Ramón García-Sanz

Bisphosphonate‐related osteonecrosis: genetic and acquired risk factors

The objectives of this study were to review epidemiological, clinical and biological aspects associated with the development of bisphosphonate-related osteonecrosis of the jaw (BRONJ) in multiple myeloma (MM) patients, with special emphasis on the genetic aspects. A detailed review of previously described risk factors as well as recent genetic findings mostly comprises this work. The most recent meeting abstracts and relevant articles published in journals covered by the Science Citation Index and Medline are also examined. The review pays special attention to the genetic component of BRONJ. A total of 15 series and 14 guidelines or revisions were selected to fit the aims of the review. Gene variability was reviewed in depth to give a clinical illustration on the genetic aspects of BRONJ. Crude prevalence and 5-year cumulative incidence were considered as the most important end points for predictive purposes. Several acquired factors were recognized as predictors for BRONJ in MM, especially intravenous bisphosphonates, dental trauma and advanced age. Among genetic factors, polymorphisms on CYP2C8 gene arise as a promising risk factor. Bisphosphonate-related osteonecrosis of the jaw can be predicted with a conjunction of genetic and environmental risk factors.

Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients.

Although multiple myeloma (MM) is predominantly a disease of the elderly, few studies have focused on the identification of prognostic factors in this group of patients. Four hundred twenty five MM patients >65 years were uniformly treated with chemotherapy (MP or VCMP/VBAD). Multivariate analysis identified 4 factors with independent unfavorable prognostic influence: high percentage of S‐phase bone marrow plasma cells (>2.5%); elevated β2 microglobulin (B2M) (>4 mg/L); age >80 years old; and LDH serum levels (above normal limit). The S‐phase value was the most powerful independent prognostic factor to discriminate subgroups of patients with different prognosis. Thus, 3 main risk categories could be identified according to S‐phase values: ≤1%, 1–3% and >3%, with median survivals of 34, 22 and 12 months, respectively (p < 0.0001). Our study also proved the value for elderly patients of the recently developed International Score System (ISS) based on B2M and albumin. Furthermore, the number of S‐phase cells helped to subdivide the ISS III Group identifying a subset of patients with very poor prognosis defined by an additional high S‐phase, who displayed a median survival of only 8 months. These results demonstrate that elderly patients can be accurately classified according to prognosis, which may be particularly valuable when comparing the efficacy of new treatment strategies. Moreover, our results underline the high prognostic value of proliferative activity of PC, a parameter that should be considered in routine laboratory investigations of MM.

Pretreatment characteristics and clinical outcome of acute promyelocytic leukaemia patients according to the PML‐RARα isoforms: a study of the PETHEMA group

Of 167 newly diagnosed acute promyelocytic leukaemia patients, 83 patients were long (L)‐form (50%), eight variable (V)‐form (5%) and 76 short (S)‐form (45%). The V‐form and S‐form groups presented a significantly higher percentage of patients with white blood cell counts > 10 × 109/l (P < 0·05). The S‐form cases displayed a significantly higher number of cases with M3v microgranular features (P = 0·005) and CD34 expression (P < 0·0001). There were no differences between the three isoforms in complete remission (CR) rate (overall CR 90%), but the 3‐year disease‐free survival was lower for V‐form cases than it was for L‐ and S‐form cases (62% vs. 94% and 89%, P = 0·056). We conclude that the V‐form and S‐form types are associated with some negative prognostic features at diagnosis. However, our data were only able to demonstrate an association with adverse prognosis in the V‐form type and, moreover, as the number of cases was limited, needs to be confirmed in large, uniformly treated series.

Multiple myeloma: differential diagnosis and prognosis

Multiple myeloma is the second most common hematological malignancy. It is defined by the presence of monoclonal plasma cells capable to produce a monoclonal paraprotein causing clinical abnormalities such as anemia, renal insufficiency, hypercalcemia, or bone lesions. New chromosomal or molecular abnormalities have been identified allowing a better management. Multiple myeloma is treatable and, although it remains incurable, the patient prognosis and quality of life has notably improved, so it is not rare to see series with a median survival longer than 5 years. Even more, it is possible by now to expect improvements respect to the standard autologous stem cell transplantation. This must be attributed to the emergence of a number of new therapies entering clinical practice over the last 6 years: thalidomide (Thalidomid Pharmion, Boulder, CO, USA), lenalidomide (Revlimid, Celgene Corporation, Summit, NJ, USA) and bortezomib (Velcade, Janssen Pharmaceutica N.V., Belgium). Finally, we also will review the current clinical experience in supportive therapy, which has also contributed to the patient outcome improvement with approaches such as: new indications for dialysis, use of erythropoietin receptor stimulating agents and bisphosphonates, and new surgical therapies such as vertebroplastia and kyphoplastia.

The presence of DRB1*01 allele in multiple myeloma patients is associated with an indolent disease

The human leukocyte antigen (HLA) system could play an essential role in multiple myeloma (MM) disease control. This report describes the results comparing HLA-DRB1 phenotypic frequencies in 181 MM patients (53 smoldering/indolent MM and 128 symptomatic MM patients) and healthy individuals. Higher DRB1*01 phenotypic frequencies were found in the smoldering patients compared with symptomatic MM patients (38% vs 14%, P = 0.001) and with the healthy individuals (38% vs 22%, P = 0.01). Additionally, higher DRB1*07 phenotypic frequencies were found in symptomatic MM compared with control population (38% vs 28%, P = 0.01). The present data suggest that HLA-DRB1*01 individuals may have a better ability to efficiently present myeloma-related antigens to immunocompetent cells, which could favor a better immune response against the tumor. This would translate into a more appropriate disease control associated with more indolent disease and prolonged survival.

Prognosis and Staging of Multiple Myeloma

Multiple myeloma (MM) is still considered an incurable disease and has a median survival ranging between 3 and 6 years. Nevertheless, the response rate and outcome are highly variable among MM patients, with some surviving for more than 10 years and others living for only a few months [1, 2]. In the main, this heterogeneity relates to specific characteristics of the tumor itself and of the host. The identification of those characteristics associated with either a good or a poor prognosis is most important not only for doctors but also for patients, in order to obtain more individualized information about disease outcome, instead of simply offering a general median survival rate.

Waldenström’s Macroglobulinemia Immunophenotype

Multiparametric Flow Cytometry (MFC) for Immunophenotyping is a very useful tool for diagnosis of Waldenstrom’s macroglobulinemia (WM). It can be used for the distinction between different entities that can be responsible for an IgM monoclonal component, including IgM monoclonal gammopathy undetermined significance (MGUS), asymptomatic WM, and symptomatic WM, as well as other close B-cell lymphoproliferative disorders, such as chronic lymphocytic leukemia, marginal zone lymphoma and IgM multiple myeloma. The identification and quantification of a clonal cell population with a typical WM phenotype is almost diagnostic of this disorder. Clonal WM lymphocytes are characterized by the constant expression of pan-B markers (CD19, CD20, CD22, CD24) and surface immunoglobulin, and are usually positive for FMC7, CD25, CD27, CD45RA, and BCL-2. Moreover, these lymphocytes are almost always negative for CD103, CD11c, CD10 antigens, and frequently negative for CD5 and CD23. Plasma cells present in WM are characterized by an immunophenotype indistinguishable from normal plasma cells, although they belong to the tumor clone. Immunophenotyping also helps to evaluate the response of the disease to the therapy, and it is probably a better monitoring parameter that the M-component, the usual way to evaluate the disorder outcome. In this work, all these concepts are reviewed in detail to help in the comprehension of the use of MFC in WM.