Rajkumar, S Vincent

Abstract Hyperdiploid multiple myeloma (H-MM) is the most common form of myeloma. In this gene expression profiling study, we show that H-MM is defined by a protein biosynthesis signature that is primarily driven by a gene dosage mechanism as a result of trisomic chromosomes. Within H-MM, four independently validated patient clusters overexpressing nonoverlapping sets of genes that form cognate pathways/networks that have potential biological importance in multiple myeloma were identified. One prominent cluster, cluster 1, is characterized by high expression of cancer testis antigen and proliferation-associated genes. Tumors from these patients were more proliferative than tumors in other clusters (median plasma cell labeling index, 3.8; P < 0.05). Another cluster, cluster 3, is characterized by genes involved in tumor necrosis factor/nuclear factor-κB signaling and antiapoptosis. These patients have better response to bortezomib as compared with patients within other clusters (70% versus 29%; P = 0.02). Furthermore, for a group of patients generally thought to have better prognosis, a cluster of patients with short survival (cluster 1; median survival, 27 months) could be identified. This analysis illustrates the heterogeneity within H-MM and the importance of defining specific cytogenetic prognostic factors. Furthermore, the signatures that defined these clusters may provide a basis for tailoring treatment to individual patients. [Cancer Res 2007;67(7):2982–9]

AbstractPrimary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, is highly active in patients with multiple myeloma. We studied the toxicity and efficacy of lenalidomide in patients with AL. Patients with symptomatic AL, a measurable plasma cell disorder, and adequate hematologic and renal reserve were eligible. Patients received single-agent lenalidomide. If there was no evidence of progression after 3 months or of hematologic response after 3 cycles, dexamethasone was added. Twenty-three patients were enrolled. Thirteen were previously treated. Organ involvement was cardiac (64%), renal (73%), hepatic (23%), and nerve (14%). Within the first 3 cycles of therapy, 10 patients discontinued treatment: 4 early deaths, 3 adverse events, and 3 other causes. With a median follow-up of 17 months, 10 patients responded to treatment. In these patients, responses included 9 hematologic, 4 renal, 2 cardiac, and 2 hepatic. All but one of the responders had dexamethasone added to their treatment program. The most common grade 3 or 4 adverse events at least possibly attributable to lenalidomide were neutropenia (45%), thrombocytopenia (27%), rash (18%), and fatigue (18%). In AL patients, we saw limited activity of single-agent lenalidomide, but significant activity of the combination with dexamethasone, which warrants further investigation.

Abstract This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

Abstract An abnormal serum immunoglobulin free light chain (FLC) ratio at diagnosis may identify risk of progression to myeloma in patients with solitary bone plasmacytoma (SBP). In the cohort of 116 patients, 43 have progressed to myeloma, with a median time to progression of 1.8 years. The FLC ratio was determined in all 116 patients on serum collected at time of diagnosis and was abnormal in 54 patients (47%). An abnormal FLC ratio was associated with a higher risk of progression to myeloma (P = .039). The risk of progression at 5 years was 44% in patients with an abnormal serum FLC ratio at diagnosis compared with 26% in those with a normal FLC ratio. One to 2 years following diagnosis, a persistent serum M protein level of 5 g/L (0.5 g/dL) or higher was an additional risk factor for progression. A risk stratification model was constructed using the 2 variables of FLC ratio and M protein level: patients with a normal FLC ratio at baseline and M protein level less than 5 g/L (0.5 g/dL) at 1 to 2 years following diagnosis (low risk, n = 31); with either risk factor abnormal (intermediate risk, n = 26); and with both an abnormal FLC ratio and M protein level of 5 g/L (0.5 g/dL) or higher (high risk, n = 18). The corresponding progression rates at 5 years were significantly different in the low, intermediate, and high groups: 13%, 26%, and 62%, respectively (P < .001).

Abstract To assess fractures in monoclonal gammopathy of undetermined significance (MGUS), the precursor of multiple myeloma, we followed 488 Olmsted County, MN, residents with MGUS in a retrospective cohort study. There was a 2.7-fold increase in the risk of axial fractures but no increase in limb fractures. The pathophysiologic basis for the increased axial fractures should be determined. Introduction: Multiple myeloma is often preceded by monoclonal gammopathy of undetermined significance (MGUS). Fractures are common in myeloma as a result of lytic bone lesions, generalized bone loss, and elevated bone turnover from excessive cytokine production. Whether fractures are also increased in MGUS is unknown. Materials and Methods: In a population-based retrospective cohort study, 488 Olmsted County, MN, residents with MGUS first diagnosed in 1960–1994 (52% men; mean age, 71.4 ± 12.8 years) were followed for 3901 person-years; follow-up was censored at progression to myeloma. The relative risk of fractures was assessed by standardized incidence ratios (SIRs), and risk factors were evaluated in proportional hazards models. Results and Conclusions: Altogether, 200 patients experienced 385 fractures. Compared with expected rates in the community, statistically significant increases were seen for fractures at most axial sites, for example, vertebrae (SIR, 6.3; 95% CI, 5.2–7.5). There was a slight increase in hip (SIR, 1.6; 95% CI, 1.2–2.2) but not distal forearm fractures (SIR, 0.8; 95% CI, 0.4–1.5). The relative risk (SIR) of any axial fracture was 2.7 (95% CI, 2.3–3.1) compared with only 1.1 (95% CI, 0.9–1.4) for all limb fractures combined. In a multivariate analysis, the independent predictors of any subsequent fracture were age (hazard ratio [HR] per 10-year increase, 1.4; 95% CI, 1.2–1.6) and corticosteroid use (HR, 1.8; 95% CI, 1.2–2.6); greater weight at diagnosis (HR per 10 kg, 0.8; 95% CI, 0.8–0.9), and IgG monoclonal protein (HR, 0.7; 95% CI, 0.5–0.97) were protective. Baseline monoclonal protein level, a determinant of myeloma progression, did not predict fracture risk. Thus, the risk of axial, but not peripheral, fractures is increased among MGUS patients even before progression to myeloma. The pathophysiologic basis for this should be determined because elevated bone turnover, for example, might be treatable.

Abstract Pathologic fractures, especially of the axial skeleton, are extremely common in patients with multiple myeloma and cluster around the time of diagnosis. Osteoporotic fractures seem to be less of a problem in these patients. Introduction: It is generally believed that fractures are common in patients with multiple myeloma as a result of lytic bone lesions, generalized bone loss, and/or elevated bone turnover from excessive cytokine production, but the actual risk of pathologic versus osteoporotic fractures has not been quantified. Materials and Methods: In a population-based retrospective cohort study, 165 Olmsted County, MN, residents with myeloma diagnosed from 1945 to 2001 (55% men; mean age, 70.7 ± 11.1 years) were followed for 537 person-years. The relative risk of fractures was assessed by standardized incidence ratios (SIRs), and risk factors were evaluated in proportional hazards models. Results: Altogether, 134 patients experienced 463 fractures. In the year before diagnosis, 16 times more fractures were observed than expected, mostly pathologic fractures of the vertebrae and ribs. Subsequently, there was a 9-fold increase in fracture risk. However, 69% of these fractures were pathologic, and another 11% were found incidentally on myeloma monitoring. With the latter two groups excluded, subsequent fracture risk was elevated 3-fold, with a 2-fold increase in the risk of an osteoporotic fracture. In multivariate analyses, the predictors of overall fracture risk were oral corticosteroid use and elevated serum calcium levels, whereas pathologic fractures were additionally predicted by use of chemotherapy. Conclusion: There is a dramatic increase in fractures around the time of diagnosis of myeloma, most of which are pathologic fractures. The most important predictor of overall fracture risk is oral corticosteroid use.

AbstractThe immunoglobulin free light chain (FLC) is the precursor protein of amyloid in primary systemic amyloidosis (AL). Historically, the ability to monitor the amyloid protein precursor protein has been crude. We evaluated the utility of the FLC assay in a retrospective analysis of patients with AL undergoing peripheral blood stem cell transplantation (PBSCT). Ninety-three such patients had serial FLC measurements performed. The prognostic effects of the initial concentration and the extent of reduction of monoclonal FLC on survival were studied. There was a significantly higher risk of death in patients with higher baseline FLC (hazard ratio 2.6, P < .04). Baseline FLC correlated with serum cardiac troponin levels, and higher FLC levels were associated with more organs involved by amyloid, suggesting that high FLC levels may be associated with more advanced disease. The percent FLC reduction did not predict for survival, but the absolute level of FLC achieved after therapy did. Normalization of FLC level after PBSCT predicted for both organ response and complete hematologic response. Achievement of FLC response was a better predictor of survival than achievement of complete hematologic response or normalization of the FLC ratio. FLC measurements both before and after PBSCT are important predictors of patient outcome.

The mechanisms underlying aneuploidy in multiple myeloma (MM) are unclear. Centrosome amplification has been implicated as the cause of chromosomal instability in a variety of tumors and is a potential mechanism causing aneuploidy in MM. Using immunofluorescent (IF) staining, centrosome amplification was detected in 67% of monoclonal gammopathies, including monoclonal gammopathy of undetermined significance (MGUS). We also investigated the gene expression of centrosome proteins. Overall, gene expression data correlated well with IF-detected centrosome amplification, allowing us to derive a gene expression-based centrosome index (CI) as a surrogate for centrosome amplification. Clinically, MM patients with high CI (> 4) are associated with poor prognostic genetic and clinical subtypes (chromosome 13 deletion, t(4; 14), t(14;16), and PCLI > 1%, P < .05) and are shown here to have short survival (11.1 months versus 39.1 months, P < .001). On multivariate regression, a high CI is an independent prognostic factor. Given that centrosome amplification is already observed in MGUS and probably integral to early chromosomal instability and myeloma genesis, and patients with more extensive centrosome amplification have shorter survival, the mechanisms leading to centrosome amplification should be investigated because these may offer new avenues for therapeutic intervention.

Purpose To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma. Patients and Methods Patients were randomly assigned to receive thalidomide plus dexamethasone or dexamethasone alone. Patients in arm A received thalidomide 200 mg orally for 4 weeks; dexamethasone was administered at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20. Cycles were repeated every 4 weeks. Patients in arm B received dexamethasone alone at the same schedule as in arm A. Results Two hundred seven patients were enrolled: 103 were randomly assigned to thalidomide plus dexamethasone and 104 were randomly assigned to dexamethasone alone; eight patients were ineligible. The response rate with thalidomide plus dexamethasone was significantly higher than with dexamethasone alone (63% v 41%, respectively; P = .0017). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively). Conclusion Thalidomide plus dexamethasone demonstrates significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone. However, this must be balanced against the greater toxicity seen with the combination.

AbstractDetection of circulating myeloma cells (CMCs) by flow cytometry in patients with multiple myeloma (MM) indicates active disease. We hypothesized that detection of CMCs at the time of stem-cell collection prior to autologous stem-cell transplantation (ASCT) identifies patients at high risk of rapid progression. A cohort of patients undergoing ASCT was identified. CMCs were determined by gating on CD38+/CD45- cells using flow cytometry. The impact of CMCs on overall survival (OS) and time to progression (TTP) was evaluated in univariate and multivariate analyses. Of 246 patients undergoing ASCT, 95 had CMCs. Complete response (CR) rates after transplantation were 32% and 36% for patients with and without CMCs, respectively (P = .50). OSs were 33.2 and 58.6 months (P = .01) whereas TTPs were 14.1 and 22 months, respectively (P = .001). On multivariate analysis, CMCs remained independent of cytogenetics and disease status at time of transplantation (P = .03). CMCs and cytogenetics were combined in a new scoring system. Patients with neither, one, or both parameters had a median OS of 55, 48, and 21.5 months and a median TTP of 22, 15.4, and 6.5 months, respectively. CMCs at the time of ASCT is an independent prognostic factor and in combination with cytogenetics provides a powerful scoring system that stratifies patients and guides management.