We observed increased Treg function, both in vivo and in vitro, due at least partially to an increase in CTLA-4 expression by concurrent treatment with dexamethasone and immune modulatory compounds (iMiDs). We suggest that immunoregulatory balance is important during active chemotherapy and that conclusions related to the immunostimulatory effect of iMiDs based on in vitro testing must be considered with caution.

Autologous hematopoietic cell transplantation (AHCT) as initial therapy of patients with multiple myeloma (MM) improves survival. However, data to support this approach for relapsed/progressive disease after initial AHCT (AHCT1) are limited. Using Center for International Blood and Marrow Transplant Research data, we report the outcomes of 187 patients who underwent a second AHCT (AHCT2) for the treatment of relapsed/progressive MM. Planned tandem AHCT was excluded. Median age at AHCT2 was 59 years (range, 28 to 72), and median patient follow-up was 47 months (range, 3 to 97). Nonrelapse mortality after AHCT2 was 2% at 1 year and 4% at 3 years. Median interval from AHCT1 to relapse/progression was 18 months, and median interval between transplantations was 32 months. After AHCT2, the incidence of relapse/progression at 1 and 3 years was 51% and 82%, respectively. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46%. In multivariate analyses, those relapsing ≥36 months after AHCT1 had superior progression-free (P = .045) and overall survival (P = .019). Patients who underwent AHCT2 after 2004 had superior survival (P = .026). AHCT2 is safe and feasible for disease progression after AHCT1. In this retrospective study, individuals relapsing ≥36 months from AHCT1 derived greater benefit from AHCT2 compared with those with a shorter disease-free interval. Storage of an adequate graft before AHCT1 will ensure that the option of a second autologous transplantation is retained for patients with relapsed/progressive MM., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The transfer of membrane proteins between cells during contact, known as trogocytosis, can create novel cells with a unique phenotype and altered function. We demonstrate that trogocytosis is more common in multiple myeloma (MM) than chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia; that T cells are more probable to be recipients than B or natural killer cells; that trogocytosis occurs independently of either the T-cell receptor or HLA compatibility; and that after trogocytosis, T cells with acquired antigens can become novel regulators of T-cell proliferation. We screened 168 patients with MM and found that CD86 and human leukocyte antigen G (HLA-G) were antigens commonly acquired by T cells from malignant plasma cells. CD3+ CD86acq+ and CD3+ HLA-Gacq+ cells were more prevalent in bone marrow than peripheral blood samples. The presence of either CD86 or HLA-G on malignant plasma cells was associated with a poor prognosis. CD38++ side population cells expressed HLA-G, suggesting that these putative myeloma stem cells could generate immune tolerance. HLA-G+ T cells had a regulatory potency similar to natural Tregs, thus providing another novel mechanism for MM to avoid effective immune surveillance.

The translocation t(4;14) is associated with a poor prognosis in myeloma, but its effect in the setting of new drugs such as thalidomide, bortezomib and lenalidomide continues to be investigated, and the role of candidate genes such as FGFR3 (fibroblast growth factor receptor 3) is not yet clarified. In the Australasian Leukaemia and Lymphoma Group (ALLG) MM6 randomized study comparing consolidation thalidomide and prednisolone with prednisolone alone following autologous stem cell transplant, patients on consolidation thalidomide and prednisolone had superior progression-free (PFS) and overall survival (OS). We now show that thalidomide consolidation benefited both t(4;14)-positive (PFS 29 vs. 17 months, p =0.03) and -negative (52 vs. 24 months, p =0.04) disease. PFS for patients with normal FGFR3 expression was significantly better than for those with up-regulated FGFR3 (31 vs. 21 months, p =0.02). Consolidation thalidomide conferred an improved PFS in patients with normal FGFR3 expression (41 vs. 19 months, p =0.02), but there was no improvement in patients with up-regulated FGFR3 (31 vs. 29 months, p =0.76). We conclude that consolidation thalidomide may mitigate the poor prognostic effect of t(4;14), and improves PFS in normal but not up-regulated FGFR3 expression. Thus the level of FGFR3 expression provides additional prognostic information to t(4;14) in myeloma induction and consolidation therapy.

Obesity has implications for chemotherapy dosing and selection of patients for therapy. Autologous hematopoietic stem cell transplant (AutoHCT) improves outcomes for patients with multiple myeloma, but optimal chemotherapy dosing for obese patients is poorly defined. We analyzed the outcomes of 1087 recipients of AutoHCT for myeloma reported to the CIBMTR between 1995 and 2003 who received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal, overweight, obese, or severely obese. There was no overall effect of BMI on progression-free survival (PFS), overall survival (OS), progression, or nonrelapse mortality (NRM). In patients receiving melphalan and TBI conditioning, obese and severely obese patients had superior PFS and OS compared with normal and overweight patients, but the clinical significance of this finding is unclear. More obese patients were more likely to receive a reduced dose of melphalan, but there was no evidence that melphalan or TBI dosing variability affected PFS. Therefore, current common strategies of dosing melphalan do not impair outcomes for obese patients, and obesity should not exclude patients from consideration of autologous transplantation. Further research is necessary to optimize dosing of both chemotherapy and radiation in obese patients., (Copyright © 2011 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

This study reports on the outcome of 95 allogeneic hematopoietic cell transplants (HCTs) using reduced intensity conditioning (RIC) performed for patients with multiple myeloma (MM) in Australia and New Zealand between 1998 and 2006. The median age at HCT was 52 years. Of the 32 patients for whom the allograft was performed as a first transplant, 15 (47%) had their allograft less than 1 year from diagnosis, while for the 63 patients who had an allograft following an autograft, nine (14%) were allografted within 1 year post-diagnosis (p < 0.001). The cumulative incidence of transplant-related mortality (TRM) was 19% at 1 year post-transplant. At 5 years post-transplant the overall survival (OS) was 40% and progression-free survival (PFS) was 23%, with no apparent survival plateau. Three factors were independently favorable predictors of OS in a Cox regression model: immunoglobulin G (IgG) myeloma (hazard ratio [HR] = 0.42, 95% confidence interval [CI] 0.24-0.75, p = 0.004), a human leukocyte antigen (HLA)-identical sibling donor (HR = 0.37, 95% CI 0.18-0.74, p = 0.005), and less than 1 year between MM diagnosis and RIC HCT (HR = 0.27, 95% CI 0.12-0.59, p = 0.001). Patterns of outcome indicate that RIC HCT may offer the potential for cure for only a small group of patients with MM.

Interferons are soluble proteins produced naturally by cells in response to viruses. It has both anti-proliferative and immunomodulating properties and is one of the first examples of a biological response modifier use to treat the haematological malignancy multiple myeloma. Interferon has been used in this clinical practice for over thirty years. However, despite considerable efforts, numerous clinical trials and two large meta-analysis, its exact role in the management of multiple myeloma still remains unclear. Its role in the treatment of multiple myeloma has been as a single induction agent, a co-induction agent with other chemotherapy regimens, and as maintenance therapy after conventional chemotherapy or complete remission after autologous or allogeneic transplantation. Interferon as a single induction agent or co-induction agent with other chemotherapy agents appears only to have minimal benefit in myeloma. Its role as maintenance therapy in the plateau phase of myeloma also remains uncertain. More recently, the use of interferon must now compete with the "new drugs"--thalidomide, lenalidomide and bortezomib in myeloma treatment. Will there be a future role of interferon in the treatment of multiple myeloma or will interferon be resigned to the history books remains to be seen.

Introduction: Immunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined., Patients and Methods: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 36 patients with IgD and 11 patients with IgM myeloma among 3578 myeloma patients who received intensive therapy and auto-HCT over a 10-year period., Results: The progression-free and overall survival probabilities at 3 years were 38% (95% CI, 21%-56%) and 69% (95% CI, 51%-84%) for IgD myeloma, and 47% (95% CI, 17%-78%) and 68% (95% CI, 36%-93%), respectively, for IgM disease. Although formal statistical analysis was limited by the small sample size, these results were comparable to those for IgG and IgA patients autografted during the same time period. Transplantation-related mortality and disease relapse/progression of myeloma were also similar for all isotypes., Conclusion: This analysis demonstrates comparable outcomes in all immunoglobulin isotypes. Therefore, auto-HCT should be offered to eligible patients with IgD and IgM myeloma.

Blacks are twice as likely to develop and die from multiple myeloma (MM), and are less likely to receive an autologous hematopoietic-cell transplant (AHCT) for MM compared to Whites. The influence of race on outcomes of AHCT for MM is not well described. We compared the probability of overall survival (OS), progression-free survival (PFS), disease progression, and nonrelapse mortality (NRM) among Black (N=303) and White (N=1892) recipients of AHCT for MM, who were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2005. The Black cohort was more likely to be female, and had better Karnofsky performance scores, but lower hemoglobin and albumin levels at diagnosis. Black recipients were younger and more likely to be transplanted later in their disease course. Disease stage and treatment characteristics prior to AHCT were similar between the 2 groups. Black and White recipients had similar probabilities of 5-year OS (52% versus 47%, P=.19) and PFS (19% versus 21%, P=.64) as well as cumulative incidences of disease progression (72% versus 72%, P=.97) and NRM (9% versus 8%, P=.52). In multivariate analyses, race was not associated with any of these endpoints. Black recipients of AHCT for MM have similar outcomes compared to Whites, suggesting that the reasons underlying lower rates of AHCT in Blacks need to be studied further to ensure equal access to effective therapy., (Copyright (c) 2010 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The expanded T cell clones are associated with a prolonged survival in patients with multiple myeloma. We sought to confirm this prognostic significance in a multicenter patient cohort and investigate the effect of thalidomide on clones and T regulatory cells (T(regs)). Blood was collected from 120 patients enrolled in a Phase III trial of maintenance therapy +/- thalidomide after autologous stem cell transplantation. TCR Vbeta repertoire analysis identified T cell expansions in 48% of patients pre-transplant and 68% after 8-month maintenance. T cell expansions, previously shown to be clonal, were predominantly CD8+ (93%) and all 24 TCR Vbeta families tested were represented. Thalidomide therapy was associated with a significant increase in the incidence of patients with multiple expansions (49% vs. 23%; chi2 = 6.8; p = 0.01). The presence of expansions regardless of therapy was associated with a significantly longer median progression free survival (PFS) (32.1 vs. 17.6 months; chi2 = 5.6; p = 0.02) and overall survival (OS) (chi2 = 3.9; p < 0.05). Median PFS in the thalidomide arm was 50.9 months for patients with expansions and 28.3 months for patients without expansions (chi2 = 19.4; p = 0.0002). Thalidomide did not appear to modulate T(reg) numbers. Expanded T cell clones are prognostically significant and have an impact on progression after thalidomide therapy in a proportion of patients.

Nonsecretory myeloma (NSM) accounts for <5% of cases of multiple myeloma (MM). The outcome of these patients following autologous stem cell transplantation (ASCT) has not been evaluated in clinical trials. We compared the outcomes after ASCT for patients with NSM reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1989 and 2003, to a matched group of 438 patients (4 controls for each patient) with secretory myeloma (SM). The patients were matched using propensity scores calculated using age, Durie-Salmon stage, sensitivity to pretransplant therapy, time from diagnosis to transplant, and year of transplant. Disease characteristics were similar in both groups at diagnosis and at transplant except higher risk of anemia, hypoalbuminemia, and marrow plasmacytosis (in SM) and plasmacytoma (more in NSM). Cumulative incidence of treatment-related mortality (TRM), relapse, progression-free survival (PFS), and overall survival (OS) were similar between the groups. In multivariate analysis, based on a Cox model stratified on matched pairs and adjusted for covariates not considered in the propensity score, we found no difference in outcome between the NSM and SM groups. In this large cohort of patients undergoing ASCT, we found no difference in outcomes of patients with NSM compared to those with SM.

Many clinical observations point to active immunologic phenomena in patients with myeloma. These consist of active suppression of the host's immune system and partially successful attempts by the host's immune system to suppress the malignant B-cell population. Clinical conditions such as asymptomatic myeloma, which represents clinical presentation in the plateau phase of the disease, plateau establishment after conventional induction therapy without the ongoing need for therapy, and the positive prognostic importance of the presence of clones of cytotoxic T cells in the peripheral blood of some patients, suggest that host-tumor interaction is an active dynamic state. Regulatory T (Treg) cells comprise 5%-10% of peripheral CD4 T cells and are responsible for the control of autoimmune phenomena. Deficiency of the FoxP3 transcription factor, which normally characterizes Treg cells, leads to multiorgan autoimmune disorders in humans and mice. The role of Treg cells in the protection from malignancy is unclear, but their depletion can lead to the induction of tumor rejection in murine models, and their demonstration as tumorinfiltrating lymphocytes in malignancy point to a significant immunomodulator role. In myeloma, host-tumor immune interactions are complex. However, patients can clearly exhibit control of their B-cell malignancy for many years with stability of paraprotein levels, demonstrating a homeostasis between tumor and host. Whether Treg cells are playing a role in this homeostasis is unclear. At present, there is considerable debate in the literature regarding observations such as whether Treg cells are increased or decreased, functional or dysfunctional. In this review, we will discuss the potential importance of Treg cells and their role in myeloma, a disease characterized by a unique set of host-tumor interactions.

Relapse is the overwhelming cause of treatment failure after autologous transplantation for multiple myeloma (MM). For patients with a syngeneic donor, twin transplants provide a healthy graft that is free of myeloma. The relative impact of the graft on posttransplant relapse can be estimated by comparing risk of relapse after hematopoietic cell transplantation from genetically identical twins versus autotransplants because confounding differences in minor or major histocompatibility antigens are absent in the syngeneic transplant setting. Outcomes of 43 subjects who received twin transplants for MM were compared to 170 matched autotransplant recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Multivariate analysis was performed by fitting a Cox model stratified on matched pairs. The matched transplant patients studied were similar with respect to subject-, disease-, and transplant-related characteristics. Cumulative incidence of relapse/progression was significantly lower, and progression-free survival (PFS) was significantly higher following twin transplants. In multivariate analysis, the probability of relapse/progression was lower in twins (relative risk [RR] = 0.49, 95% confidence interval [CI] 0.28-0.86, P = .011). Twin transplants have a significantly lower relapse risk than autotransplants in MM, suggesting that graft composition may impact outcomes following high-dose chemotherapy.

Thalidomide and its immunomodulatory derivatives have provided the most significant advance in the therapy of myeloma since the introduction of high dose chemotherapy followed by stem cell transplantation nearly 20 years ago. The mechanism of action of thalidomide is complex and involves many aspects of malignant plasma cell growth and bone marrow stromal cell microenvironment interaction. Thalidomide was first used because of its anti-angiogenic properties, however it is the immunomodulatory actions that involve increasing host tumour-specific immunosurveillance by both T cell and natural killer cells which may be the most important mode of action.

The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44(+)) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up-regulate the expression of the B7 co-stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor beta(1) (TGFbeta(1)) and interleukin (IL)-10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti-TGFbeta(1). As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up-regulation was reduced in both stage I and stage III. It was demonstrated that both IL-12 and interferon-gamma neutralized the failure to stimulate CD80 up-regulation by huCD40LT in vitro. IL-12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123-) suggesting that there would be a predominantly T-helper cell type response. The addition of IL-12 or interferon-gamma to future immunotherapy trials involving these patients should be considered.

Murine T cells do not endogenously upregulate CD80 expression but rather acquire CD80 from antigen presenting cells (APC) during CD28 ligation. Murine CD80+ memory T cells undergo apoptosis in the presence of high levels of antigen while naive CD80+ T cells are capable of acting as APC and T cell:T cell ligation induces anergy and unresponsiveness to antigen rechallenge. Reversing T cell unresponsiveness may be a key factor in the development of immunotherapy strategies for patients with myeloma. We have determined that B7+ T cells (CD80+ or CD86+) are common in patients with myeloma (n = 45), can be either CD4 or CD8, tend to be associated with stable disease and are polyclonal memory T cells (CD45RO). CD80 mRNA expression was present in CD80+ monocytes but not in CD3+ cells with a similar level of CD80 antigen expression. CD80 and CD86 antigen expression was upregulated on B cells but not T cells during incubation with trimeric human CD40 ligand (huCD40LT) + IL-2. Although there was a gradual loss of expression during in vitro culture, CD80+ T cells could be purified for further study. We conclude that B7 expression is common on T cells of patients with myeloma but that this is acquired rather than endogenously produced. B7+ CD45RO+ T cells constitute a population of memory T cells chronically exposed to antigen and warrant further study.

Multiple myeloma (MM) is a malignant disease characterized by accumulation of morphologically recognizable plasma cells producing immunoglobulin (Ig) in the bone marrow. The occurrence of clonal T cells in MM, as defined by the presence of rearrangements in the T-cell receptor (TCR)-beta chains detected on Southern blotting, is associated with an improved prognosis. This review aims to describe the various ways in which we have demonstrated the presence of such T cell clones, and to describe the phenotype of these cells. Finally, the specificities of these clinically important CD8+ T cell populations will be discussed in the context of immunotherapy.

Idiotypic determinants are potential patient-specific tumor antigens in multiple myeloma (MM). In this study, we have determined the DNA sequence of the variable region of the tumor immunoglobulin (Ig) in 6 patients with MM. We then selected high affinity class I-restricted T-cell peptide epitopes in tumor Ig using two different internet-based epitope prediction programs. High affinity binding peptides were identified by at least one program in 4 out of 6 patients. Of these 35 peptides, only 3 scored high by both analyses. Given that all 6 patients had expanded T-cell clones with a cytotoxic (CD57+CD8+CD28-perforin+) phenotype, known to be associated with a longer survival and postulated to recognise tumor epitopes, this analysis indicates that such clones are unlikely to be exclusively directed towards tumor immuoglobulin, and suggests the need to expand the scope of the search for tumor epitopes with the ability to stimulate cytotoxic T cells in vivo.

Despite the advances in our knowledge of myeloma cell biology, our understanding of myeloma pathogenesis is still incomplete. In this review, we present a summary of the cellular and molecular aspects of B-cell development and immunoglobulin (lg) gene rearrangement which have been important in defining the characteristics of the myeloma plasma cell (MPC). The PMC has undergone variable gene recombination, somatic hypermutation and isotype switching, and is therefore at a postgerminal center stage of development. The finding of preswitch clonal cells and isotype variants have raised interesting questions about the cell of origin of myeloma, for which no conclusive data is as yet available. However much information has been obtained about the chromosomal and genetic aberrations in myeloma, including monosomy 13, Ig heavy chain (IgH) switch region translocations, numerical abnormalities and a multitude of heterogeneous changes. A variety of techniques have been developed to overcome the insensitivity of conventional karyotyping, utilizing molecular cytogenetic strategies ranging from the delineation of precise loci by fluorescent in situ hybridization, a more "global" assessment of the genome by multicolor spectral karyotyping, to the quantitation of chromosomal material of specific origin by comparative genomic hybridization. Whether the abnormalities detected represent oncogenic insults, are involved in disease progression or are simply "by-products" of genetic instability is still unclear. For IgH translocations, the role of candidate genes such as Cyclin D1 and FGFR3 has been studied extensively by quantitating their expression and assessment of their oncogenicity (e.g. for FGFR3) in animal models. The significance of other aberrations such as c-myc, ras and p53 has also been investigated. With the advent of oligonucleotide microarrays, the expression of thousands of genes can be efficiently examined. So far, this approach seems promising in defining subgroups of different disease behavior, and may highlight specific genes and molecular mechanisms which are important in myeloma pathogenesis.