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Summary Median overall survival (OS) has improved for patients with newly diagnosed multiple myeloma (NDMM), but prognosis varies depending on baseline patient characteristics. Current models use data from selected clinical trial populations, which prevent application to patients in an unselected community setting that reflects routine clinical practice. Using data from the Connect® MM Registry, a large, US, multicentre, prospective observational cohort study (Cohort 1: 2009–2011; Cohort 2: 2012–2016) of 3011 patients with NDMM, we identified prognostic variables for OS via the multivariable analysis of baseline patient characteristics in Cohort 1 (n = 1493) and developed a tool to examine individual outcomes. Factors associated with OS (n = 1450 treated patients; P

The International Myeloma Working Group consensus aimed to provide recommendations for the optimal use of

This article provides an overview of the current state of knowledge concerning myeloma genetics. The paucity of information in patients with early disease is contrasted with the complexity of karyotypic findings in patients with advanced disease. The molecular changes are analyzed, both in terms of the expression of a monoclonal plasma cell phenotype, as well as the intrinsic biology of myeloma cell, including the effects of cytokines and cell-to-cell interactions.

Bone lesions in multiple myeloma (MM) are screened with radiological skeletal survey (RSS) due to its widespread availability. Although bone lesions can be missed by RSS, more sensitive radiological surveys are not as yet recommended for routine use due to the low availability of the methodology and economical considerations.We report on a 68-year-old male with IgG kappa stage IIIA MM presenting with skeletal pain, fatigue and osteolytic lesions. Since the patient refrained from more intensive therapy, including autologous stem cell transplantation (auto-SCT), he was treated with vertebral irradiation and included in an institutionally guided study which randomized melphalan, prednisone (MP)-lenalidomide (MPR) to MP alone. Although he initially responded, his bone pain reoccurred after three MP cycles. The repeated RSS showed minor, if any changes. Therefore, an MRI was added which revealed extensive osteolyses and extramedullary disease. Justified by these results it was possible to convince the patient that a more intensive therapy approach, including auto-SCT, local irradiation and thalidomide maintenance, was appropriate.This case calls for an earlier integration of MRI and/or PET/CT scanning in MM, even if RSS remains unchanged, especially if initial bone disease is substantial and/or MM-related symptoms recur. The time course of information and linked decision-making point towards the future significance of an intensified integration of imaging methodologies in the classification and disease management of MM.

The ‘Workshop on Growth Factors’ which took place at the Lugano Lymphoma Conference on June 8, 1990, included a presentation by Michael Sporn on the concept that loss of inhibitory control mechanisms may be important in the development and growth of human cancer. Examples illustrating this were taken from current experimental biology research into transforming growth factor β (TGF-β) interactions. Brian Durie presented recent data on the biology of interleukin-6 (IL-6) and its putative role in plasma cell diseases. These studies have culminated in the first clinical study of the role of an antibody to a growth factor as therapy for a human cancer (anti-IL-6 antibody as therapy for patients with myeloma). Derek Crowther presented data concerning the current clinical role of the haematopoietic growth factors in patients undergoing chemotherapy for cancer. Recent clinical research has established the role of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in improving the safety of high-dose or accelerated chemotherapy, and their use is associated with enhanced neutrophil recovery following ablative therapy and bone marrow rescue. This session was followed by the presentation of three papers concerning the use of G-CSF and GM-CSF in association with chemotherapy for patients with malignant lymphoma.

PurposeThere is a need for a simple, reliable staging system for multiple myeloma that can be applied internationally for patient classification and stratification.Patients and MethodsClinical and laboratory data were gathered on 10,750 previously untreated symptomatic myeloma patients from 17 institutions, including sites in North America, Europe, and Asia. Potential prognostic factors were evaluated by univariate and multivariate techniques. Three modeling approaches were then explored to develop a staging system including two nontree and one tree survival assessment methodologies.ResultsSerum beta2-microglobulin (Sβ2M), serum albumin, platelet count, serum creatinine, and age emerged as powerful predictors of survival and were then used in the tree analysis approach. A combination of Sβ2M and serum albumin provided the simplest, most powerful and reproducible three-stage classification. This new International Staging System (ISS) was validated in the remaining patients and consists of the following stages: stage I, Sβ2M less than 3.5 mg/L plus serum albumin ≥ 3.5 g/dL (median survival, 62 months); stage II, neither stage I nor III (median survival, 44 months); and stage III, Sβ2M ≥ 5.5 mg/L (median survival, 29 months). The ISS system was further validated by demonstrating effectiveness in patients in North America, Europe, and Asia; in patients less than and ≥ 65 years of age; in patients with standard therapy or autotransplantation; and in comparison with the Durie/Salmon staging system.ConclusionThe new ISS is simple, based on easy to use variables (Sβ2M and serum albumin), and recommended for early adoption and widespread use.

Plasma cell disorders include monoclonal gammopathies of undetermined significance (MGUS), smoldering/indolent myeloma, and active myeloma. Related disorders are Waldenstrom’s macroglobulinemia, the heavy-chain diseases, primary systemic amyloidosis, and systemic light-chain deposition disease. The characteristic feature of these diseases is the involvement of cells that are either plasma cells or lymphocytes resembling plasma cells and typically the production of immunoglobulin (Ig) (heavy and/or light chains) in a monoclonal fashion. The most common myelomas are IgG or IgA κ or λ, and κ or λ Bence Jones-only myeloma. Waldenstrom’s macroglobulinemia is IgM κ or λ in type.

We aimed to develop and evaluate a staging system for multiple myeloma (MM) based on easily obtained laboratory measures. The Durie-Salmon stage is most commonly used and is an effective system of patient stratification for clinical trial research. However, the criteria are complex and many laboratory parameters are required to properly stage patients. In this analysis, we focused on two common measures with prognostic importance in MM: serum beta2 microglobulin (beta2m) and serum albumin. Pre-study data on 1555 previously untreated MM patients enrolled on four recent South-west Oncology Group (SWOG) phase III trials were used in the analysis. Staging models were developed and validated using regression tree methods for survival outcomes. SWOG stages were defined as: stage 1, beta2m2.5 mg/l (14% of patients, median overall survival of 55 months); stage 2, 2.5/= beta2m5.5 (43% of patients, median overall survival of 40 months); stage 3, beta2m/= 5.5 and albumin/= 30 g/l (32% of patients, median overall survival of 24 months); and stage 4, beta2m/= 5.5 and albumin30 g/l (11% of patients and median overall survival of 16 months). This staging scheme was also predictive of event-free survival, first-year mortality and long-term (/= 5 years) event-free survival. We conclude that although the SWOG stage does not represent a new prognostic marker for MM (cytogenetics, FISH), it could provide a simple alternative to the Durie-Salmon stage for patients with previously untreated MM. Additional evaluation in other MM patient populations is needed to confirm results.

Cytogenic studies in multiple myeloma have been very difficult because of the predominantly low proliferative activity in this disease (1-7). In the series reported to date the most commonly affected chromosomes have been chromosomes 1 and 14: a variety of translocations and structural changes have been documented. Chromosome 14 in particular has been involved in translocations to several chromosomes, including t(11;14), t(8;14) and t (14;18). In addition to these translocations, acquisition of miscellaneous chromosomal fragments and unidentified markers (UMARS) is very frequent. Gains and losses of numerous chromosomes have also been noted. The current report summarises a preliminary analysis of a large study of 331 bone marrow specimens from 262 patients with multiple myeloma, studied at the University of Arizona.

Interleukin 6 (IL6) is a pleiotropic cytokine which has been shown to be a very potent growth factor for myeloma cells, particularly cells derived from patients with aggressive clinical disease (1,2). Although it has been documented that myeloma cells have large numbers of IL-6 receptors and that both the bone marrow and serum of patients with active myeloma contain increased levels of IL6, the source(s) and regulation of IL6 levels are not fully understood. In some studies it has been indicated that the IL6 growth stimulatory loop appears to be autocrine in nature (3): whereas other data show that a paracrine loop is more likely with the predominant source of IL6 being accessory cells, such as macrophages, fibroblasts and probably other bone marrow cells (4). The current report is a preliminary analysis of a large study in which both cell separation and anti IL6 blocking techniques (both IL6 and IL6 receptor) were used to evaluate the sources and functions of IL6 in myeloma bone marrow specimens. The data indicate that the paracrine mechanism is crucial.

Ten patients with AML refractory to anthracyclines and cytosine arabinoside were treated with vincristine 1.4 mg/m2 and methotrexate (MTX) 2.5 gm/m2 by intravenous (IV) bolus on day 1 [citrovorum factor (CF) rescue began 24 h later], BCNU 80 mg/m2, and cyclophosphamide 900 mg/m2 IV 36 h after MTX and MGBG 300 mg/m2 IV over 1–2 h on days 3, 4, and 5. Bone marrow aplasia was achieved in all patients by day 12. Five patients (50%) achieved complete remission (CR). Two patients died of sepsis during induction. The median duration of remission was 24 weeks (range 8–38). Maintenance therapy was employed in three patients (high-dose MTX-CF in 2 and MGBG plus BCNU in 1), but did not appear to significantly increase the duration of remission. Nausea and vomiting occurred in eight patients. Five patients developed moderate stomatitis and one developed a modereately severe cutaneous reaction. This pilot experience demonstrates that patients with refractory AML can achieve CR after aggressive treatment with so-called second-line drugs, and may indicate that collateral sensitivity to MTX exists in cells which have become resistant to anthracyclines, a situation we previously described in an experimental cell line.

Pseudothrombocytopenia is an in vitro phenomenon usually associated with anticoagulant (EDTA)-dependent IgG platelet agglutinins. A low Coulter platelet count was investigated in a 63-year-old woman with multiple sclerosis and a monoclonal IgM kappa gammopathy. An unusual type of EDTA- and temperature-independent IgM platelet agglutinin was identified by in vitro agglutination of donor platelets and was removed by immunoabsorption.

The kinetics of bone marrow plasma cells were evaluated by means of in vitro 3(H)thymidine incorporation in 143 patients with monoclonal gammopathies. Fifty-three patients had symptomatic multiple myeloma (MM) at diagnosis, nine were in stable remission, six in unstable remission, and 16 in the relapse phase. Thirty-seven patients were classified has having monoclonal gammopathy of undetermined significance (MGUS) and 22 as smouldering myeloma (SM). A thymidine labelling index (LI%) of greater than 3 at initial diagnosis predicted a very short survival. High LI% values (median 2.8 +/- 1.1) were also seen at relapse. However, the major new finding was that the LI% could be used to discriminate precisely between the SM-MGUS group and the MM patients including stage I disease (P less than 0.0001). Only one patient developed MM during follow up, that being 8 months after the initial diagnosis of SM. During the unmaintained stable remission (plateau) phase a low proliferative activity was also observed (LI% = 0.6 +/- 0.2). Thus the LI% was extremely useful in identification of both poor risk groups with a LI% greater than 3 and stable patients requiring no immediate therapy with a LI% less than 1. The ability to discriminate between MGUS and SM and stage I MM should prove particularly useful clinically.

SummaryThe in vitro human tumor stem cell assay (HTSCA) has proven accurate in predicting clinical responses to a wide variety of anticancer drugs. A recent analysis of 344 clinical correlations of dr

A new radiopharmaceutical, indium-111 labeled bleomycin (IB), was evaluated as a tumor-imaging agent in 55 patients with lymphoma. Overall disease activity was correctly identified in 79% of 75 whole-body scans obtained 48 hours after intravenous administration of IB. Serial scans in 19 patients accurately reflected changes in their disease status. Lymphatic and soft tissue sites of involvement both above and below the diaphragm were most readily identified by scanning. Bone marrow and hepatic involvements were more difficult to detect because of normal tissue background in the considered organs. Five patients manifested diffuse pulmonary uptake of IB and only in one case was it explained. To determine the accuracy of scanning with IB, we evaluated 731 individual sites of potential tumor involvement with these results: true positives 90%, false negatives 10%, false positives 4%, and true negatives 96%. Thus, tumor scanning with indium-111 bleomycin is an important new technique for the initial staging and serial evaluation of patients with lymphoma.

A case is discussed in which progressive systemic sclerosis and malignant atrophic papulosis occurred in the same patient. The coincidental occurrence of the two diseases is possible but statistically improbable. Attention is drawn to the similarity of histological blood vessel changes in the two diseases. It is suggested that an immunological abnormality may be the common denominator in etiology or pathogenesis.