Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: a Belgian retrospective multicentric study.

OBJECTIVES: For better characterizing the effect of anti-CD20 therapy, we analysed the use of rituximab in Belgian patients experiencing auto-immune haemolytic anaemia (AIHA) and immune thrombocytopenic purpura (ITP). DESIGN: We performed a retrospective multicentric analysis of patients with AIHA and ITP treated with rituximab in Belgium. SETTING: Haematological departments were invited to fill in a questionnaire about patient and disease characteristics. SUBJECTS: All patients with AIHA and ITP, both primary and secondary to other diseases, who received one or more courses of rituximab during their disease course were included. Sixty-eight courses of rituximab in 53 patients with AIHA and 43 courses in 40 patients with ITP were analyzed. INTERVENTION: Response rates, duration of response and factors predictive for response were assessed. RESULTS: All patients were given rituximab after failing at least one previous line of treatment, including splenectomy in 19% and 72.5% of AIHA-patients and ITP-patients respectively. Overall response rates were 79.2% in AIHA and 70% in ITP, with a median follow-up since first rituximab administration of 15 months (range 0.5-62) in AIHA and 11 months (range 0-74) in ITP. Progression free survival at 1 and 2 years were 72% and 56% in AIHA and 70% and 44% in ITP. In this retrospective analysis we were not able to identify pretreatment characteristics predictive for response to rituximab. Nine patients with AIHA and three patients with ITP were given one or more additional courses of rituximab. Most of these patients, who had responded to a previous course, experienced a new response comparable to the previous one, both in terms of quality and of duration of response. Finally, the outcome of patients who failed to respond to rituximab therapy was poor both in terms of response to subsequent therapy and in terms of survival. CONCLUSIONS: This study confirms that rituximab induces responses in a majority of previously treated patients with AIHA and ITP. Response duration generally exceeds 1 year. Retreatment with rituximab in responding patients is most often successful. The outcome of patients who fail on rituximab is poor. We were not able to identify pretreatment patient characteristics predicting for response.

RGDS and DGEA-induced [Ca2+]i signalling in human dermal fibroblasts.

A pulse of short peptides, RGDS and DGEA in the millimolar range, immediately elicits in normal human fibroblasts a transient increase of intracellular Ca2+ ([Ca2+]i). In the present study, we show that this [Ca2+]i occurs in an increasing number of cells as a function of peptides concentration. It is specific of each peptide and inhibited at saturating concentration of the peptide in the culture medium. The [Ca2+]i transient depends on signalling pathways slightly different for DGEA and RGDS involving tyrosine kinase(s) and phosphatase(s), phospholipase C, production of inositol-trisphosphate and release of Ca2+ from the cellular stores. GFOGER, the classical collagen binding peptide of alpha1- alpha2- and alpha11-beta1 integrins, in triple helical or denatured form, does not produce any Ca2+ signal. The [Ca2+]i signalling induced by RGDS and DGEA is inhibited by antibodies against beta1 integrin subunit while that mediated by RGDS is also inhibited by antibodies against the alpha3 integrin. Delay in the acquisition of responsiveness is observed during cell adhesion and spreading on a coat of fibronectin for RGDS or collagen for DGEA or on a coat of the specific integrin-inhibiting antibodies but not by seeding cells on GFOGER or laminin-5. This delay is suppressed specifically by collagenase acting on the collagen coat or trypsin on the fibronectin coat. Our results suggest that free integrins and associated focal complexes generate a Ca2+ signal upon recognition of DGEA and RGDS by different cellular pathways.

Translocation t(1;6)(p35.3;p25.2): a new recurrent aberration in "unmutated" B-CLL.

Although reciprocal chromosomal translocations are not typical for B-cell chronic lymphocytic leukemia (B-CLL), we identified the novel t(1;6)(p35.3;p25.2) in eight patients with this disorder. Interestingly, all cases showed lack of somatically mutated IgV(H). Clinical, morphological, immunologic, and genetic features of these patients are described. Briefly, the age ranged from 33 to 81 years (median: 62.5 years) and the sex ratio was 6M:2F. Most of the patients (6/8) presented with advanced clinical stage. Therapy was required in seven cases. After a median follow-up of 28 months, five patients are alive and three died from disease evolution. Three cases developed transformation into diffuse large B-cell lymphoma. Translocation t(1;6) was found as the primary karyotypic abnormality in three patients. Additional chromosomal aberrations included changes frequently found in unmutated B-CLL, that is, del(11)(q), trisomy 12 and 17p aberrations. Fluorescence in situ hybridization analysis performed in seven cases allowed us to map the t(1;6) breakpoints to the 1p35.3 and 6p25.2 chromosomal bands, respectively. The latter breakpoint was located in the genomic region coding for MUM1/IRF4, one of the key regulators of lymphocyte development and proliferation, suggesting involvement of this gene in the t(1;6). Molecular characterization of the t(1;6)(p35.3;p25.2), exclusively found in unmutated subtype of B-CLL, is in progress.

Is the small non-cleaved-cell lymphoma histologic subtype a poor prognostic factor in adult patients? A case-controlled analysis. The Groupe d'Etude des Lymphomes de l'Adulte.

PURPOSE: To study the prognostic significance of the small non-cleaved-cell lymphoma (SNCCL) histologic subtype, we compared the outcome of adult patients with SNCCL with that of patients with aggressive lymphoma other than SNCCL by means of two case-controlled studies. PATIENTS AND METHODS: We analyzed the results of the doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) regimen used as a reference scheme in our cooperative study group (Groupe d'Etude des Lymphomes de l'Adult [GELA]) in 52 adult SNCCL patients with no bone marrow (BM) or CNS involvement. Forty-five SNCCL patients younger than 60 years could be compared with two separate case-matched groups of patients with aggressive lymphoma other than SNCCL undergoing the same therapeutic regimen. In the first case-controlled study, matching ensured identity of each risk factor of the age-adjusted International Index (ie, Ann Arbor stage, performance status, and lactate dehydrogenase [LDH] level); in the second study, matching was performed according to the number of presenting risk factors (zero, one, two, or three), regardless of their nature. RESULTS: The 5-year overall survival rates were not significantly different between SNCCL and control patients in both case-controlled studies: 48% versus 51% in the first study, and 48% versus 55% in the second study. CONCLUSION: These results support the thesis that in patients with no bone marrow or CNS involvement, the SNCCL histologic subtype does not confer a prognosis worse than that of other aggressive lymphoma.

A single course of 2-chloro-deoxyadenosine does not eradicate leukemic cells in hairy cell leukemia patients in complete remission.

The nucleoside analog 2-chlorodeoxyadenosine (2-CdA) has recently emerged as a most promising treatment for hair-cell leukemia (HCL). The response rates are high regardless of prior therapy, and the duration of complete responses (CR) after a single course of treatment is longer than with any other therapeutic agent. We investigated the presence of minimal residual disease (MRD) in ten HCL patients treated in our institution with 2-CdA. The presence of residual leukemic cells was investigated in patients in CR following one course of treatment, using the polymerase chain reaction (PCR) and heavy-chain immunoglobulin genes (IgH), or TCR delta derived clonospecific probes. Eight patients achieved a complete remission after a single course of treatment, as evaluated at 6 months. Among these patients, seven are still in CR with a median follow-up of 12 months (range, 6-20 months) and one has relapsed after 15 months. Using PCR, all the evaluable patients remaining in CR showed persistent evidence of detectable MRD with no sign of decrease over the observation period. From this small series, we conclude that a single course of 2-CdA does not eradicate HCL and that persistence of residual leukemic cells appears to be common in patients in complete morphologic remission. Whether persistence of MRD will have an impact on long-term outcome, or whether HCL patients in morphologic CR with persistent MRD will remain so, is a matter of longer follow-up.

Phase I/II study of 2-chloro-2'-deoxyadenosine with cyclophosphamide in patients with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma.

Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m2/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m2, and was escalated by 100 mg/m2 increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m2, was 300 mg/m2. Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% CI, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenström macroglobulinemia.

Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin).

We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor antibiotic) in the treatment of 101 patients > or =60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m(2) for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.

Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group.

First results of a randomized trial (APL91 trial) and other randomized or non-randomized studies have shown that ATRA followed by chemotherapy significantly increased event-free survival (EFS) and survival, and decreased the incidence of relapse by comparison to chemotherapy alone in newly diagnosed APL. We present here long-term follow-up of the APL91 trial. In this trial, 101 patients had been randomized between ATRA followed by three courses of daunorubicin-AraC chemotherapy (ATRA group) and the same chemotherapy alone (chemotherapy group). Results were reanalyzed 73 months after closing of patient entry. Updated results of APL 91 trial found a Kaplan-Meier estimate of EFS and relapse rate at 4 years of 63% and 31% in the ATRA group, as compared to 17% and 78% in the chemotherapy group (P= 10(-4) and relative risk 2.95, P= 10(-4) and relative risk 3.68, respectively). Kaplan-Meier survival at 4 years was 76% in the ATRA group and 49% in the chemotherapy group (P= 0.026, relative risk 2.7). In the chemotherapy group, seven of the 27 relapses occurred after 18 months, but no relapse was seen after 43 months. In the ATRA group, four of the 17 relapses occurred after 18 months, including two late relapses (at 58 and 74 months). In the chemotherapy group, 23 of the 25 patients who relapsed achieved a second CR with ATRA, and the Kaplan-Meier estimate of second relapse was 40% at 30 months. In the ATRA group, the 10 patients who relapsed and were retreated with ATRA achieved a second CR. In conclusion, long-term results of APL91 trial confirm the superiority of the combination of ATRA and chemotherapy over chemotherapy alone in newly diagnosed APL, and that ATRA should be incorporated in the front-line treatment of APL.

Azacitidine access program for Belgian patients with myelodysplastic syndromes, acute myeloid leukemia or chronic myelomonocytic leukemia.

OBJECTIVE: Azacitidine (Vidaza *) is approved in Europe for treatment of myelodysplastic syndromes (MDS), acute myeloid leukemia (AML) with 20-30% bone marrow (BM) blasts, and chronic myelomonocytic leukemia (CMML) with 10-29% BM blasts and no myeloproliferative syndrome (i.e. <13.000/µL white blood cells). In Belgium, the azacitidine reimbursement process can take several months, and is often delayed at submission for medical assessment by the Belgian National Institute for Health and Disability Insurance of incomplete patient dossiers, due to disease complexity and classification, and administrative burden. We describe the Vidaza Access Program and its application to an initial 175 patients. Individual medical dossiers were reviewed for completeness to facilitate patient access to treatment in Belgium. METHODS: A standardized anonymized patient information form is completed by the physician and sent for review to the Belgian Celgene Medical Department. The form is reviewed within three working days and, for complete dossiers, Celgene grants a financial guarantee for treatment with azacitidine. The patient can then be treated without the hospital being subjected to financial risk. RESULTS: Between January 2013 and June 2014, 63 physicians (53 Belgian hospitals) recruited 175 patients. In total, 163 patient dossiers were approved by Celgene (120 MDS, 36 AML, and 7 CMML), of which 104 dossiers were also approved by the review committee and 49 have been waiting for a final decision for a median of 6 months; no information is currently available for the remaining 10. No dossiers approved by Celgene have been rejected by the review committee. CONCLUSIONS: The Celgene Vidaza Access Program offers support to healthcare professionals in the appropriate use of azacitidine. By facilitating the assessment of patient dossiers and providing a financial guarantee for prescribers and hospitals, treatment can be initiated more rapidly and patients may better benefit from azacitidine treatment.

Safety and efficacy of azacitidine in Belgian patients with high-risk myelodysplastic syndromes, acute myeloid leukaemia, or chronic myelomonocytic leukaemia: results of a real-life, non-interventional post-marketing survey.

OBJECTIVES: We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. METHODS: This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study. Treatment response [complete response (CR), partial response (PR), haematological improvement (HI), stable disease (SD), treatment failure (TF)) and transfusion-independence (TI) were evaluated at completion of a 1-year observation period (1YOP) or at treatment discontinuation, and overall survival (OS), at study conclusion. RESULTS: The median age of patients was 74·7 (range: 43·9-87·8) years; 69·4% had MDS, 26·5% had primary or secondary AML, and 4·1% had CMML. Treatment-related TEAEs, grade 3-4 TEAEs, and TESAEs were reported in 67·3%, 28·6%, and 18·4% of patients, respectively. During 1YOP, patients received a median of 7 (1-12) treatment cycles. Treatment response was assessed for 38/49 patients. Among MDS and CMML patients (n = 29), 41·4% had CR, PR, or HI, 41·4% had SD, and 17·2% had TF. Among AML patients (n = 9), 44·4% had CR or PR, 33·3% had SD, and 22·2% had TF. TI was observed in 14/32 (43·8%) patients who were transfusion-dependent at baseline. Median (95% confidence interval) OS was 490 (326-555) days; 1-year OS estimate was 0·571 (0·422-0·696). CONCLUSIONS: Our data support previous findings that azacitidine has a clinically acceptable safety profile and shows efficacy.

Myelofibrosis patients in Belgium: disease characteristics.

OBJECTIVE: To date, only a small number of epidemiological studies on myelofibrosis have been performed. The current study aimed to characterize the myelofibrosis patient population in Belgium according to pre-defined disease parameters (diagnosis, risk categories, hemoglobin <10 g/dl, spleen size, constitutional symptoms, platelet count, myeloblast count), with a view to obtaining a deeper understanding of the proportion of patients that may benefit from the novel myelofibrosis therapeutic strategies. METHODS: A survey was used to collect data on prevalence and disease parameters on all myelofibrosis patients seen at each of 18 participating hematologic centers in 2011. Aggregated data from all centers were used for analysis. Analyses were descriptive and quantitative. RESULTS: A total of 250 patients with myelofibrosis were captured; of these, 136 (54%) were male and 153 (61%) were over 65 years old. One hundred sixty-five (66%) of myelofibrosis patients had primary myelofibrosis and 85 (34%) had secondary myelofibrosis. One hundred ninety-three myelofibrosis patients (77%) had a palpable spleen. About a third of patients (34%) suffered from constitutional symptoms. Two hundred twenty-two (89%) myelofibrosis patients had platelet count ≧50 000/µl and 201 (80%) had platelet count ≧100 000/µl. Of 250 patients, 85 (34%) had a myeloblast count ≧1%. Six (2%) patients had undergone a splenectomy. Thirteen (5·2%) patients had undergone radiotherapy for splenomegaly. CONCLUSIONS: The results of this survey provide insight into the characteristics of the Belgian myelofibrosis population. They also suggest that a large proportion of these patients could stand to benefit from the therapies currently under development.

Feminizing testicular Leydig cell tumor: hormonal profile before and after unilateral orchidectomy.

The effect of chronic hyperestrogenism on gonadal function was studied in three men who had estrogen-secreting Leydig cell tumors before unilateral orchidectomy and for 11-43 months after surgery. All three men had low plasma gonadotropin and testosterone levels and increased estradiol levels. Impairment of testicular steroidogenesis was also suggested by increased progesterone to 17-hydroxyprogesterone and 17-hydroxyprogesterone to androstenedione ratios in both spermatic venous plasma and the medium of Leydig tumor cells from one patient incubated in vitro. Before surgery, spermatogenesis was abnormal in two men. Testicular endocrine function and spermatogenesis did not return to normal after surgery. During the follow-up period, plasma gonadotropin levels were high in all three men, and testosterone was low normal. Estradiol levels decreased to normal immediately after surgery and then returned to the upper normal limit. The response to hCG stimulation in one man was subnormal. We conclude that chronic hyperestrogenism produced hypothalamo-pituitary inhibition as well as direct steroidogenic blockade at the testicular level. Long term impairment of both endocrine and exocrine testicular functions may be secondary to slowly reversible (or irreversible) estrogen-induced damage to tubular and Leydig cells.

Karyotype in acute myeloblastic leukemia: prognostic significance in a prospective study assessing bone marrow transplantation in first remission.

To evaluate the prognostic value of the karyotype in acute myeloblastic leukemia when patients are allocated to have either autologous bone marrow transplantation (BMT) or allogeneic BMT at the time of first remission (CR1), we have prospectively followed 134 consecutive patients from diagnosis. CR was achieved in 118 patients. Allogeneic BMT and autologous BMT were performed in 25 and 43 CR1 patients, respectively. Applying the karyotype classification of Keating et al for remission duration (favorable: t(15;17), inv(16); intermediate: normal, X -Y, t(8;21); unfavorable: other abnormalities), 10 patients had a favorable, 49 an intermediate, and 44 an unfavorable karyotype. The 5-year leukemia-free survival (LFS) probabilities for patients with a good, intermediate and unfavorable karyotype were 65%, 32% and 11%, respectively (log rank test P = 0.0019). The probabilities of relapse were 35% in patients with a favorable karyotype, 52% with an intermediate karyotype and 87% with an unfavorable karyotype (P = 0.0004). In the patients who had autologous BMT in CR1, the LFSs were 100%, 33% and 10% with favorable, intermediate and unfavorable karyotype, respectively (P = 0.04). The karyotype was of no prognostic value in patients receiving allogeneic BMT who had BMT in CR1. This study shows that the karyotype retains its prognostic value when the intentions is to treat patients with acute myeloblastic leukemia in CR1 with BMT. Autologous BMT was not able to improve the poor prognosis associated with an unfavorable karyotype.

Multiple myeloma presenting as hepatic nodular lesion.

The diffuse infiltration by plasma cells in the liver is not uncommon in multiple myeloma (MM). However, a MM with hepatic mass is very unusual. We report a case of a 75-year-old male with hepatomegaly and a lesion occupying a voluminous space in the liver. A lambda light chain multiple myeloma was found in the check-up of this hepatic mass. We also provide a literature review.

Lenalidomide in relapsed refractory myeloma patients: impact of previous response to bortezomib and thalidomide on treatment efficacy. Results of a medical need program in Belgium.

The prognosis of multiple myeloma patients has significantly improved since the introduction of the novel agents thalidomide, bortezomib and lenalidomide. We report the data of a medical need programme with lenalidomide plus dexamethasone, conducted in Belgium between August 2007 and March 2008, and including 98 relapsed refractory multiple myeloma patients. In addition to chemotherapy and steroids, all patients had received prior treatment with bortezomib, and 84% of them had been exposed to thalidomide. In 52 patients response data could be retrieved by post-hoc analysis. A partial remission or better was achieved in 52% (49% partial and 3% complete response) of patients, despite a median of 5 previous anti-myeloma treatment lines. Responses were rapid while the majority of patients received lenalidomide with once weekly (also called low-dose) dexamethasone. Treatment with lenalidomide plus dexamethasone did prolong overall survival by nearly half a year in this population with end-stage myeloma. Overall response and quality of response were independent of previous response to thalidomide and bortezomib, although the time to progression tended to be shorter in thalidomide- and bortezomib-refractory patients. It can be concluded that lenalidomide plus dexamethasone is an effective and safe treatment regimen in highly refractory multiple myeloma patients, and that these responses are irrespective of previous exposure or sensitivity to thalidomide and bortezomib.

Immune thrombocytopenic purpura at the diagnosis of Hodgkin disease.

We describe the case of a 76-year-old male presenting a thrombocytopenia at the diagnosis of Hodgkin disease. Basing on bone marrow biopsy and evolution, we diagnosed an immune thrombocytopenia and treated with intravenous gammaglobulins. The platelet count normalized in a few days under this therapy. Immune thrombocytopenia purpura (ITP) is a rare complication of Hodgkin disease (HD). It seems to be due to the production of antibodies directed against platelet membrane proteins. The patient's and the lymphoma's characteristics are not predictive for it to happen. The evolution of HD is also not influenced by its occurrence. Various treatments (including corticoids and immunomodulating agents) have been tried with different efficiencies.

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis.

Epigenetic code modifications by histone deacetylase inhibitors have recently been proposed as potential new therapies for hematological malignancies. Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new treatments. CLL B cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as the bone marrow and lymph nodes. In this study, we analyzed gene expression modifications in CLL B cells after treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. CLL B cells obtained from 14 patients were treated in vitro with a concentration of 1 mM VPA for 4 h. VPA effects on gene expression were thereafter studied using Affymetrix technology, and some identified genes were validated by real-time PCR and western blot. We observed that VPA induced apoptosis by downregulating several anti-apoptotic genes and by upregulating pro-apoptotic genes. Furthermore, VPA significantly increased chemosensitivity to fludarabine, flavopiridol, bortezomib, thalidomide and lenalidomide. VPA inhibited the proliferation of CpG/IL2-stimulated CLL B cells and modulated many cell cycle messenger RNAs. In conclusion, exposure of CLL B cells to VPA induced apoptosis, potentiated chemotherapeutic agent effects and inhibited proliferation. These data strongly suggest the use of VPA in CLL treatment, particularly in combination with antileukemia agents.

Hypercalcemia, chronic lymphocytic leukemia and multiple myeloma: uncommon association.

A fifty-nine year old woman is admitted with severe hypercalcemia and other metabolic disorders. The buffy coat showed plasmoblasts in association with chronic lymphocytic leukemia cells (CLL). Immunophenotyping revealed different light chains on CLL cells and in plasmoblasts. We discuss the association of hypercalcemia and CLL, its physiopathology and the distinction with Richter's Syndrome. We also review literature descriptions of the uncommon association of CLL and Multiple Myeloma and raise the question of its clonal origin.