Low Grade Fibromyxoid Sarcomas and Multiple Myeloma in the Same Patient: One Case Report and Literature Review

Introduction Multiple myeloma (MM) is a neoplastic plasma cell dyscrasia char-acterized by anemia; a monoclonal protein(M-protein) in the serum and/or urine; abnormal bone radiographs and bone pain;hypercal-cemia; and renal insuf.ciency or failure.According to the results of immunoelectrophoresis, patients are separated to Ig type (IgG, IgA, IgD, IgE and IgM); light chain; nonsecretory[1].     

例IgD多发性骨髓瘤患者多柔比星脂质体化疗后胸腔积液消退

IgD myelomas account for only 2% of all myelomas. This kind of hematological malignancy is severe and carries a bleak prognosis. Pleural effusion is very rare in multiple myeloma. We reported a case in which pleural effusion appeared at the end of the illness of IgD myeloma and treated with liposomal doxorubicin.     

Smoldering multiple myeloma and monoclonal gammopathy of undetermined significance

Opinion statement Smoldering multiple myeloma (SMM) consists of the presence of a serum M protein of 30 g/L or more and/or 10% or more bone marrow plasma cells (BMPCs), with no clinical manifestations or symptoms of myeloma. It accounts for approximately 10% of all myelomas, and the median time to progression to a symptomatic multiple myeloma ranges from 2 to 3 years. The main factors for progression are the plasma cell mass (M-protein size and percent of BMPCs), the spinal MRI pattern, the plasma cell proliferative index, and the variant of SMM (“evolving≓ vs “nonevolving≓). Although treatment with thalidomide is promising (based on the results of two phase II trials), outside the context of a clinical trial, a watch-and-wait approach with clinical evaluation every 4 months is recommended until evident symptomatic disease progression occurs. Patients with monoclonal gammopathy of undetermined significance (MGUS) have a serum M protein lower than 30 g/L and a proportion of BMPCs of less than 10%, with no clinical findings or symptoms attributable to the monoclonal gammopathy. MGUS has a high prevalence, and its annual rate of malignant transformation is 1%, such that the actuarial probability of progression to a symptomatic monoclonal gammopathy at 25 years of follow-up is as high as 40%. The factors associated with a higher probability of malignant transformation are a relatively high plasma cell mass, immunoglobulin A M-protein type, and the “evolving≓ variant. It is recommended that patients with MGUS are monitored annually. Importantly, patients with asymptomatic monoclonal gammopathies must not be treated before the development of overt multiple myeloma.     

Immunoglobulin D myeloma--problems with diagnosing and staging (own experience and literature review)

Immunoglobulin D (IgD) myeloma is a rare disease accounting for about 2% of all myelomas. The distinctive features are the predominant occurrence in males and young patients, short survival time, uncertain appearance of M-component in serum electrophoresis, predominance of lambda light chains, frequent renal impairment, hypercalcemia and amyloidosis. The aim of the present study was to show diagnostic difficulties resulting from a variety of non-specific initial symptoms and laboratory findings as well as to compare the staging system proposed by Durie and Salmon with the new risk grouping by Shimamoto. Case histories of 7 patients were analyzed retrospectively. Five of them were diagnosed as IgD multiple myeloma (IgD MM), 1 as non-secretory IgD myeloma and 1 as solitary bone IgD plasmocytoma that evolved to an IgD MM. All patients were staged according to the Durie and Salmon classification and the new risk grouping by Shimamoto. We report diagnostic problems with IgD myeloma in our patients, with special emphasis on non-specific rheumatoidal and neurological symptoms in 1 case. There was a very good correlation of the Japanese classification with the severity of the disease and the risk of death. In conclusion, the initial symptoms of IgD myeloma can be very misleading. Wide differential diagnosis, including autoimmunological disorders of the connective tissue, is necessary. The new Japanese risk grouping seems to be of greater prognostic significance for IgD myeloma than the Durie and Salmon staging system.     

Outcome of patients with IgD and IgM multiple myeloma undergoing autologous hematopoietic stem cell transplantation: a retrospective CIBMTR study

IntroductionImmunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined.Patients and MethodsUsing the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 36 patients with IgD and 11 patients with IgM myeloma among 3578 myeloma patients who received intensive therapy and auto-HCT over a 10-year period.ResultsThe progression-free and overall survival probabilities at 3 years were 38% (95% CI, 21%-56%) and 69% (95% CI, 51%-84%) for IgD myeloma, and 47% (95% CI, 17%-78%) and 68% (95% CI, 36%-93%), respectively, for IgM disease. Although formal statistical analysis was limited by the small sample size, these results were comparable to those for IgG and IgA patients autografted during the same time period. Transplantation-related mortality and disease relapse/progression of myeloma were also similar for all isotypes.ConclusionThis analysis demonstrates comparable outcomes in all immunoglobulin isotypes. Therefore, auto-HCT should be offered to eligible patients with IgD and IgM myeloma.     

Analysis of PTEN deletions and mutations in multiple myeloma

Clonal plasma cells from patients with multiple myeloma (MM), plasma cell leukemia (PCL) and human myeloma cell lines (HMCLs) were analyzed for deletions/mutations of the tumor suppressor gene PTEN. By interphase-FISH, hemizygous PTEN deletions were detected in 4 (5.6%) of 71 MM patients, 2 (20%) of 10 PCLs, and 2 (20%) of 10 HMCLs. PTEN deletions were detected in 4 MM patients at diagnosis with stage III disease (Durie-Salmon). Of the six cases with PTEN deletions, 1 MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. Sequencing analysis did not detect PTEN mutations in 11 primary MM and 5 PCL cases. Our results indicate that alterations of PTEN are uncommon in MM patients, and PTEN deletions tend to occur in advanced disease suggesting that they are secondary, rather than primary, events in the pathogenesis of MM.     

Immunoglobulin D multiple myeloma: response to therapy,survival, and prognostic factors in 75 patients

BackgroundTo analyze the clinical features, outcomes including efficacy of treatment, and prognostic factors of patients with immunoglobulin D multiple myeloma (IgD MM).Design and methodsSeventy-five patients diagnosed with IgD MM were selected from the Korean Myeloma Registry database (www.myeloma.or.kr).ResultsMedian age was 57 years and the main presenting features were bone pain (77%). Renal function impairment and hypercalcemia were present in 40 (53%) and 20 (27%) patients. Sixty-seven patients (89%) had lambda light chains. Forty-eight patients (64%) were of stage III by International Staging System. Twenty-six patients (53%) had chromosomal abnormalities mostly by conventional cytogenetics. Thirty-nine patients (54%) were treated with vincristine, adriamycin, and dexamethasone chemotherapy; the overall response rate (ORR) of 56%. Sixteen patients (22%) received first-line chemotherapy including new drugs (bortezomib or thalidomide), with an ORR of 81%. At a median follow-up time of 28.6 months, median overall survival (OS) was 18.5 months. Age, extramedullary plasmacytoma, del(13) or hypoploidy, serum β₂ microglobulin level, and platelet count were significant prognostic factors for OS.ConclusionsIgD MM is an aggressive disease that is usually detected at an advanced stage. Despite a positive initial response, survival after relapse was dismal. Intensive treatment strategies before and following stem cell transplantation may improve outcomes in younger patients.     

Efficacy and safety of bortezomib in patients with plasma cell leukemia

BACKGROUND: The prognosis of patients with plasma cell leukemia (PCL), an aggressive variant of multiple myeloma (MM), is usually poor. Bortezomib is the first proteasome inhibitor approved for the treatment of advanced MM. Currently available information regarding the role of bortezomib in PCL is scanty and derives from anecdotal, single-case reports. METHODS: The authors conducted a retrospective survey of unselected Italian patients with primary or secondary PCL who were treated with bortezomib outside of clinical trials. Twelve evaluable patients were recorded who had received bortezomib for 1 to 6 cycles as either a single agent or variously combined with other drugs. Three patients were treated with bortezomib as frontline therapy, and 9 patients received bortezomib after 1 to 4 lines of chemotherapy, including autologous stem cell transplantation and thalidomide. RESULTS: According to the International uniform response criteria of the International Myeloma Working Group, 5 partial responses (defined as a reduction in M-protein of >50%), 4 very good partial responses (defined as a reduction of >90% in M-protein), and 2 complete responses (defined as negative immunofixation) were achieved, for a response rate of 92%. Responses did not appear to be influenced by previous treatments or by other clinical or biologic parameters, including chromosome 13 deletion or the combination of bortezomib with other drugs. The median progression-free and overall survivals after bortezomib were 8 months and 12 months, respectively. At the time of last follow-up, 8 patients were alive 6 to 21 months after treatment with bortezomib, 4 of whom were in very good partial or complete responses. Grade 3/4 hematologic or neurologic toxicities (graded according to the Common Terminology Criteria for Adverse Events [CTCAE; version 3]) were reported to occur in 9 patients and 1 patient, respectively, whereas 6 patients experienced possible or documented infections. CONCLUSIONS: Bortezomib appears to be an effective drug for PCL that could significantly improve the usually adverse clinical outcome of these patients.     

IgD型多发性骨髓瘤的诊治现状及展望

IgD型多发性骨髓瘤（IgD multiple myeloma，IgD MM）是多发性骨髓瘤（multiple myeloma，MM）中一种罕见类型，以年轻男性患者居多。主要表现为高钙血症、肾衰竭、贫血、骨损害、髓外浸润和系统性淀粉样变性等，具有侵袭性高，预后较差的特点。近年来，随着免疫调节剂（沙利度胺、来那度胺）、蛋白酶抑制剂（硼替佐米）等药物以及自体造血干细胞移植（autologous stem cell transplantation，ASCT）的应用，IgD型MM的预后得到明显改善。新一代蛋白酶体抑制剂、CD38单克隆抗体、组蛋白去乙酰化酶抑制剂（histone deacetylase inhibitor,HDACI）、新型免疫治疗技术等治疗方法也为IgD型MM 的治疗提供了新的方向。目前关于IgD型MM的相关报道较少，本文就IgD型MM的临床特点、诊断、治疗、预后及新药研究现状进行如下综述。     

Induction and maintenance therapy in multiple myeloma. Results of a multicenter study

In a prospective study by the German Myeloma Treatment Group, 320 untreated patients with multiple myeloma, stage II and III, were randomized into 2 groups receiving courses of either MP or VCMP as induction treatment every 6 months. 72% of the patients evaluable by TCM changes remitted, 21% showed a no change, and progress occurred in 7%. The corresponding results in BJ and nonsecretory myelomas were 56% remissions, 11% no change, 33% progress. The response rates were equal in both treatment groups. The overall survival was 60% after 4 years. However, MP-treated patients lived significantly longer than patients in the VCMP group. After successful remission induction, patients were randomized into one group with maintenance treatment using the induction scheme Q 8 weeks, and another group without further chemotherapy. Although the relapse rate of the latter group was significantly higher, differences between both groups concerning survival have not been observed.     

Expression of Adhesion Molecules on Myeloma Cells

We investigated the expression of adhesion molecules including LFA-1α (CD11a), Mac-1 (CD11b), LFA-1β (CD18), VLA-β₁, (CD29), H-CAM (CD44), VLA-4 (CD49d), VLA-5 (CD49e), ICAM-1 (CD54), N-CAM (CD56), LFA-3 (CD58), VNR-β (CD61), and LECAM-1 (CD62L) on fresh myeloma cells and human myeloma cell lines. By two-color flow cytometric analysis with anti-CD38 antibody, we demonstrated that myeloma cells were located in the strongly CD38-positive (CD38⁺⁺) fractions. Fresh myeloma cells were obtained from 28 patients with multiple myeloma (MM) and 3 patients with plasma cell leukemia (PCL). All myeloma cells expressed VLA-4 on their surface. Most of the myeloma cells also expressed VLA-5, ICAM-1, and LFA-3. H-CAM was strongly expressed in 3 cases of PCL and 2 cases of aggressive myeloma, and moderately expressed in other MMs. N-CAM was expressed in 68% of MMs, but none of the 3 PCLs. LFA-1 was expressed in two cases of aggressive myeloma, but not expressed in other non-aggressive myelomas. Most of the myeloma cells did not express Mac-1, VNR-β, or LECAM-1. These results suggest that VLA-4, VLA-5, ICAM-1, LFA-3, and H-CAM are involved in cellular interaction and migration in MM, and that the expression of N-CAM and LFA-1 varies with disease activity in MM.     

Primary plasma cell leukemia occuring in the young

Plasma Cell Leukemia (PCL) is a rare form of plasma cell dyscrasia. Plasma cell leukemia has two variants: the primary form presents de novo in patients with no previous history of multiple myeloma (MM); the secondary form consists of a leukemic transformation in a previously recognized MM. In contrast to myeloma, PCL has an aggressive course. Median age at presentation is usually above 50 years. Here we report a case of primary PCL presenting at age of 21 years, which is extremely rare. She was treated with combination chemotherapy (VAD). Although she had a good response initially, later the disease progressed and she died 6 months after the diagnosis.     

不分泌型多发性骨髓瘤11例的临床及实验室特点

 目的　加深对不分泌型多发性骨髓瘤（NSM）的临床及实验室特点的认识。方法　对11例NSM患者进行免疫球蛋白IgG、IgA、IgM、IgD、IgE及轻链,血清蛋白电泳（PE）,免疫固定电泳（IFE）及血清游离轻链（FLC）检测。结果　11例患者均有严重多处骨骼疼痛,均有溶骨性骨质破坏。PE、IFE、尿FLC检测均为阴性。2例初治患者血清FLC升高,κ／λ比值均异常;1例平台期患者FLC正常。11例患者骨髓浆细胞均>30 %。其总生存时间与典型多发性骨髓瘤（MM）相同。结论　NSM均有多处严重骨骼疼痛,均有溶骨性骨质破坏。PE、IFE、尿FLC检测均为阴性。初治、复发时血清FLC升高,κ／λ比值异常;平台期FLC正常或降低。NSM患者的骨髓浆细胞均>30 %。NSM的治疗和预后与典型MM相同。     

Smoldering,asymptomatic stage 1, and indolent myeloma

Opinion statement Of patients presenting with multiple myeloma, 5% to 15% satisfy criteria for the diagnosis of multiple myeloma but have no or minimal symptoms and do not require chemotherapy (NRC). These patients are classified as having smoldering, asymptomatic stage 1, or indolent multiple myeloma in order of their increasing risk of progression. We avoid chemotherapy, especially with alkylating agents in such patients, and we either closely monitor them or use a nonchemotherapeutic intervention. If significant bone lesions, renal failure, or hypercalcemia occur, chemotherapy or transplant is recommended. Patients with mild anemia or with small or isolated bone lesions who are asymptomatic or minimally symptomatic because of anemia may be monitored and are classified as having indolent multiple myeloma. Unnecessary treatment with melphalan or cyclophosphamide probably has no benefit in multiple myeloma NRC and can cause significant risk. In long-term follow up, 25% of patients receiving alkylating agents develop myelodysplastic syndrome or acute leukemia. Patients who do not receive chemotherapy must be monitored closely to avoid complications of overt multiple myeloma, including anemia, bone lesions, renal failure, and hypercalcemia. We and others have begun to take a more active approach with the use of nonchemotherapeutic agents in selected patients. We use bisphosphonates in patients with bone lesions or osteoporosis or when there is a progressive rise in M-protein. We use dexamethasone alone in NRC multiple myeloma to reduce tumor burden in selected patients who do not yet have overt multiple myeloma or who are not candidates for chemotherapy. We use bisphosphonates to prevent osteoporosis in such patients. We use erythropoietin to correct anemia, and dexamethasone and erythropoietin together in patients with higher tumor burden (eg, indolent multiple myeloma). Future progress in treating multiple myeloma NRC depends on better identification of new therapeutic targets that control progression from the stable asymptomatic to the progressive symptomatic phase of multiple myeloma. We need to better understand the biologic target of new agents like thalidomide to design more effective treatment for this early phase of multiple myeloma. Although these approaches may delay chemotherapy, it is not known whether survival is prolonged. Nonchemotherapeutic approaches must be systematically studied in clinical trials in order to be put to better use.     

Elevated level of plasma basic fibroblast growth factor in multiple myeloma correlates with increased disease activity.

Recent reports that bone marrow angiogenesis is increased in multiple myeloma prompted us to examine plasma concentrations of angiogenic growth factors and to elucidate their clinical and biological significance. In 45 cases including 36 cases of multiple myeloma and 9 cases of monoclonal gammopathies of undetermined significance (MGUS), plasma concentrations of basic fibroblast growth factor (FGF-2) and vascular endothelial growth factor (VEGF) were evaluated. FGF-2 was significantly elevated in 25 out of 45 (56%) of the patients with multiple myeloma compared with control subjects (median 9.01 pg ml vs. 1.58 pg/ml, P < 0.0001). The 25 cases were all active multiple myeloma, and none of the non-active myeloma and MGUS patients showed a high FGF-2 level. VEGF level was also elevated in 26 out of 45 patients (58%) compared with control subjects (median 42.0 pg/ml vs. 15.8 pg/ml, P < 0.0001 for VEGF). VEGF concentration was high in 20 active myelomas, but also in one non-active myeloma and five MGUS. Elevation of FGF-2 level was associated with beta2-microglobulin level, anemia and bone marrow plasma cell percentage, which represent disease activity. Interestingly, none of five Bence-Jones type myelomas, including four clinically active cases, revealed a high plasma FGF-2 level, while all of them showed a high VEGF level. In all five responders, the plasma FGF-2 levels were significantly decreased after chemotherapy. FGF-2 was immunohistochemically detected in the bone marrow myeloma cells of the patients with high plasma FGF-2 level. We conclude that plasma concentration of FGF-2 can be a useful indicator of disease activity.     

IgD Subtype But Not IgM or Non-Secretory Is a Prognostic Marker for Poor Survival Following Autologous Hematopoietic Cell Transplantation in Multiple Myeloma. Results From the EBMT CALM (Collaboration to Collect Autologous Transplant Outcomes in Lymphomas and Myeloma) Study

BackgroundThe Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study has provided an opportunity to evaluate the real-world outcomes of patients with myeloma. The aim of this study was to compare the outcome according to the different subtypes of myeloma using CALM data.PatientsThis study compared overall survival (OS), progression-free survival (PFS), and complete remission (CR) and the impact of novel versus non-novel drug containing induction regimens prior to autologous hematopoietic cell transplantation (HCT) of 2802 patients with “usual” and “rare” myelomas.ResultsOur data suggest that IgM and non-secretory myeloma have superior PFS and OS compared with IgD myeloma and outcomes comparable to those for usual myeloma. Patients who received novel agent induction had higher rates of CR prior to transplant. Non-novel induction regimens were associated with inferior PFS but no difference in OS. Although not the primary focus of this study, we show that poor mobilization status is associated with reduced PFS and OS, but these differences disappear in multivariate analysis suggesting that poor mobilization status is a surrogate for other indicators of poor prognosis.ConclusionWe confirm that IgD myeloma is associated with the worst prognosis and inferior outcomes compared with the other isotypes.     

Management of renal dysfunction in multiple myeloma

Opinion statement Multiple myeloma is frequently associated with renal dysfunction. In addition, it has been shown that the presence of renal failure indicates a higher tumor burden and consequently more aggressive disease. Patients who are diagnosed with renal insufficiency should be aggressively treated because reversal of renal insufficiency results in survival outcomes similar to patients who have normal renal function at diagnosis. However, the presence of renal impairment could add significantly to the morbidity of these patients and make it difficult to tolerate aggressive treatment regimens. Therefore, the treatment approach to this group of patients should include a thorough understanding of the feasibility and outcomes of the various antimyeloma treatments that are available, including newer options such as thalidomide. We recommend the following sequence of treatment in newly diagnosed patients with multiple myeloma with renal insufficiency (creatinine > 2 mg/dL): correction of hypercalcemia with fulldose bisphosphonates in patients with hypercalcemia, induction therapy that may be initiated before correction of hypercalcemia with bolus VAD (vincristine 2 mg, doxorubicin 40 mg/m², dexamethasone 40 mg on days 1–4, 9–12, and 17–20), and stem cell collection (cyclophosphamide 2.5–3 g/m²) with high-dose melphalan (140–150 mg/m²) with autologous stem cell transplant. Dialysis support should be considered whenever necessary for all newly diagnosed patients if renal function does not improve with aggressive initial therapy. For patients who develop renal insufficiency later in the course of the disease, therapeutic options need to be tailored to the patient’s treatment history, disease status, and performance status.     

t(11;14) multiple myeloma: A subtype associated with distinct immunological features,immunophenotypic characteristics but divergent outcome

t(11;14)(q13;q32) is the most common chromosome translocation in multiple myeloma (MM), but a consensus of clinicopathological features and impact on survival is yet to be reached. We analyzed a cohort of 350 patients with various plasma cell malignancies, including newly diagnosed MM (NDMM, n = 253), relapsed/refractory MM (RRMM, n = 77), as well as primary and secondary plasma cell leukemia (PCL, n = 10 and n = 10, respectively). Results: A remarkably higher frequency of t(11;14) was observed in the PCL than in the NDMM. A high incidence of t(11;14) was detected in the IgD, IgM, and nonsecretory MM. The t(11;14) MM group was associated with a significantly higher positive rate of B-lineage associated antigens CD20 and CD79a as well as the lack of CD56 expression. t(11;14) was less likely to be accompanied by 13q14 deletion than 13q14 deletion frequency in non-t(11;14) population (p = 0.026), and fewer patients displaying t(11;14) were identified as belonging to the high-risk cytogenetic group due to the extremely low incidence of t(4;14) and t(14;16). As a whole, patients exhibiting t(11;14) had a comparable outcome with the control cohort in NDMM, but CD20 was able to identify two subsets of the disease with dissimilar outcomes. Among patients receiving bortezomib-based treatment, patients harboring t(11;14) without CD20 expression had a significantly shortened PFS (11.0 versus 43.0 months, p = 0.005) and OS (16.5 versus 54.0 months, p = 0.016) compared with patients displaying t(11;14) with CD20. Our findings suggest that although the t(11;14) plasma cell disorder displayed distinct biological, clinical and laboratory features, it was a heterogeneous disease with divergent outcome.