Multiple myeloma. An update on diagnosis and management

Patients with multiple myeloma must be differentiated from those with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). The plasma cell labeling index is helpful in differentiating MGUS or SMM from multiple myeloma (MM). No difference in survival was noted between patients given a single alkylating agent and those given a combination of alkylating agents. Alternating cycles of interferon alpha 2 and VBMCP (vincristine, BCNU, melphalan, cyclophosphamide, prednisone) produced a complete or near-complete response in 41% of patients. Allogeneic or syngeneic bone marrow transplantation has produced some benefit. Autologous bone marrow transplantation is potentially applicable to treat more patients. Major problems are eradication of myeloma cells from the bone marrow and removal of myeloma cells from autologous bone marrow. Purging of myeloma cells with monoclonal antibodies and chemotherapy may be helpful. Stem cells from autologous peripheral blood are being used for rescue after high-dose chemotherapy and total-body irradiation.     

Cytokine and chemokine profiles in multiple myeloma; significance of stromal interaction and correlation of IL-8 production with disease progression

Multiple myeloma (MM) is a product of interactions between tumor plasma cells and multiple cell types native to the bone marrow (BM). We have used antibody array technology to examine the proteins produced by BM stromal cells in response to stimulation by BM taken from patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and MM. We observed increased production of the chemokine IL-8 by stromal cells co-cultured with supernatants from bone marrow cells of patients with active myeloma. IL-8 production is correlated with active disease and is dependent upon IL-1beta and NF-kappaB signaling. Consistent with the pro-angiogenic activity of IL-8, increased BM microvessel density (MVD) correlated with stimulation of stromal cell IL-8 production. In addition, the majority of MM cell lines and MM patient plasma cells were found to express IL-8 receptors CXCR1 and CXCR2. We conclude that stromal cell IL-8 production parallels MM disease activity, is IL-1beta induced, and correlates with bone marrow angiogenesis.     

Immunohistological diagnosis of plasma cell myeloma based on cytoplasmic kappa/lambda ratio of CD138-positive plasma cells

Abstract For differentiating reactive plasmacytosis from clonal plasma cell neoplasms such as plasma cell myeloma (PCM), it is important to determine the expression of the cytoplasmic light chain accurately. Through retrospective analysis, we studied the cytoplasmic kappa/lambda ratio of CD138-positive plasma cells in bone marrow from 50 patients with PCM and 50 controls by immunohistological analysis. The percentage of cytoplasmic light chain immunoreactive cells out of the total plasma cell population was shown by a novel quantitative image analysis approach using an Aperio ScanScope CS and the Membrane v9 algorithm. PCM cells were distinguished from normal plasma cells by cut-off levels between 0.35 and 5.5, a sensitivity of 100% and a specificity of 98.0%. Detection of the cytoplasmic kappa/lambda ratio of CD138-positive plasma cells could be a useful tool for simple, efficient and accurate diagnosis of PCM.     

Coexistence of myelodysplastic syndrome and multiple myeloma

We describe the simultaneous presentation of myelodysplastic syndrome (MDS) and multiple myeloma (MM). Our patient had MDS (RAEB type) and bone marrow infiltration (40% plasma cells), as well as biclonal paraprotein. Patients with MM, MDS have been reported after chemotherapy but few cases documenting the coexistence of MDS and MM at diagnosis have been reported in the literature.     

RAS mutations are uncommon in multiple myeloma and other monoclonal gammopathies

Monoclonal gammopathies are a group of diseases characterised by the proliferation of a single clone of plasma cells that produce a homogeneous monoclonal protein (M protein or myeloma protein) that consist of two heavy polypeptide chains of the same class and subclass and two light polypeptide chains of the same type. Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) are the most common monoclonal gammopathies. Despite advances in systemic and supportive therapies, MM is an incurable hematological malignancy with a median survival of between two and three years. Point mutations in the Ras genes can be detected in a variety of human malignancies, indicating that ras activation represents a widespread oncogenic event. Several studies have analysed the incidence of Ras mutation in MM and MGUS with great differences in their results. To date, the etiopathogenesis of these diseases is still unknown and the relevance of Ras mutation to the clinical and biological behaviour of monoclonal gammopathies remains to be elucidated. In this study, we have analysed K-ras codon 12 and N-ras codon 61 mutations on anti-CD138 sorted bone marrow plasma cell samples of 44 cases of monoclonal gammopathies: 30 MM, 13 MGUS and 1 plasma cell leukaemia, using polymerase chain reaction. No mutations within either codon 12 of K-ras or codon 61 of N-ras have been found in any of the samples. These results indicate that Ras mutations do not play a significant role in the pathogenesis of MM in the Spanish population.     

Gain of 1q21 and distinct adverse cytogenetic abnormalities correlate with increased microcirculation in multiple myeloma

To identify genetic mechanisms controlling bone marrow microcirculation and angiogenesis in patients with plasma cell disease we simultaneously performed bone marrow dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and cytogenetics (iFISH) on CD138 purified plasma cells of MGUS (n=31) and untreated multiple myeloma (MM) (n = 87) patients. The adverse cytogenetic abnormalities gain of 1q21, deletion 17p13 and deletion 13q14 significantly correlated with at least one DCE-MRI finding (aberrant "focal" microcirculation pattern, increase in median microcirculation parameter Amplitude A or exchange rate constant kep). We conclude that gain of 1q21, deletion 13q14 and deletion 17p13 trigger the angiogenic cascade in MM. Our findings will have important implications for the design, analysis and stratification for clinical studies of patients with MM in particular if compounds with antiangiogenic activity are used.     

Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance.

Since deletion of chromosome 13q is a clinically relevant feature in multiple myeloma (MM), we analyzed bone marrow plasma cells from 29 patients with monoclonal gammopathy of undetermined significance (MGUS) to investigate the chromosome 13 status in MGUS. Studies were performed by interphase fluorescence in situ hybridization (FISH) with a panel of 13q14-specific probes (RB1, D13S319, D13S25, D13S31). Plasma cells with a deletion of at least one of the 13q14 loci were detected in 13 patients (44.8%) with MGUS. In five patients (17.2%), deletions of all four 13q14-specific probes were observed, and the additional deletion of a 13q telomeric region (D13S327) suggested loss of the entire 13q arm or monosomy 13. Loss of 13q14 was observed to be monoallelic and to occur in 11.0 to 35.0% of plasma cells (cut-off levels for a deletion <10% with all probes). Nine of 17 patients (52.9%) with MM progressing from a pre-existing MGUS had evidence for a deletion of 13q14 as determined by FISH with the RB1 probe. These results suggest that deletion of 13q14 is an early event in the development of monoclonal gammopathies, but its role for the eventual progression to MM remains to be determined prospectively.     

Determination of plasma cell secreting potential as an index of maturity of myelomatous cells and a strong prognostic factor

According to the widely accepted myeloma staging system, the bulk of paraprotein is the main determinant of disease stage. However, myelomatous plasma cells differ considerably in their ability to synthesize and secrete monoclonal paraprotein. We determined plasma cell secreting potential (PCSP) as the amount of M-component, divided by the percentage of marrow plasmacytic infiltration, in 240 patients with myeloma, and correlated our results with chain isotype, plasma cell morphology, severity of bone disease, well-recognized prognostic factors, such as serum LDH, CRP, albumin and beta2-microglobulin, treatment response and overall survival. PCSP was higher in IgG than in other myeloma types, and was an almost constant parameter for each individual patient, in 134/166 cases. A > 10% decrease of PCSP in 26 patients was associated with disease aggressiveness and treatment failure. Patients with MGUS had significantly higher PCSP than those with myeloma of the same chain type. Higher PCSP was associated with stage I, absence of Bence-Jones proteinuria and indolent forms of disease with lower proliferating cell nuclear antigen (PCNA) positivity, serum LDH, alpha2-globulins, CRP and beta2-microglobulin and higher albumin levels. Conversely, patients with immature/plasmablastic morphology and those with severe bone disease had lower PCSP. Good responders to treatment had significantly higher PCSP than moderate and poor responders and PCSP was strongly correlated with overall survival in IgG and IgA myeloma. In conclusion, PCSP reflects the maturation status of myelomatous cells and therefore can be used as a prognostic factor, since patients with high secreting potential represent a lower malignancy group, in comparison to those with a low secreting potential.     

Malignant transformation of monoclonal gammopathy of undetermined significance: cumulative incidence and prognostic factors.

The cumulative incidence of malignant transformation was studied in 88 patients with monoclonal gammopathy of undetermined significance (MGUS) that had a complete prospective follow-up. At a median follow-up of 6.75 years, 10 patients developed multiple myeloma (MM) (11.4%) and 2 developed immunocytoma (2.3%). The cumulative incidence of malignant transformation was 9.1, 21.3, 38 and 48.3% at 5, 10, 15 and 20 years, respectively. In univariate analysis on 102 MGUS patients, M-component level, bone marrow plasma cell percentage and kappa light chain correlated significantly with the development of a malignancy (p=0.0289, 0.0265 and 0.0013, respectively). In multivariate analysis, light chain type of M-component and plasma cell percentage had independent prognostic significance. A high-risk (M-component level > 10 g/l and/or plasma cell percentage > 2%) and a low-risk group ( M-component level < 10 g/l and/or plasma cell percentage < 2%) of MGUS patients was identified, which differed significantly in the cumulative incidence of developing a malignancy (p<0.001 for M-component level and p=0.007 for plasma cell percentage). These results imply that high-risk patients should receive a more frequent follow-up, in comparison to low-risk patients.     

Hyperdiploidy is a common finding in monoclonal gammopathy of undetermined significance and monosomy 13 is restricted to these hyperdiploid patients.

PURPOSE: Two pathways, hyperdiploid and nonhyperdiploid, are proposed for progression to plasma cell neoplasia. Implication of monosomy 13 (Delta13) is unclear in monoclonal gammopathy of undetermined significance (MGUS), and data on DNA content of plasma cells [DNA index (DI)] are rare. EXPERIMENTAL DESIGN: We ascertained DI in 169 multiple myeloma (MM) and 96 MGUS patients. Interphase fluorescence in situ hybridization (FISH) coupled to cytoplasmic staining of specific Ig (cIg-FISH) was done to look for trisomies and to ascertain Delta13. RESULTS: Hyperdiploidy and hypodiploidy were found in 54% and 11.5% of MGUS patients and in 59.5% and 25% of MM patients, respectively. In MGUS patients tested using probes for odd chromosomes, cIg-FISH showed association between trisomies for chromosomes 3, 7, 9, 11, or 15 and hyperdiploidy. Delta13 was found in 45.3% and 24.6% of MM and MGUS patients, respectively. Most Delta13 cases observed in MGUS were found within hyperdiploid clones, 38% versus 11% in hypodiploid cases, in sharp contrast with the occurrence of Delta13 in MM patients, 31.9% and 76.3%, respectively. That peculiar distribution of Delta13 according to DI persisted with other thresholds used to ascertain hyperdiploidy, such as DI >or= 1.05. A strong relationship between IgA peak and hypodiploidy (P = 0.007) was only observed in MM, whereas lambda light chain was significantly associated with hypodiploidy in MGUS (P = 0.001) and MM (P = 0.05). Hyperdiploidy shows similar pattern in MGUS and MM. CONCLUSION: This fits well a hyperdiploid pathway leading to MM after a preceding MGUS stage. Yet-to-be-determined secondary event(s) needs to occur for the transition to MM, unrelated to changes in chromosome number or to loss of chromosome 13. In contrast, the "nonhyperdiploid" pathway needs to be clarified further because hypodiploidy is less common in MGUS than in MM and Delta13 is rare in hypodiploid MGUS patients compared with hypodiploid MM patients.     

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the presence of a serum monoclonal (M) protein level less than 3 g/dL, less than 10% clonal plasma cells in the bone marrow, and the absence of hypercalcemia, renal insufficiency, anemia, or bone lesions attributable to a clonal plasma cell disorder. Patients may be tested for a monoclonal gammopathy by serum protein electrophoresis, immunofixation, and the free light chain (FLC) assay. The prevalence of MGUS is 3% for persons more than 50 years of age and 5% in those more than 70 years of age. The risk of progression to multiple myeloma or a related disorder is 1% per year. The size and type of M protein, the number of bone marrow plasma cells, and the results of the FLC ratio are independent risk factors for progression. Smoldering multiple myeloma (SMM) is a more advanced premalignant phase than MGUS and is characterized by more than 3 g/dL of serum M protein, more than 10% clonal plasma cells in the bone marrow, or both, with no evidence of end-organ damage.     

Both IGH translocations and chromosome 13q deletions are early events in monoclonal gammopathy of undetermined significance and do not evolve during transition to multiple myeloma.

Molecular and genetic events associated with the transition from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) are still poorly characterized. We investigated serial bone marrow specimens from 11 patients with MGUS who eventually progressed to MM (MM post-MGUS) by interphase fluorescence in situ hybridization for immunoglobulin heavy-chain gene (IgH) translocations and chromosome 13q deletions (del(13q)). In nine patients, IgH translocations were present both in MGUS and MM post-MGUS plasma cells, including three t(11;14)(q13;q32) and one t(4;14)(p16;q32), which was observed already 92 months prior to MM. Similarly, all five MM patients with del(13q) had this aberration already at the MGUS stage. Two patients without IgH translocation and del(13q) had chromosomal gains suggesting hyperdiploidy, but IgH translocations and/or del(13q) did not emerge at MM post-MGUS. IgH translocations and del(13q) are early genetic events in monoclonal gammopathies, suggesting that additional events are required for the transition from stable MGUS to progressive MM.     

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。     

Bone marrow angiogenesis in 400 patients with monoclonal gammopathy of undetermined significance, multiple myeloma, and primary amyloidosis.

PURPOSE: To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma. EXPERIMENTAL DESIGN: Four hundred patients with the following disorders were studied: MGUS (76 patients); smoldering (indolent; early-stage) multiple myeloma (SMM; 112 patients); newly diagnosed, active multiple myeloma (MM; 99 patients); relapsed (advanced) multiple myeloma (RMM; 26 patients); and primary amyloidosis (AL; 87 patients). Forty-two normal control BM samples were studied for comparison. BM angiogenesis was studied in a blinded manner by immunohistochemical staining for CD34 to identify microvessels. RESULTS: The median (range) microvessel density (MVD) per x400 high power field was 1.3 (0-11) in the controls, 1.7 (0-10) in AL, 3 (0-23) in MGUS, 4 (1-30) in SMM, 11 (1-48) in newly diagnosed MM, and 20 (6-47) in RMM; P < 0.001. MVD was significantly higher in MGUS, SMM, newly diagnosed MM, and RMM compared with controls and AL; P < 0.001. MVD was not significantly different between controls and AL. By grading, high-grade angiogenesis was present in 0% of controls and AL, 1% of MGUS, 3% of SMM, 29% of newly diagnosed MM, and 42% of RMM; P < 0.001. MVD correlated with the BM plasma cell labeling index (rho = 0.46, P < 0.001) and BM plasma cell percentage (rho 0.5, P < 0.001). Survival was 28 months in SMM and newly diagnosed MM with high-grade angiogenesis, compared with 53 months for those with low- and intermediate-grade angiogenesis; P = 0.02. CONCLUSIONS: BM angiogenesis progressively increases along the spectrum of plasma cell disorders, from the more benign MGUS stage to advanced myeloma, indicating that angiogenesis may be related to disease progression.     

Prognostic Biomarkers in the Progression From MGUS to Multiple Myeloma: A Systematic Review

Multiple myeloma (MM), characterized by malignant plasma cells in the bone marrow, is consistently preceded by asymptomatic premalignant stage monoclonal gammopathy of undetermined significance (MGUS). These MGUS patients have an annual risk of 1% to progress to MM. Clinical, imaging, and genomic (genetic and epigenetic) factors were identified, whose presence increased the risk of progression from MGUS to MM. In this systematic review we summarize the currently identified clinical, imaging, and genomic biomarkers suggested to increase the progression risk or shown to be differentially expressed/present between both cohorts of patients. Despite the wide range of proposed markers, there are still no reliable biomarkers to individually predict which MGUS patient will progress to MM and which will not. Research on biomarkers in the progression from MGUS to MM will give more insight in the unknown pathogenesis of this hematological malignancy. This would improve research by elucidating new pathways and potential therapeutic targets as well as clinical management by closer follow-up and earlier treatment of high-risk MGUS patients.     

Risk of Japanese carriers of hyperphosphorylated paratarg-7, the first autosomal-dominantly inherited risk factor for hematological neoplasms, to develop monoclonal gammopathy of undetermined significance and multiple myeloma

Hyperphosphorylated paratarg-7 (pP-7) is a frequent target of paraproteins in German patients with monoclonal gammopathy of undetermined significance (MGUS)/multiple myeloma (MM). The frequency of MGUS/MM is lower in Japan than in Europe. As pP-7, the first molecularly defined autosomal-dominant risk factor for any hematological neoplasm, is inherited in a dominant fashion, we determined the incidence of the pP-7 carrier state in a Japanese population, and compared the frequency of pP-7-specific paraproteins and the pP-7 carrier state in Japanese and German patients with MGUS/MM. Peripheral blood from 111 Japanese patients with MGUS/MM and 278 healthy blood donors was analyzed for the pP-7 carrier state by isoelectric focusing and for pP-7-specific antibodies by ELISA. The Japanese group was compared with 252 German MGUS/MM patients and 200 healthy controls. Five of 111 (4.5%) Japanese and 35/252 (13.9%) German IgA/IgG MGUS/MM patients had a pP-7-specific paraprotein (P=0.009). The prevalence of healthy pP-7 carriers in the Japanese study group was 1/278 (0.36%), whereas it was 4/200 in the German group (P=0.166). The relative risk for pP-7 carriers developing MGUS/MM had an odds ratio of 13.1 in the Japanese and 7.9 in the German group. In conclusion, the fraction of pP-7 carriers with a pP-7-specific paraprotein is lower among Japanese than in German patients with MGUS/MM, but pP-7 carriers in both ethnic groups have a high risk of developing MGUS/MM.     

Special IgD-λ type multiple myeloma based on bone marrow cell morphology: A case report

We aimed to explore the changes of laboratory indexes of IgD-λ type multiple myeloma with special cell morphology, and to improve the cognition of IgD-λ type MM. To explore the changes of laboratory indexes of IgD-λ type 1 multiple myeloma with special cell morphology, and to improve the cognition of IgD-λ type MM. The morphology of bone marrow cells, immunofixation electrophoresis, serum free light chain (sFLC) and other detection indexes of a patient with IgD-λ type MM treated in Handan Central Hospital in December 2020 were analyzed. The patient bone marrow smears showed 62％ of abnormal cells–which were distributed in clusters and resembled lymphoma and metastatic cancer cells. The Flowcytometry indicates that the cell is a plasma cell tumor.Immunoglobulin IgG, IgA and IgM were all lower than the normal range.There is a monoclonal light chain λ component in immunofixation electrophoresis.The serum free light chain λ was 2700.00 mg/ L, light chain k/λ is 0.0023, the high of serum calcium, LDH, β2 microglobulin. IgD-λ type MM is a rare type of MM. The age of onset is young, the invasiveness is strong, the prognosis is poor, the clinical manifestation is complex, and it is easy to be misdiagnosed or missed. The analysis of the clinical symptoms and laboratory characteristics of the disease plays a positive role inthe diagnosis, treatment and prognosis of the disease .     

Understanding biology to tackle the disease: Multiple myeloma from bench to bedside,and back

Answer questions and earn CME/CNE Multiple myeloma (MM) is a cancer of antibody‐producing plasma cells. The pathognomonic laboratory finding is a monoclonal immunoglobulin or free light chain in the serum and/or urine in association with bone marrow infiltration by malignant plasma cells. MM develops from a premalignant condition, monoclonal gammopathy of undetermined significance (MGUS), often via an intermediate stage termed smoldering multiple myeloma (SMM), which differs from active myeloma by the absence of disease‐related end‐organ damage. Unlike MGUS and SMM, active MM requires therapy. Over the past 6 decades, major advancements in the care of MM patients have occurred, in particular, the introduction of novel agents (ie, proteasome inhibitors, immunomodulatory agents) and the implementation of hematopoietic stem cell transplantation in suitable candidates. The effectiveness and good tolerability of novel agents allowed for their combined use in induction, consolidation, and maintenance therapy, resulting in deeper and more sustained clinical response and extended progression‐free and overall survival. Previously a rapidly lethal cancer with few therapeutic options, MM is the hematologic cancer with the most novel US Food and Drug Administration‐approved drugs in the past 15 years. These advances have resulted in more frequent long‐term remissions, transforming MM into a chronic illness for many patients. CA Cancer J Clin 2014;64:422–444. © 2014 American Cancer Society.     

Selective depletion of human myeloma clonogenic stem cells from bone marrow cell preparations by a plasma-cell reactive antibody and complement

The monoclonal antibody MM4 reacts with human myeloma cells from plasma cell dyscrasia (PCD)-derived cell lines and bone marrow (BM) biopsies from PCD patients, but not with normal BM or peripheral blood mononuclear (PBM) cells. We examined cytotoxicity of MM4 and rabbit complement (MM4:C') on mixtures of normal BM mononuclear cells and myeloma cells from three different PCD-derived cell lines, RPMI 8226, GM 1312, or ARH-77. For cell preparations containing 10% myeloma cells, treatment with MM4 (500 micrograms per 10(5) cells, 4 degrees C, 60 min) and two cycles of complement (1:8, 23 degrees C, 2 x 30 min) consistently eliminated 2 logs or more of clonogenic myeloma stem cells, as determined by colony growth assays and limiting dilution analysis (99.4%, 98.9%, and 99.96% reduction of RPMI 8226, GM 1312, and ARH-77 cells, respectively). The majority of normal marrow progenitors were spared (inhibition of CFU-C: 10-13%; BFU-E: 0%). These observations suggest that MM4 may be useful for selective depletion of human myeloma clonogenic stem cells from bone marrow ex vivo.