Chromosome 13 deletion/hypodiploidy and prognosis in multiple myeloma patients.

The application of high-dose treatment with autologous stem cell transplant(s) has improved survival, when compared to standard treatment, in patients with multiple myeloma. However, this benefit is mostly enjoyed by specific patient subgroups characterized by the absence of high-risk disease features. High-risk features are, first and foremost, the detection of unfavorable cytogenetic abnormalities (chromosome 13 deletion, hypodiploidy and myelodysplastic-type abnormalities in an otherwise typical myeloma karyotype) prior to treatment; elevated serum lactate dehydrogenase and C-reactive protein levels at diagnosis and high beta-2 microglobulin levels prior to transplant also convey poor prognosis, although they account for less variability of the observed outcome than the cytogenetic abnormalities. While high-dose treatment with autologous stem cell transplant(s) can cure a sizable minority of patients with low-risk disease features and significantly prolongs survival in others with similar characteristics, patients with high-risk features are virtually incurable and their survival benefit is much less pronounced. As the tremendous clinical variability of myeloma can now be traced to its underlying genetic abnormalities, routine cytogenetic analysis at diagnosis and relapse are absolutely indicated. Based on this stratification, high-risk patients are excellent candidates for novel therapeutic approaches, such as planned non-myeloablative allogeneic transplants following an autologous transplant.

Multiple myeloma invasion of the central nervous system.

BACKGROUND: Although neurologic manifestations often complicate the course of patients with multiple myeloma (MM), direct central nervous system invasion is rare. OBJECTIVE: To describe the neurologic symptoms and signs, imaging, cerebrospinal fluid findings, and the clinical course of patients with central nervous system myeloma invasion, all of whom had leptomeningeal myelomatosis. DESIGN AND PARTICIPANTS: Review of 23 patients with MM and leptomeningeal myelomatosis proven by malignant plasma cells in their cerebrospinal fluid. SETTING: Tertiary-care university medical center. RESULTS: Twenty-one patients had advanced-stage MM. Leptomeningeal myelomatosis was diagnosed up to 29 months (median, 13 months) after diagnosis of MM. Symptoms precipitating neurologic evaluation included manifestations of diffuse cerebral dysfunction, cranial nerve palsies, and spinal radiculopathies. Cerebrospinal fluid was abnormal in all patients, usually exhibiting pleocytosis and elevated protein content, plus positive cytologic findings. Specific magnetic resonance imaging findings suggestive of central nervous system invasion were found in 70% of the patients. These included leptomeningeal contrast enhancement and evidence of meningeal-based lesions sometimes masquerading as intraparenchymal lesions. Despite aggressive systemic and local treatment, the outcome was poor, reflecting the aggressiveness of the underlying MM. CONCLUSION: Leptomeningeal myelomatosis, although rare, should be considered in patients with MM and symptoms suggestive of widespread nervous system involvement.

Myeloma of the central nervous system: strong association with unfavorable chromosomal abnormalities and other high-risk disease features.

Involvement of the central nervous system (CNS) by multiple myeloma, defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We present the characteristics of 25 such patients (18 previously reported) intended to receive high-dose treatment at the University of Arkansas over the last 12 years; an extensive review of the published literature since 1968, including 71 patients, is also presented. In both patient groups, high tumor burden was overwhelmingly present while circulating plasma cells were detected in a significant proportion of cases. We also observed a strong association of CNS involvement with unfavorable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), plasmablastic morphology and additional extramedullary myeloma manifestations. The presence of these features should alert clinicians to the possibility of CNS involvement. The prognosis of such patients is poor despite aggressive systemic and local treatment and reflects the underlying disease biology. Application of allogeneic transplantation and administration of prophylactic CNS treatment are also discussed. Further elucidation of the factors predisposing patients with high-risk disease features to CNS myeloma involvement is needed.

Multiple myeloma: clinical review and diagnostic imaging.

Multiple myeloma (MM) is a malignant clonal neoplasm of plasma cells of B-lymphocyte origin that commonly results in overproduction of large amounts of monoclonal immunoglobulins. Important advances in the therapeutic management of this disease in the past decade have resulted in higher rates of durable complete remission, prolonged event-free survival, and improved overall survival. Clearer understanding of the effects of abnormal plasma cells on bone has led to therapeutic approaches that help prevent vertebral body fractures. Current imaging technologies and, in particular, survey marrow studies with magnetic resonance (MR) imaging have improved detection of the extent and location of disease in MM patients. In newly diagnosed cases, MR surveys of the axial skeleton accurately demonstrate the extent of disease-diffuse or focal involvement-and the presence of associated compression fractures and cord compression. After treatment, MR images show the effects of treatment and the presence of residual disease. Multiple sites of focal bone lesions detected on MR studies allow a more appropriate choice of biopsy site than the usual random iliac marrow biopsy. Use of MR to determine biopsy sites and computed tomographic guidance for biopsy performance have increased the safety and accuracy of sampling. These biopsies have resulted in increased identification of cytogenetic abnormalities, particularly the presence of chromosome 13 deletion, which is a grave prognostic indicator in MM.

Survival after relapse following tandem autotransplants in multiple myeloma patients: the University of Arkansas total therapy I experience.

Despite the superiority of high-dose (compared with standard) treatment in multiple myeloma, relapses still occur. We evaluated relapse patterns, salvage treatments employed and outcome in patients given tandem transplants on our total therapy I protocol. We focused on 146 patients (of 231 enrolled) who received tandem autotransplants < or =12 months apart and survived > or =2 months after the second transplant. With a median follow-up of 9 years after enrollment, 31 (21%) patients remain in complete or stable partial remission. Ninety-five (65%) patients received therapy for relapsing myeloma. The median time from the first transplant to relapse was 2.9 years. The median overall survival from relapse was 2.4 years. In one-quarter (23/95) of cases, the postrelapse interval exceeded the interval from the first transplant to relapse. On multivariate analysis, the presence of any cytogenetic abnormalities [P<0.001, Hazard Ratio (HR): 3.84] and beta-2 microglobulin levels >4 mg/l at relapse (P<0.001, HR: 2.87) were significant for poor survival after relapse. The median survival after relapse was 5.1, 1.3 and 0.7 years in patients with none (44%), one (46%) and two (10%) poor-risk factors, respectively. In conclusion, a sizeable fraction of myeloma patients relapsing after tandem autotransplants without poor-risk features enjoyed meaningful survival prolongation when appropriately treated.

Predicting long-term survival in multiple myeloma patients following autotransplants.

Multiple myeloma is a B-cell malignancy with a highly variable outcome. Despite the marked recent improvements in its management, especially due to the widespread application of high-dose treatment and autologous stem cell transplantation, relapses eventually occur in the majority of patients. Systematic research at University of Arkansas over the last 10 years, has revealed that the absence of unfavorable cytogenetic abnormalities (deletion of chromosome 13 and hypodiploidy), low beta-2 microglobulin levels prior to transplant, a normal lactate dehydrogenase level at diagnosis and early application of high-dose treatment (< 12 months of preceding standard treatment) define a subgroup of myeloma patients with a high likelihood of long (> 5 years) event-free survival; a sizable minority of these patients may be considered cured. Recognition of the importance of these prognostic factors should lead to routine cytogenetic evaluation of all patients and early referral to specialized transplant centers. Furthermore, patients with less favorable outcome should be identified early in their disease course and should be managed with novel and hopefully more effective treatments.

Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients.

High-dose treatment (HDT) with autologous stem cell transplant (ASCT) is superior to conventional chemotherapy in multiple myeloma. However, relapses eventually occur, especially in the presence of unfavourable cytogenetic abnormalities, high beta-2 microglobulin levels prior to transplant and extensive prior treatment. Cytotoxic consolidation chemotherapy, following tandem transplants (TT), was given to 75 myeloma patients with at least one poor prognostic factor. When their outcome was compared with that of 75 matched controls who received dexamethasone +/- interferon post TT, no event-free or overall survival advantage was observed. Other approaches may be required to improve survival in multiple myeloma.

Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma.

Complete or partial deletion of chromosome 13 or translocations involving 13q (delta13) by conventional cytogenetic analysis confers a poor prognosis in multiple myeloma (MM) patients, even with timely application of tandem autologous transplants. It was recently suggested that the prognostic significance of delta13 is related to its frequent association with hypodiploidy but by itself does not have a poor prognostic significance. We therefore analysed our experience in 1475 consecutive MM patients in whom we intended treatment with tandem transplants after a melphalan-based conditioning regimen. Patients with abnormal cytogenetic analysis were grouped into hypodiploid/hypotetraploid, pseudodiploid and hyperdiploid groups, according to their modal chromosome number. Their event-free and overall survival were compared with those of patients with a normalkaryotype. Both hypodiploidy and delta13 were found to independently confer poor prognosis in MM patients. Furthermore, these parameters in combination with easily obtained pretransplant levels of beta-2 microglobulin and albumin define three groups of MM patients with clearly distinct outcomes.

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.