Chromosome abnormalities clustering and its implications for pathogenesis and prognosis in myeloma.

The nonrandom recurrent nature of chromosome abnormalities in myeloma suggests a role for them in disease pathogenesis. We performed a careful cytogenetic analysis of patients with abnormal karyotypes (n = 254), to discern patterns of association, search for novel abnormalities and elucidate clinical implications. Patients with karyotypic abnormalities suggestive of myelodysplasia/acute leukemia were excluded. In this study we compared survival by abnormality only between patients with abnormal karyotypes. Patients with abnormalities were more likely to have features of aggressive disease as compared to all other patients without abnormalities entered into the myeloma database (lower hemoglobin, higher beta(2)-microglobulin, labeling-index and plasmocytosis; all P < 0.0001). Several groups of patients could be readily identified; hypodiploid (22%), pseudodiploid (36%), hyperdiploid (31%) and near-tetraploid (11%). Clustering associations were seen among several trisomies and monosomy of chromosome 13 and 14. Several monosomies (-2, -3, -13, -14 and -19), 1p translocations/ deletions, and hypodiploidy were associated with a significantly shorter survival. Trisomy of chromosome 13 was rare ( <2%). Even among patients with abnormal karyotypes, specific chromosome abnormalities can impart biologic variability in myeloma, including several monosomies, hypodiploidy and abnormalities of 1p.     

Prognostic value of circulating plasma cells in monoclonal gammopathy of undetermined significance.

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) progresses to multiple myeloma or another related plasma cell disorder (PCD) at a rate of approximately 1% per year. Identification of patients with MGUS at high risk of progression will allow development of preventive strategies. We studied the prognostic value of circulating plasma cells (PCs) in patients with MGUS to predict progression. PATIENTS AND METHODS: Patients were eligible for this retrospective analysis if they were seen at the Mayo Clinic between 1984 and 1997, were diagnosed with MGUS, and had an analysis of the peripheral blood for circulating PCs by the slide-based immunofluorescence method. Patients were observed for progression to another PCD. RESULTS: Three hundred twenty-five patients were eligible and 63 (19%) had circulating PCs. Patients with circulating PCs were twice as likely (hazard ratio, 2.1) to experience progression to another PCD (most commonly myeloma), compared with those without circulating PCs (95% CI, 1.1 to 4.3; P = .03). In patients with circulating PCs, the median progression-free survival was 138 months compared with a median not yet reached for those without circulating PCs (P = .028). The median overall survival also was shorter for those with circulating PCs. Other factors with prognostic value were high levels of M protein and non-immunoglobulin G heavy-chain type. CONCLUSION: The presence of circulating PCs, especially when combined with other known prognostic factors such as M protein concentration and immunoglobulin isotype, identify a group of individuals with MGUS at higher risk of progression to overt multiple myeloma.     

Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy.

PURPOSE: To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy. PATIENTS AND METHODS: This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly. RESULTS: The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, -3.8 to +5.3) compared with 2.8 g/dL (range, -2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a > or = 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with -2.1 for the nonresponders (P = .006). CONCLUSION: Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.     

Long‐term analysis of phase II studies of single‐agent lenalidomide in relapsed/refractory mantle cell lymphoma

Mantle cell lymphoma (MCL) is a type of non‐Hodgkin lymphoma (NHL) with aggressive disease characteristics resulting in multiple relapses after initial treatment. Lenalidomide is an immunomodulatory agent approved in the US for patients with relapsed/refractory MCL following bortezomib based on results from 3 multicenter phase II studies (2 including relapsed/refractory aggressive NHL and 1 focusing on MCL post‐bortezomib). The purpose of this report is to provide longer follow‐up on the MCL‐001 study (follow‐ups were 6.8 [NHL‐002], 7.6 [NHL‐003], and 52.2 [MCL‐001] months). The 206 relapsed MCL patients treated with single‐agent lenalidomide (25 mg/day PO, days 1 to 21 every 28‐days) had a median age of 67 years (63% ≥65 years), 91% with stage III/IV disease, and 50% with ≥4 previous treatment regimens. With a median follow‐up of X, the combined best overall response rate (ORR) was 33% (including 11% with complete remission [CR]/CR unconfirmed CRu). Lenalidomide produced rapid and durable responses with a median time to response of 2.2 months and median duration of response (DOR) of 16.6 months (95% CI: 11.1%‐29.8%). The safety profile was consistent and manageable; myelosuppression was the most common adverse event (AE). Overall, single‐agent lenalidomide showed consistent efficacy and safety in multiple phase II studies of heavily pretreated patients with relapsed/refractory MCL, including those previously treated with bortezomib.     

Outcomes and treatments of patients with immunoglobulin light chain amyloidosis who progress or relapse postautologous stem cell transplant

Immunoglobulin light chain (AL) Amyloidosis is a condition whereby misfolded proteins generated by plasma cells deposit in tissues causing organ dysfunction. Chemotherapy and autologous stem cell transplant when eligible are standard treatment options. Several studies report long‐term outcomes of patients post‐transplant. However, there is a paucity of literature describing outcomes of relapsed patients post‐transplant. We performed a retrospective study to assess outcomes and therapies employed upon relapse after transplant. Between 1996 and 2009, 410 patients received transplant at the Mayo Clinic as first‐line therapy. Of those patients, 42 (10%) died within 3 months of transplant, 64 (16%) died without documented relapse, 158 (38%) were alive without documented progression, and 146 (36%) had documented progression. Those 146 patients are the subject of our study, and their median time to hematologic relapse/progression was 23.6 months (95%CI 18.3, 26.3 months). Their median overall survival and 5‐yrs overall survival from post‐transplant relapse/progression was 51.7 months (95%CI 34.1–62.3) and 39%, respectively. The most common first regimen for treatment after relapse was lenalidomide or thalidomide. In conclusion, our study indicates that patients with AL amyloidosis fare well post‐transplant relapse/progression. Additionally, it provides a yardstick to design clinical trials to determine best treatment options.     

Targeting NF-kappaB in Waldenstrom macroglobulinemia

The nuclear factor-B (NF-B) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-B pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-B activity. We demonstrated that perifosine and bortezomib both targeted NF-B through its recruitment to the promoter of its target gene IB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-B pathway.      

Proteomic analysis of mantle-cell lymphoma by protein microarray

Mantle-cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma (NHL) that behaves aggressively and remains incurable. In order to understand the pathogenesis of MCL and design new therapies, it is important to accurately analyze molecular changes in pathways dysregulated in MCL. We used antibody microarrays to compare patterns of protein expression between CD19(+) purified B lymphocytes from normal tonsil and 7 cases of histologically confirmed MCL. Protein overexpression was defined as a higher than 1.3-fold or 2-fold increase in at least 67% of tumor samples compared with normal B-cell control. Of the polypeptides, 77 were overexpressed using the higher than 1.3-fold cutoff, and 13 were overexpressed using the 2-fold cutoff. These included cell cycle regulators (regulator of chromosome condensation 1 [RCC1], murine double minute 2 [MDM2]), a kinase (citron Rho-interacting kinase [CRIK]), chaperone proteins (heat shock 90-kDa protein [Hsp90], Hsp10), and phosphatase regulators (A-kinase anchor protein 1 [AKAP149], protein phosphatase 5 [PP5], and inhibitor 2). The elevated expression of some of these polypeptides was confirmed by immunoblotting and immunohistochemistry, whereas elevated expression of others could not be confirmed, illustrating the importance of confirmatory studies. This study describes a novel technique that identifies proteins dysregulated in MCL.     

Peripheral blood lymphocyte/monocyte ratio at diagnosis and survival in nodular lymphocyte-predominant Hodgkin lymphoma

The pathological background in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) consists of lymphocytes and histocytes. This study analysed the peripheral blood absolute lymphocyte count/absolute monocyte count ratio at diagnosis (ALC/AMC-DX) on the impact of survival in NLPHL. One hundred and three consecutive NLPHL patients that were followed at Mayo Clinic from 1974 to 2010 were included in the study. Receiver operating characteristic and area under the curve were used for ALC/AMC-DX cut-off value analysis and proportional-hazards models were used to compare survival based on the ALC/AMC-DX ratio. With a median follow-up of 8·9 years (range: 0·3-31 years), an ALC/AMC-DX ≥2·1 was the best cut-off value for survival with an area under the curve of 0·82, a sensitivity of 70% and specificity of 84%. After adjusting for the International Prognostic Score (IPS), ALC/AMC-DX remained an independent prognostic factor for overall survival [Hazard Ratio (HR), 0·33, 95% confidence interval (CI), 0·15-0·71%, P < 0·004]; lymphoma-specific survival (HR, 0·05; 95%CI, 0·01-0·68%, P < 0·002); progression-free survival (HR, 0·30; 95%CI, 0·14-0·60%, P < 0·006), and time to progression (HR, 0·06, 95%CI, 0·04-0·30%, P < 0·004). ALC/AMC-DX is a low cost, already standarized, biomarker to predict clinical outcomes in NLPHL.