Rajkumar, S. Vincent

AbstractThe objective of this case-control study was to compare the efficacy and toxicity of lenalidomide plus dexamethasone (len/dex) versus thalidomide plus dexamethasone (thal/dex) as initial therapy for newly diagnosed myeloma. We retrospectively studied 411 newly diagnosed patients treated with len/dex (228) or thal/dex (183) at the Mayo Clinic. The differences were similar in a matched-pair analysis that adjusted for age, sex, transplantation status, and dexamethasone dose. The proportions of patients achieving at least a partial response to len/dex and thal/dex were 80.3% versus 61.2%, respectively (P < .001); very good partial response rates were 34.2% and 12.0%, respectively (P < .001). Patients receiving len/dex had longer time to progression (median, 27.4 vs 17.2 months; P = .019), progression-free survival (median, 26.7 vs 17.1 months; P = .036), and overall survival (median not reached vs 57.2 months; P = .018). A similar proportion of patients in the 2 groups experienced at least one grade 3 or 4 adverse event (57.5% vs 54.6%, P = .568). Main grade 3 or 4 toxicities of len/dex were hematologic, mainly neutropenia (14.6% vs 0.6%, P < .001); the most common toxicities in thal/dex were venous thromboembolism (15.3% vs 9.2%, P = .058) and peripheral neuropathy (10.4% vs 0.9%, P < .001). Len/dex appears well-tolerated and more effective than thal/dex. Randomized trials are needed to confirm these results.

AbstractImmune-related deficiencies are well-known complications of chronic lymphocytic leukemia (CLL). Although recent data indicate that almost all CLL patients are preceded by a monoclonal B-cell lymphocytosis precursor state, patterns of immune defects preceding CLL diagnosis are unclear. We identified 109 persons who developed CLL from the prospective and nationwide Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with 77 469 participants, with serially collected prediagnostic serum samples. We assayed monoclonal (M)–proteins, κ/λ free light chains (FLCs) in prediagnostic obtained up to 9.8 years before CLL diagnosis. The prevalence of an abnormal FLC ratio, M-protein, and hypogamma-globulinemia before CLL diagnosis was 38% (95% confidence interval, 29%-47%), 13% (7%-21%), and 3% (1%-8%), respectively. M-proteins and abnormal FLC ratios were detected up to 9.8 years before CLL diagnosis in a total of 48 persons (44%). Hypogammaglobulinemia was not present until 3 years before the diagnosis of CLL. Among 37 patients with information on tumor cell immunophenotype, an association between immunophenotype and involved FLC (P = .024, Fisher exact test) was observed. Among 61 persons with a normal FLC ratio and without an M-protein, 17 had elevated κ and/or λ FLC levels, indicating polyclonal B-cell activation in 17 of 109 (16%) patients. These findings support a role for chronic immune stimulation in CLL genesis.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is a common premalignant plasma cell proliferative disorder with a lifelong risk of progression to multiple myeloma. Because myeloma is an incurable malignancy, strategies to delay or prevent progression in high-risk patients are of considerable importance. (Clin Cancer Res 2009;15(18):5606–8)

Purpose Thalidomide and lenalidomide are immunomodulatory drugs (IMiDs) that produce high remission rates in the treatment of multiple myeloma. Pomalidomide is a new IMiD with high in vitro potency. We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma. Patients and Methods Pomalidomide was administered orally at a dose of 2 mg daily on days 1 through 28 of a 28-day cycle. Dexamethasone 40 mg daily was administered orally on days 1, 8, 15, and 22 of each cycle. Responses were recorded using the criteria of the International Myeloma Working Group. Results Sixty patients were enrolled. Thirty-eight patients (63%) achieved confirmed response including complete response in three patients (5%), very good partial response in 17 patients (28%), and partial response in 18 patients (30%). Responses were seen in 40% of lenalidomide-refractory patients, 37% of thalidomide-refractory patients, and 60% of bortezomib-refractory patients. Responses were seen in 74% of patients with high-risk cytogenetic or molecular markers. Toxicity consisted primarily of myelosuppression. Grade 3 or 4 hematologic toxicity consisted of anemia (5%), thrombocytopenia (3%), and neutropenia (32%). One patient (1.6%) had a thromboembolic event. The median progression-free survival time was 11.6 months and was not significantly different in patients with high-risk disease compared with patients with standard-risk disease. Conclusion The combination of pomalidomide and low-dose dexamethasone is extremely active in the treatment of relapsed multiple myeloma, including high response rates in patients refractory to other novel agents.

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).

Purpose Inconsistencies and errors resulting from nonstandard processes, together with redundancies, rework, and excess workload, lead to extended time frames for clinical trial protocol development. This results in dissatisfaction among sponsors, investigators, and staff and restricts the availability of novel treatment options for patients. Methods A team of experts from Mayo Clinic formed, including Protocol Development Unit staff and management from the three Mayo Clinic campuses (Florida, Minnesota, and Arizona), a systems and procedures analyst, a quality office analyst, and two physician members to address the identified deficiencies. The current-state process was intensively reviewed, and improvement steps were taken to accelerate the development and approval of cancer-related clinical trials. The primary goal was to decrease the time from receipt of a new protocol through submission to an approving authority, such as the National Cancer Institute or institutional review board. Results Using the Define, Measure, Analyze, Improve, Control (DMAIC) framework infused with Lean waste-reduction methodologies, areas were identified for improvement, including enhancing first-time quality and processing new studies on a first-in/first-out basis. The project was successful in improving the mean turnaround time for internally authored protocols (P < .001) from 25.00 weeks (n = 41; range, 3.43 to 94.14 weeks) to 10.15 weeks (n = 14; range, 4.00 to 22.14 weeks). The mean turnaround time for externally authored protocols was improved (P < .001) from 20.61 weeks (n = 85; range, 3.29 to 108.57 weeks) to 7.79 weeks (n = 50; range, 2.00 to 20.86 weeks). Conclusion DMAIC framework combined with Lean methodologies is an effective tool to structure the definition, planning, analysis, and implementation of significant process changes.

The past decade has witnessed a paradigm shift in the initial treatment of multiple myeloma with the introduction of novel agents such as thalidomide, lenalidomide, and bortezomib, leading to improved outcomes. High-dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. Before the advent of the novel agents, patients underwent stem cell collection prior to significant alkylating agent exposure, given its potential deleterious effect on stem cell collection. With increasing use of the novel agents in the upfront setting, several reports have emerged raising concerns about their impact on the ability to collect stem cells. An expert panel of the International Myeloma Working Group (IMWG) was convened to examine the implications of these therapies on stem collection in patients with myeloma and to develop recommendations for addressing these issues. Here we summarize the currently available data and present our perspective on the problem and potential options to overcome this problem. Specifically, we recommend early mobilization of stem cells, preferably within the first 4 cycles of initial therapy, in patients treated with novel agents and encourage participation in clinical trials evaluating novel approaches to stem cell mobilization.

Abstract Background: The repertoire of serologic tests for identifying a monoclonal gammopathy includes serum and urine protein electrophoresis (PEL), serum and urine immunofixation electrophoresis (IFE), and quantitative serum free light chain (FLC). Although there are several reports on the relative diagnostic contribution of these assays, none has looked at the tests singly and in combination for the various plasma cell proliferative disorders (PCPDs). Methods: Patients with a PCPD and all 5 assays performed within 30 days of diagnosis were included (n = 1877). The diagnoses were multiple myeloma (MM) (n = 467), smoldering multiple myeloma (SMM) (n = 191), monoclonal gammopathy of undetermined significance (MGUS) (n = 524), plasmacytoma (n = 29), extramedullary plasmacytoma (n = 10), Waldenström macroglobulinemia (WM) (n = 26), primary amyloidosis (AL) (n = 581), light chain deposition disease (LCDD) (n = 18), and POEMS syndrome (n = 31). Results: Of the 1877 patients, 26 were negative in all assays. Omitting urine from the panel lost an additional 23 patients (15 MGUS, 6 AL, 1 plasmacytoma, 1 LCDD), whereas the omission of FLC lost 30 patients (6 MM, 23 AL, and 1 LCDD). The omission of serum IFE as well as urine lost an additional 58 patients (44 MGUS, 7 POEMS, 5 AL, 1 SMM, and 1 plasmacytoma). Conclusions: The major impact of using a simplified screening panel of serum PEL plus FLC rather than PEL, IFE, and FLC is an 8% reduction in sensitivity for MGUS, 23% for POEMS (7 patients), 4% for plasmacytoma (1 patient), 1% for AL, and 0.5% for SMM. There is no diminution in sensitivity for detecting MM, macroglobulinemia, and LCDD.

Abstract Pesticides are associated with excess risk of multiple myeloma, albeit inconclusively. We included 678 men (30-94 years) from a well-characterized prospective cohort of restricted-use pesticide applicators to assess the risk of monoclonal gammopathy of undetermined significance (MGUS). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Age-adjusted prevalence estimates of MGUS were compared with MGUS prevalence in 9469 men from Minnesota. Associations between pesticide exposures and MGUS prevalence were assessed by logistic regression models adjusted for age and education level. Among study participants older than 50 years (n = 555), 38 were found to have MGUS, yielding a prevalence of 6.8% (95% CI, 5.0%-9.3%). Compared with men from Minnesota, the age-adjusted prevalence of MGUS was 1.9-fold (95% CI, 1.3- to 2.7-fold) higher among male pesticide applicators. Among applicators, a 5.6-fold (95% CI, 1.9- to 16.6-fold), 3.9-fold (95% CI, 1.5- to 10.0-fold), and 2.4-fold (95% CI, 1.1- to 5.3-fold) increased risk of MGUS prevalence was observed among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil, respectively. In summary, the prevalence of MGUS among pesticide applicators was twice that in a population-based sample of men from Minnesota, adding support to the hypothesis that specific pesticides are causatively linked to myelomagenesis.