Citations

Abstract The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).

Background— Primary amyloidosis has a poor prognosis as a result of frequent cardiac involvement. We recently reported a high prevalence of intracardiac thrombus in cardiac amyloid patients at autopsy. However, neither the prevalence nor the effect of anticoagulation on intracardiac thrombus has been evaluated antemortem. Methods and Results— We studied all transthoracic and transesophageal echocardiograms of cardiac amyloid patients at the Mayo Clinic. The prevalence of intracardiac thrombosis, clinical and transthoracic/transesophageal echocardiographic risks for intracardiac thrombosis, and effect of anticoagulation were investigated. We identified 156 patients with cardiac amyloidosis who underwent transesophageal echocardiograms. Amyloidosis was the primary type (AL) in 80; other types occurred in 76 patients, including 56 with the wild transthyretin type, 17 with the mutant transthyretin type, and 3 with the secondary type. Fifth-eight intracardiac thrombi were identified in 42 patients (27%). AL amyloid had more frequent intracardiac thrombus than the other types (35% versus 18%; P =0.02), although the AL patients were younger and had less atrial fibrillation. Multivariate analysis showed that atrial fibrillation, poor left ventricular diastolic function, and lower left atrial appendage emptying velocity were independently associated with increased risk for intracardiac thrombosis, whereas anticoagulation was associated with a significantly decreased risk (odds ratio, 0.09; 95% CI, 0.01 to 0.51; P <0.006). Conclusions— Intracardiac thrombosis occurs frequently in cardiac amyloid patients, especially in the AL type and in those with atrial fibrillation. Risk for thrombosis increased if left ventricular diastolic dysfunction and atrial mechanical dysfunction were present. Anticoagulation therapy appears protective. Timely screening in high-risk patients may allow early detection of intracardiac thrombus. Anticoagulation should be carefully considered.

Abstract Waldenström's macroglobulinemia (WM) is a distinct clinicobiological entity defined as a B-cell neoplasm characterized by a lymphoplasmacytic infiltrate in bone marrow (BM) and IgM paraprotein production. Cytogenetic analyses were historically limited by difficulty in obtaining tumor metaphases, and the genetic basis of the disease remains poorly defined. Here, we performed a comprehensive analysis in 42 WM patients by using a high-resolution, array-based comparative genomic hybridization approach to unravel the genetic mechanisms associated with WM pathogenesis. Overall, 83% of cases have chromosomal abnormalities, with a median of three abnormalities per patient. Gain of 6p was the second most common abnormality (17%), and its presence was always concomitant with 6q loss. A minimal deleted region, including MIRN15A and MIRN16-1, was delineated on 13q14 in 10% of patients. Of interest, we reported biallelic deletions and/or inactivating mutations with uniparental disomy in tumor necrosis factor (TNF) receptor–associated factor 3 and TNFα-induced protein 3, two negative regulators of the nuclear factor-κB (NF-κB) signaling pathway. Furthermore, we confirmed the association between TRAF3 inactivation and increased transcriptional activity of NF-κB target genes. Mutational activation of the NF-κB pathway, which is normally activated by ligand receptor interactions within the BM microenvironment, highlights its biological importance, and suggests a therapeutic role for inhibitors of NF-κB pathway activation in the treatment of WM. [Cancer Res 2009;69(8):3579–88]

Abstract The outcome of patients with multiple myeloma is dictated primarily by cytogenetic abnormalities and proliferative capacity of plasma cells. We studied the outcome after initial therapy with lenalidomide-dexamethasone among 100 newly diagnosed patients, risk-stratified by genetic abnormalities and plasma cell labeling index. A total of 16% had high-risk multiple myeloma, defined by the presence of hypodiploidy, del(13q) by metaphase cytogenetics, del(17p), IgH translocations [t(4;14), or t(14;16)] or plasma cell labeling index more than or equal to 3%. Response rates were 81% vs 89% in the high-risk and standard-risk groups, respectively. The median progression-free survival was shorter in the high-risk group (18.5 vs 36.5 months, P < .001), but overall survival was comparable. Because of unavailability of all tests for every patient, we separately analyzed 55 stringently classified patients, and the results were similar. In conclusion, high-risk patients achieve less durable responses with lenalidomide-dexamethasone compared with standard-risk patients; no significant differences in overall survival are apparent so far. These results need confirmation in larger, prospectively designed studies.

AbstractThe survival of patients with Waldenstrom macroglobulinemia (WM) varies enormously. The development of prognostic models in WM has been fraught by limited follow-up in current studies. Here, we update the outcome of a prospective WM trial with a median follow-up of 10 years for live patients. Of the 59 previously untreated patients who initially were observed, only 12 patients (21%) required therapy at a median follow-up of 100 months. Multivariate analysis among the 183 patients requiring therapy reaffirmed age 70 years or greater, previous nonprotocol therapy, and β-2 microglobulin (B2M) of 3 mg/dL or greater as prognostic factors. Importantly, increased serum lactate dehydrogenase (LDH) was identified as an additional independent variable, which improved risk assessment beyond the recent WM international prognostic scoring system (ISSWM). By using age, previous therapy, B2M, and LDH, we identified 3 risk groups with 8-year survival estimates of 55%, 33%, and 5% (P < .001). These data provide novel insights into factors predicting long-term outcome in WM. This trial has been registered with www.cancer.gov under ID 4852904.

Background— Patients with primary amyloidosis (AL type) have a poor prognosis, in part due to frequent cardiac involvement. Although intracardiac thrombus has been reported in anecdotal cases, neither its frequency nor its role in causing mortality is known. Furthermore, the clinical and echocardiographic variables that may be associated with thromboembolism in cardiac amyloidosis have not been defined. Methods and Results— A total of 116 autopsy or explanted cases of cardiac amyloidosis (55 AL and 61 other type) were identified in the Mayo Clinic. Forty-six fatal nonamyloid trauma cases served as controls. Each heart was examined for intracardiac thrombus. The cause of death was determined from autopsy and clinical notes. Intracardiac thrombosis was identified in 38 hearts (33%). Twenty-three had 1 thrombus, whereas 15 had 2 to 5 thrombi. Although subjects in the AL group were younger and had less atrial fibrillation than those with other types of amyloidosis, the AL group had significantly more intracardiac thrombus (51% versus 16%, P <0.001) and more fatal embolic events (26% versus 8%, P <0.03). Control hearts had no intracardiac thrombus. The presence of both atrial fibrillation and AL was associated with an extremely high risk for thromboembolism (odds ratio 55.0 [95% confidence interval 8.1 to 1131.4]). By multivariate analysis, AL type (odds ratio 8.4 [95% confidence interval 1.8 to 51.2]) and left ventricular diastolic dysfunction (odds ratio 12.2 [95% confidence interval 2.7 to 72.7]) were independently associated with thromboembolism. Conclusions— A high frequency of intracardiac thrombosis was present in cardiac amyloidosis. Furthermore, thromboembolism caused significant fatality. Several risk factors for thromboembolism were identified. Early screening, especially in high-risk patients, and early anticoagulation might reduce morbidity and mortality.

Treatments for myeloma have expanded in the last decade, but it is not clear if the introduction of novel therapies and the increased use of high-dose therapy have translated into better outcome for patients with myeloma. We examined the outcome of 2 groups of patients seen at a single institution, one from time of diagnosis and the other from the time of relapse, to examine the survival trends over time. Among 387 patients relapsing after stem-cell transplantation, a clear improvement in overall survival from the time of relapse was seen, with those relapsing after 2000 having a median overall survival of 23.9 versus 11.8 months (P < .001) for those who relapsed prior to this date. This improvement was independent of other prognostic factors. Patients treated with one or more of the newer drugs (thalidomide, lenalidomide, bortezomib) had longer survival from relapse (30.9 vs 14.8 months; P < .001). In a larger group of 2981 patients with newly diagnosed myeloma, those diagnosed in the last decade had a 50% improvement in overall survival (44.8 vs 29.9 months; P < .001). In this study, we demonstrate improved outcome of patients with myeloma in recent years, both in the relapsed setting as well as at diagnosis.

Purpose High-dose therapy with autologous stem-cell transplantation (HDT-ASCT) is now almost standard therapy for many patients with multiple myeloma, partly because of higher complete response (CR) rates. Some studies suggest that tandem transplantation gives superior results. The aim of this study was to determine whether the depth of the response to HDT-ASCT leads to an improvement in time to progression (TTP) and overall survival (OS). We hypothesized that patients with CR before HDT-ASCT (BCR) will have their disease burden reduced further and experience a longer TTP and perhaps OS. Patients and Methods All patients who achieved BCR or CR after HDT-ASCT (ACR) were identified. The characteristics and long-term outcome of these patients were evaluated. Results We identified 14 patients with BCR and 103 patients with ACR who were treated in similar fashion. The patients have been followed for more than 6 years, and the median for OS has not been reached (60-month survival, 55% for BCR and 63% for ACR; P = .83). The median TTP was 43 months for BCR and 34 months for ACR (P = .39). Conclusion The depth of the response in myeloma does not necessarily lead to an improvement in TTP and OS. Tumor dynamics considerations show that the yield from sequential cycles of chemotherapy decreases. Patients who achieve CR with the first transplant can be safely observed without jeopardizing OS.

Abstract Purpose: 2-Methoxyestradiol (2ME2) is an endogenous product of estradiol metabolism with antiangiogenic and antineoplastic properties. We report on the first phase II trial of 2ME2 in multiple myeloma. Experimental Design: 2ME2 was administered orally at a dose of 1,000 mg daily. Sixty patients (31 men and 29 women) were treated. After 39 patients were accrued, the dose was increased to 800 mg twice daily for the remaining patients. Results: Thirty-one patients had relapsed or refractory multiple myeloma, and 29 had plateau phase multiple myeloma. Median age was 60 years (range, 27-84 years). Therapy was well tolerated. Common adverse events included anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flushes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most adverse events were mild (grade 1-2); 12% experienced grade 3-4 adverse events. Median time to progression was 3.8 months, with 5.6 months for plateau phase disease and 2.3 months for relapsed multiple myeloma. Estimated progression-free survival rates for all patients at 1, 2, and 3 years were 24%, 17%, and 11%, respectively. Three patients, all with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months, respectively. Minor response was noted in 2 patients. Conclusions: Although no partial responses have been seen thus far, the minor responses and prolonged stable disease seen with 2ME2 therapy are promising. Plasma levels indicate that the dose of 2ME2 was inadequate. A new formulation with better bioavailability will be tested soon in multiple myeloma.