Multiple Myeloma

Multiple myeloma. also known as plasma cell myeloma or Kahler's disease, is a types of abnormal growth of plasma cells collected in the none marrow where they grow and multiple to interfere with the production of normal blood cells. Paraprotein, an abnormal antibody produced by the plasma cell myeloma not only can cause kidney problem but also interference with the Roche automated total bilirubin assay caused by precipitate formation of that can cause clinical confusion, according to the study by the Harvard Medical School, Boston(1). Other study indicated that the production of paraproteins caused spurious results on individual analytes including total bilirubin (TBIL), direct bilirubin (DBIL), or HDL-cholesterol (HDL-C)(b). there is also a report of a 50 years old
chloride resistant metabolic alkalosis in a patient with hypercalcemia related to Multiple Myeloma (MM)(c).

I. Symptoms
1. Bone and back pain
Bone pain, especially back pain, is a common presenting feature of myeloma patients. According to the study by the University of Arkansas for Medical Sciences, there is a report of three multiple myeloma patients with exacerbations of back pain and referred shoulder pain resulting from vertebral infections(1).

2. Infections
Multiple myeloma (MM) is a malignancy of clonal plasma cells, resulting in an increased production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. According to the study by The John Theurer Cancer Center at Hackensack University Medical Center, patients with MM are at increased risk of infectious complications, particularly streptococcal and staphylococcal infections(2).

3. Fatigue, pain, sleep and mood disturbances, and diminished functional performance.
Cancer-related fatigue and insomnia are common distressing symptoms and may affect mood and performance status. In the study to describe fatigue, sleep, pain, mood, and performance status and the relationships among these variables in 187 patients with newly diagnosed multiple myeloma (MM) and conduct an analysis using the correlates of fatigue, showed that patients with newly diagnosed MM presented with fatigue, pain, sleep and mood disturbances, and diminished functional performance. The regression model, which included all of these variables along with age, sex, and stage of disease, was statistically significant with a large measure of effect. Mood was a significant individual contributor to the model(3).

4. Vertebral fracture
Patients with painful vertebral compression fractures produced by multiple myeloma (MM) often experience reduction in pain after spinal augmentation with kyphoplasty or vertebroplasty, according to teh study by the The University of Texas MD Anderson Cancer Center(4)


5. Others symptoms
According to the study by the Sultan Qaboos University Hospital, Multiple myeloma is a rare, largely incurable malignant disease of plasma cells. Patients usually present with hypercalcemia, renal insufficiency, anemia and/or lytic bony lesions along with a monoclonal protein in the serum and/or urine in addition to an increase in the number of clonal plasma cells in the bone marrow(5). Other study indicated that patients with MM reported a mean decrease (e.g., worsening) between baseline and 1-yr follow-up scores for: quality of life (mean, 68 vs. 55, respectively, P < 0.001; 74% of patients had a deteriorated score), fatigue (33 vs. 39, P < 0.05; 50%), nausea and vomiting (6.3 vs. 13, P < 0.05; 71%), pain (33 vs. 43, P < 0.05; 59%), and dyspnea (17 vs. 33, P < 0.001; 66%). The most bothering symptoms during the past week were tingling hands/feet (32%), back pain (28%), bone aches/pain (26%), pain in arm/shoulder (19%), and feeling drowsy (18%)(6).

II. Causes and Risk factors
A. Causes
1. Monoclonal gammopathy of undetermined significance (MGUS)
Monoclonal gammopathy of undetermined significance (MGUS) has been associated with an increased risk of smoldering multiple myeloma (SMM. Strong evidence showed that multiple myeloma is consistently preceded by a precursor state at the molecular level, there is urgent need to better understand mechanisms that regulate transformation from precursor to full-blown multiple myeloma(7).

2. Genetic abnormalities
a. Dysregulation of c-myc Gene
Dysregulation of c-myc by translocation to the switch regions of the IgH locus occurs in most murine plasmacytomas. Translocations involving 14q32 have been reported in 20-40% of abnormal karyotypes from human multiple myeloma (MM), and involve a variety of loci(8).

b. Gene (IgH)
Chromosome translocations involving the immunoglobulin heavy chain gene (IgH) on 14q32 are a seminal event in the pathogenesis of many B-cell malignancies. According to the study by the New York Presbyterian Hospital-Weill Medical College of Cornell University, , Recurrent Ig translocations identify at least three distinct molecular subtypes of myeloma(9).

c. Chromosome translocations
(11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf))
Four chromosomal partners appear to account for the majority of primary IgH translocations: 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (FGFR3 and MMSET), and 16q23 (c-maf). They are mediated primarily by errors in IgH switch recombination and less often by errors in somatic hypermutation, with the former dissociating the intronic and 3' enhancer(s), so that potential oncogenes can be dysregulated on each derivative chromosome (e.g., FGFR3 on der14 and MMSET on der4). Secondary translocations, which sometimes do not involve Ig loci, are more complex, and are not mediated by errors in B cell specific DNA modification mechanisms(10).

d. Cytogenetic alteration and/or hyperdiploidy
At diagnosis, 96% of cases with multiple myeloma versus 77% of monoclonal gammopathy of undetermined significance cases showed at least one cytogenetic alteration and/or hyperdiploidy(11).

3. Etc.

B. Risk Factors
1. Age
The risk of Multiple myeloma increase with Age and multiple myeloma (MM) is the second most common hematological malignancy in China. According to the study by the Beijing Chaoyang Hospital, Capital Medical University, in the retrospectively analyzed study of 264 newly diagnosed MM patients from the Beijing Chaoyang Hospital showed that the median patient age was 59 years (range, 28-84) and the most common monoclonal protein (42%) was the IgG subtype(12).

2. Gender
In the study to to characterize gender disparities in myeloma, showed that
a. Genetic lesions (13q- trisomy 1q, and an IGH)
Disparities were found in the prevalence of primary genetic lesions with immunoglobulin heavy chain gene (IGH) translocations being more common in women (50% of female patients vs. 38% of male patients, P < 0.001).
b. Hyperdiploidy
Hyperdiploidy is being more common in men (50% female vs. 62% male, P < 0.001)(13).

3. Excess body weight
Excess body weight is a risk factor for multiple myeloma. According to the stdy by the National Institute of Environmental Medicine suggested that excess risk of multiple myeloma (MM) among obese persons could be the result of altered circulating levels of adipokines, polypeptide hormones with pro- and anti-inflammatory properties secreted by adipose tissue as adiponectin may play an important role in obesity-related myelomagenesis(14).

4. Body build or nutritional status
In an exploratory study conducted of common clinical conditions as predictors of subsequent cancer in 143,574 outpatients of a health maintenance organization (in California, USA), suggest that body build or nutritional status may be involved in the development of MM by mechanisms that are presently unknown(15).

5. Race
Epidemiological data have suggested that African Americans (AA) are twice as likely to be diagnosed with multiple myeloma (MM) as compared to European Americans (EA)(16).


III. Complications and diseases associated to Multiple myeloma
A. Complications
1. Deteriorated quality of life
patients with MM reported a mean decrease (e.g., worsening) between baseline and 1-yr follow-up scores for: quality of life (mean, 68 vs. 55, respectively, P < 0.001; 74% of patients had a deteriorated score)(17).

2. Immue dysfucntion
Mesenchymal stem cells (MSCs), a key regulator for immunomodulatory function, have decreased osteogenic potential in MM patients opf that can lead to impaied immunity. According to the study by the Second Affiliated Hospital of Soochow University, T cells from normal donors possessed the ability to promote osteoblastic differentiation of ND-MSCs, but this ability of T cells both directly from MM patients and co-cultured with MM-MSCs was impaired which in turn lose the ability to stimulate osteogenesis of MSCs(18).

3. Osteogenesis imperfecta
Osteogenesis imperfecta (OI) also known as brittle bone disease, is a congenital bone disorder that causes extremely fragile bones.There is a report of a case of osteogenesis imperfecta with multiple fractures already from childhood, myelomatosis was diagnosed at the age of 52 years as a result of a serum M-component (IgG, lambda), Bence Jones proteinuria, myeloma cells in the bone marrow, and osteolytic skeletal lesions of that can lead to erosion of bone mass and fractures. She died 10 months later. A partial postmortem examination of a larger bone lesion confirmed the diagnosis.(19).

4. Renal insufficiency
Renal insufficiency is an independent risk factor in MM. An impaired renal function in light chain associated disorders may be caused by myeloma cast nephropathy (MCN) but also by AL-amyloidosis (AL-A) and monoclonal immundeposition disease (MIDD), according to the study by Heinrich Braun Klinikum Zwickau(20).

5. Anemia
Anemia is a common complication in patients with multiple myeloma (MM) and occurs in more than two thirds of all patients as MM can inetrfere with the production of normal blood cells. According to the study by Department of Medicine I, Wilhelminenspital, the most frequent underlying pathophysiological mechanism is anemia of chronic disease (ACD), relative erythropoietin (EPO) deficiency (due partly to renal impairment) and myelosuppressive effects of chemotherapy, but many other factors may account for or contribute to anemia in myeloma(21).

6. Pseudomonas endocartiditis
There is a report of a case of a is reported a rare case in a 73-year-old man with multiple myeloma who developed endocarditis due to pseudomonas(21a).

Etc.

B. Diseases associated to Multiple myeloma
1. Bone diseases
Multiple myeloma is a plasma cell malignancy characterized by the frequent development of osteolytic bone lesions. According to the study by the University of Pittsburgh, and Division of Hematology/Oncology, Veterans Administration Pittsburgh Healthcare System, Research and Development, the multiple myeloma-induced bone destruction is a result of the increased activity of osteoclasts that occurs adjacent to multiple myeloma cells. This activity is accompanied by suppressed osteoblast differentiation and activity, resulting in severely impaired bone formation and development of devastating osteolytic lesions(22).

2. Bilateral ovarian involvement
Extramedullary spread of multiple myeloma is extremely rare. There is a report of a case of bilateral ovarian involvement in plasma cell myeloma of a 48-year-old Persian woman who experienced constitutional symptoms, bone pain and flashing for one year. Her condition showed multiple myeloma with lytic lesions of the skull, plasma cell infiltration in bone marrow and positive light chain lambda type in serum(23).

3. Gaucher's disease
There is a report of a case of the evolution of a monoclonal gammopathy of undetermined significance to multiple myeloma in a patient with Gaucher's disease of a 64-year-old woman who, 12 years after receiving a diagnosis of Gaucher's disease with concurrent monoclonal gammopathy of undetermined significance, developed worsening thrombocytopenia and bone pain(24).

4. Acetabular osteolysis
There is a report of a case of 71 year old man was operated in December 2005 with a total uncemented hip arthroplasty. Immediate evolution was favourable but at 4 months postoperatively he came with the complaints of left back pain irradiating in the left thigh. X-rays revealed the presence of a lytic lesion around the acetabulum with secondary dispalcement of the acetabular cup. Further investigations ruled out infection and confirmed the presence of multiple myelom(25).

5. Paget Disease (PD)
Although the Coexistence of Paget Disease (PD) and symptomatic Multiple Myeloma (MM) has rarely been described, there is a report of a 73 years old man with a diagnosis of Paget Disease (PD) and symptomatic Multiple Myeloma (MM). PD mimics many of the features of bone destructive process in MM, making differential diagnosis more complicated. In addition, the presence of serious muscolo-skeletal and metabolic complications in both diseases makes management of patients difficult, worsening the prognosis(26).

6. Multiple myeloma associated precursor diseases
Multiple myeloma and chronic lymphocytic leukaemia share common biological and clinical features including the presence of defined precursor conditions (monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis respectively), according to the study by the National Institutes of Health, Bethesda(27).


IV. Misdiagnosis and Diagnosis
A. Misdiagnosis
1. Spinal epidural metastasis
There is a report of a 42-year-old man presented with a one-month history of upper back pain and a two-week history of progressive spastic paraparesis. Thoracic spinal MRI showed an epidural mass with spinal cord compression at T6-8 but no bony involvement. The patient underwent T6-8 laminectomy for decompression. Lumbosacral MRI and CT scans revealed bony abnormalities on the sacrum and left posterior iliac bone. Immunohistochemical studies confirmed the diagnosis of multiple myeloma (MM)(28).

2. Orbital mass
There is a report of a case of a 28-year-old African-American woman presented with new onset of left exophthalmos and diplopia with initially vomputed tomography of the head showed a solitary mass in the left orbit, But excisional biopsy revealed a diffuse infiltrate composed of exclusively λ-restricted monotypic plasma cells based on morphology and immunohistochemistry, consistent with a plasma cell neoplasia. A subsequent staging bone marrow biopsy showed involvement of the bone marrow by λ-restricted monotypic plasma cells, consistent with a plasma cell myeloma. Serum protein electrophoresis and immunofixation studies on the peripheral blood showed a monoclonal band of IgE-λ; thus, an IgE-λ plasma cell myeloma(29).

3. Acute liver diseases
According to the study by St. Vincent's Comprehensive Cancer Center, there is a report of a case of a 55-year-old woman with MM who presented with painless jaundice, mild pruritus, and abnormal liver function tests resembling acute cholestatic hepatitis without the stigmata of chronic liver disease, but clinical manifestations of liver involvement in multiple myeloma (MM) are uncommon. Rare cases of MM present as acute liver disease(30).

4. Pituitary mass lesion
there is a report of a case of a 71-year-old female patient affected by an extramedullary IgG-lambda multiple myeloma presenting as a pituitary mass lesion. The diagnostic approaches confirmed the diagnosis of multiple myeloma and describe treatment outcome after therapy, according to the study by Medizinische Klinik Campus Innenstadt, Klinikum der LMU(31).

5. Intrasellar plasmacytoma
Plasmacytomas are unusual causes of a sellar mass. Occasionally, they can be misdiagnosed as a nonfunctioning adenoma because of radiological and clinical similarities. there is a report of a 70-year-old woman presented with a recurrent hypophysial mass. Initial diagnosis of a nonfunctioning pituitary adenoma was later overruled by a repeat biopsy, which showed a plasmacytoma. The tumor stained positively for CD138 and kappa light chain(32).

6. Pituitary adenoma
There is a report of a case of multiple myeloma which presented as a solitary intrasellar tumor. The initial radiographic and light microscopic findings were interpreted as being consistent with pituitary adenoma. Subsequently, when systemic disease developed and a bone marrow biopsy demonstrated multiple myeloma(33),

7. Chromophobe adenoma
62-year-old woman presenting with intracranial lesion eroding the sella with compression of optic chiasma was found to have plasmacytoma of the pituitary area. At the time of initial surgery, the patient had no biochemical, immunologic or marrow findings of multiple myeloma. The intracranial tumor was interpreted initially as chromophobe adenoma on light microscopy, but the diagnosis of plasmacytoma was established by electron microscopic examination of the tumor(34).


8. Etc.

B. Diagnosis
If you are experience some of the above symptoms, after recording the complete family history and physical examination, the test which your doctor orders may include
1. Standard Blood and urine tests
The aim of the tests are to detect the presence of M proteins of which may be an indication of Multiple myeloma. If M protein is found in the test, additional boold test for beta-2-microglobulin may be necessary for the comfirmation of outcome.

2. Serum Free Light Chain Assays
Free light chain (FLC) assays are important in the diagnosis and monitoring of patients with multiple myeloma (MM). Elevated immunoglobulin free light chain (FLC) level and abnormal FLC ratio are commonly seen in multiple myeloma (MM) and have prognostic implications, accosing to the study by the Division of Hematology, Mayo Clinic, a combination of the risk factors; either abnormal FLC estimate and/or the presence of high-risk IgH translocation, achieved better prognostic stratification. We conclude that patients with IgH translocations have higher FLC levels and abnormal ratios, but the prognostic effect of FLC is only partially explained by translocation status. A system including both these risk factors allows better prediction of outcome(35).

3. Imaging
In multiple myeloma, imaging is required to determine the stage of disease and to anticipate impending bone fractures. According to the study by the Department of Radiology, German Cancer Research Center, modern systems include
a. MRI findings. MRI is most sensitive to both diffuse bone marrow involvement as well as solid plasma cell tumors.
b. Whole-body low-dose CT (WBCT) may replace plain films in the near future, since it is quicker, more sensitive, and is better tolerated by patients. Intramedullary lesions are well seen as long as they are located in long bones where they are surrounded by fat. Diffuse bone marrow infiltration as well as intravertebral lesions, however, are difficult to detect with WBCT in the absence of frank destruction of cancellous bone.
c. PET or PET-CT with 18-fluoro-deoxyglucose (FDG) are insensitive to diffuse bone marrow infiltration, but may help to assess treatment response in solitary or multiple solid plasma cell tumors which have a high FDG uptake before treatment(36).

4. Bone marrow examination
There have been suggestions to eliminate the need for BM examinations as a result of a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. In the study to evaluate of 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)(37).

V. Preventions
A. Diet to prevent Multiple myeloma
1. Turmeric
In the study of Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis, scientists at the The University of Texas MD Anderson Cancer Center, showed that Curcumin suppressed the constitutive IkappaBalpha phosphorylation through the inhibition of IKK activity. Curcumin also down-regulated the expression of NF-kappaB-regulated gene products, including IkappaBalpha, Bcl-2, Bcl-x(L), cyclin D1, and interleukin-6. This led to the suppression of proliferation and arrest of cells at the G(1)/S phase of the cell cycle. Suppression of NF-kappaB complex by IKKgamma/NF-kappaB essential modulator-binding domain peptide also suppressed the proliferation of MM cells. Curcumin also activated caspase-7 and caspase-9 and induced polyadenosine-5'-diphosphate-ribose polymerase (PARP) cleavage. Curcumin-induced down-regulation of NF-kappaB, a factor that has been implicated in chemoresistance, also induced chemosensitivity to vincristine and melphalan(38)

2. Green tea
(-)-epigallocatechin-3-gallate extracted from green tea have exerted the inhibitory effect against multiple myeloma cells. Dr. Shammas MA and the research team at Veterans Administration Boston Health Care System, and Dana Farber Cancer Institute/Harvard Medical School, showed that EGCG interacts with the 67-kDa laminin receptor 1 (LR1), which is significantly elevated in myeloma cell lines and patient samples relative to normal PBMCs. RNAi-mediated inhibition of LR1 resulted in abrogation of EGCG-induced apoptosis in myeloma cells, indicating that LR1 plays an important role in mediating EGCG activity in MM while sparing PBMCs. Evaluation of changes in gene expression profile indicates that EGCG treatment activates distinct pathways of growth arrest and apoptosis in MM cells by inducing the expression of death-associated protein kinase 2, the initiators and mediators of death receptor-dependent apoptosis (Fas ligand, Fas, and caspase 4), p53-like proteins (p73, p63), positive regulators of apoptosis and NF-kappaB activation (CARD10, CARD14), and cyclin-dependent kinase inhibitors (p16 and p18)(39)

3. Skins and seed of grape and wine
In the study to investigate the effect of Resveratrol trans-3, 4', 5,-trihydroxystilbene, insuppressing the multiple myeloma (MM), found that Resveratrol activated IRE1α as evidenced by XBP1 messenger RNA splicing and phosphorylation of both IRE1α and its downstream kinase c-Jun N-terminal kinase in MM cells. These responses were associated with resveratrol-induced cytotoxicity of MM cells. Resveratrol selectively suppressed the transcriptional activity of XBP1s while it stimulated gene expression of the molecules that are regulated by the non-IRE1/XBP1 axis of the ER stress response. Luciferase assays indicated that resveratrol suppressed the transcriptional activity of XBP1s through sirtuin 1, a downstream molecular target of resveratrol. Chromatin immunoprecipitation studies revealed that resveratrol decreased the DNA binding capacity of XBP1 and increased the enrichment of sirtuin 1 at the XBP1 binding region in the XBP1 promoter(40)

4. Carrot
Retinoic acid found of a measure amount in carrot has a potential in prevent and treat Myeloma (Multiple Myenoma). Study showed that The inhibitory effect of cRA was significantly superior to tRA (P = 0.0129) and IFN-alpha, similar to IFN-gamma and DEX. The combinations of cRA + IFN alpha, tRA + IFN-gamma, tRA + DEX did not show any synergistic effect on myeloma proliferation. In contrast, the combination cRA + DEX (0.29 +/- 0.04, M +/- SEM) markedly increased the effect of both cRA and DEX used as single agents. Ig synthesis was not significantly affected by CRA, tRA, IFN-gamma and the combination tRA + IFN-gamma. As expected, only IFN-alpha (P = 0.002) and DEX (P < 0.001) inhibited Ig production(41).

5. Black tea
In the study to assess the effect of its polyphenols, theaflavins found in black tea on the tumor's cellular proteasome function, an important biological target in cancer prevention, found that black tea extract (T5550) enriched in theaflavins inhibited the chymotrypsin-like (CT) activity of the proteasome and proliferation of human multiple myeloma cells in a dose-dependent manner(41a)

B. Phytochemicals to prevent Multiple myeloma
1. Curcumin
Curcumin (diferuloylmethane), a yellow pigment in turmeric, has been shown to inhibit the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor closely linked to chemoresistance in multiple myeloma cells. According to the study by The University of Texas M. D. Anderson Cancer Center,, curcumin inhibited the proliferation of human multiple myeloma cells regardless of their sensitivity to dexamethasone, doxorubicin, or melphalan. Curcumin also potentiated the apoptotic effects of thalidomide and bortezomib by down-regulating the constitutive activation of NF-kappaB and Akt, and this correlated with the suppression of NF-kappaB-regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, TRAF1, cIAP-1, XIAP, survivin, and vascular endothelial growth factor(42).

2. Epigallocatechin-3-gallate (EGCG)
Epigallocatechin-3-gallate (EGCG), a polyphenol extracted from green tea, is an antioxidant with chemopreventive and chemotherapeutic actions. Based on its ability to modulate growth factor-mediated cell proliferation.(43).

3. Resveratrol
Resveratrol exerts its chemotherapeutic effect on human MM cells through mechanisms involving the impairment of the pro-survival XBP1 signaling and the activation of pro-apoptotic ER stress response(44).

4. Retinoic acid
All-trans retinoic acid (ATRA) is a derivative of vitamin A. ATRA inhibits the growth of human myeloma cell lines and freshly isolated myeloma cells in vitro mainly by down-regulating interleukin-6 receptor. In the study of patients with stable multiple myeloma after conventional chemotherapy received ATRA alone for 2 months, followed by a combination of ATRA and the chemotherapy regimen, showed that the bone marrow cells of responding patients were sensitive to ATRA in vitro. These results show that ATRA alone is not effective to treat multiple myeloma. There may be some beneficial effect of ATRA in combination chemotherapy in selected patients who have activated IL-6 signalingm, according to Turku University Central Hospital(45).

C. Antioxidants to prevent Multiple myeloma
According to the study by University of Iowa, Iowa Cityprovides, there is stronge evidence that increases in MnSOD expression mediate IL-6-induced resistance to Dex and radiation in myeloma cells. The results indicate that inhibition of antioxidant pathways could enhance myeloma cell responses to radiotherapy and/or chemotherapy(46).
According to the study by the Chinese Academy of Medical Sciences and Peking Union Medical College, 4 antioxidant constituents from black tea, namely theaflavin (TF1), theaflavin-3-gallate (TF2A), theaflavin-3'-gallate (TF2B) and theaflavin digallate (TF3) have stronger antioxidant activity than that of BHT (Butylated hydorxytoluene)(47).
1. Theaflavin (TF1)
Black tea extract (T5550) enriched in theaflavins inhibited the chymotrypsin-like (CT) activity of the proteasome and proliferation of human multiple myeloma cells in a dose-dependent manner, according to Chinese Academy of Medical Sciences and Peking Union Medical College(48).

2. Vitamin A
Retinoids are vitamin A derivatives that critically regulate several physiological and pathological processes, including immune functions and cancer development. According to the study by the Seràgnoli University of Bologna, in vitro treatment with retinoids decreases bcl-2 protein expression and enhances dexamethasone-induced cytotoxicity and apoptosis in multiple myeloma cells(49).

3. Quercetin and myricetin
Dietary flavonoids, quercetin and myricetin, which are abundant in plasma, inhibited bortezomib-induced apoptosis of primary CLL and malignant B-cell lines in a dose-dependent manner. This inhibitory effect was associated with chemical reactions between quercetin and the boronic acid group, -RB(OH)2, in bortezomib. The addition of boric acid diminished the inhibitory effect of both quercetin and plasma on bortezomib-induced apoptosis. The protective effect was also reduced when myeloma cell lines, but not B-cell lines, were preincubated with quercetin, indicating a direct effect of quercetin on myeloma cells. At high doses, quercetin itself induced tumor cell death(50).

4. Betulinic acid
According to the study by The University of Texas M. D. Anderson Cancer Center, in the study to investigate Whether betulinic acid, a pentacyclic triterpene, can modulate the STAT3 pathway, was investigated in human multiple myeloma (MM) cells, indicated that betulinic acid inhibited constitutive activation of STAT3, Src kinase, JAK1 and JAK2. Pervanadate reversed the betulinic acid-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase (PTP). Furthermore, betulinic acid induced the expression of the PTP SHP-1 and silencing of the SHP-1 gene abolished the ability of betulinic acid to inhibit STAT3 activation and rescued betulinic acid-induced cell death. Betulinic acid also downregulated the expression of STAT3-regulated gene products such as bcl-xL, bcl-2, cyclin D1 and survivin(50a)

VI. Treatments
A. In conventional medicine perspective
There is no cure for multiple myeloma. The aim of the treatment is to relieve the symptoms and bring back the normal quality of life in the patients.
A.1. Standard treatment
Thalidomide (T) and lenalidomide (R) had been used as first line therapy for previously untreated myeloma. In the study to to assess the treatment effects of lenalidomide-versus thalidomide-based regimen via common comparators, found that lenalidomide seemed to be a more potent and less toxic agent than thalidomide in the treatment of patients with multiple myeloma. Further the direct head-to-head trial comparing lenalidomide versus thalidomide is clearly warranted(51a). Other study indicated that LBCT is more efficient in the treatment of MM and has significant role in serum protein alterations especially in the reduction of M-protein in the MM patients(51b).
1. Immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib, carfilzomib) and chemotherapy
Immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib, carfilzomib) can induce apoptosis of myeloma plasma cells and suppress cytokine release and metabolic ways which sustain the disease. These novel agents demonstrate substantial activity either alone or as part of a range of combination regimens. MM therapy is now based on 1 or 2 new drugs plus standard chemotherapy, according to Azienda Ospedaliera Careggi(51). Other study indicated that although high-dose therapy with stem cell transplantation (SCT) and novel targeted therapies (thalidomide, its more potent analogues, and bortezomib) represent two approaches for overcoming resistance of multiple myeloma (MM) cells to conventional therapies, Gene expression profiling (GEP) will help to improve the management of MM not only by identifying prognostic subgroups but also by defining molecular pathways that are associated with these subgroups and that are possible targets for future therapies(52).

2. Corticosteroids
Corticosteroids may be used in patients of multiple myeloma with Disorder of glucose metabolism regulation. According to the study by Interní hematoonkologická klinika Lékarské fakulty MU a FN Brno, The deterioration of glucose tolerance leads to worsening of morbidity and mortality of seriously ill patients. In glucocorticoid-induced diabetes mellitus the highest levels of glucose are seen in the afternoon, in the evening and postprandially: Normal levels of glucose are seen in the morning. Excluding 11 patients with diabetes (16%), we idenfied 7 (10%) patients with normal glucose tolerance, 13 (19%) patients with impaired fasting glucose or/and impaired glucose tolerance and glucocorticoid-induced diabetes mellitus we found in 37 (55%) patients treated in our department with diagnosis of myeloma multiplex in the year 2004 intermitently with 40 mg dexamethason(53).

3. Radiation therapy for local symptoms
In the review of the experience at the University of Arizona in an effort to define the minimum effective radiation dose for durable pain relief in the majority of patients with symptomatic multiple myeloma of of 101 patients with multiple myeloma irradiated for palliation at the University of Arizona between 1975 and 1990, found that rtherapy is effective in palliating local symptoms in multiple myeloma. A total dose of 10 Gy should provide durable symptom relief in the majority of patients(54).

4. Stem cell transplantation
A high dose of melphalan followed by autologous stem cell transplantation (ASCT) is considered as the standard therapy for multiple myeloma(55).

5. Treatments and Supportive care
Treatment of younger fit patients with Multiple myeloma is with induction therapy consisting of steroids with one or more novel anti-myeloma agents followed by high dose melphalan and autologous stem cell transplantation, while older and less fit patients are treated with melphalan-based combination chemotherapy. Supportive care is of paramount importance and includes the use of bisphosphonates, prophylactic antibiotics, thrombosis prophylaxis and the use of hematopoietic growth factors along with the treatment of complications of disease and its therapy(56).

A.2. Initial therapy for myeloma
Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. The choice of initial therapy is affected by two main factors: risk-stratification and eligibility for autologous hematopoietic cell transplantation (HCT) and it has the potential for cure, but as a cost of increased treatment-related mortality.
The introduction of plerixafor as a peripheral blood stem cell mobilization agent has allowed more patients with multiple myeloma, non-Hodgkin's lymphoma, and Hodgkin's disease to mobilize sufficient hematopoietic progenitor cells (HPCs) to proceed to autologous transplantation, according to the study by the Columbia University, University of Pennsylvania,(57).
Hematopoietic stem cell transplantation (HSCT) is an effective therapy for hematological diseases such as lymphoma and multiple myeloma. According to the Unidad de Hematología Intensiva, Hospital del Salvador, 6 patients with Hodgkin lymphoma, three with multiple myeloma and one with a diffuse large B cell lymphoma were transplanted. Age range was 19 to 48 years and five patients were male. An average of 2.2 aphereses per patient was required. The CD 34 stem cell collection was 5.06 x 10(6) x Kg. The conditioning regimes were BEAM (carmus-tine, etoposide, cytosine arabinoside, melphalan) and melphalan 200 according to the underlying disease. Seventy percent of the patients developed mild to moderate mucositis and 50% had febrile neutropenia, with good response to treatment. In two cases there was an association with influenza. The engraftment of neutrophils and platelets was achieved on day +10 and +11 respectively. At follow-up until day +100, there was no morbidity or mortality(58).

A.3. Treatments for relapsed or treatment-resistant multiple myeloma
According to the study to estimate the efficacy of thalidomide monotherapy in the treatment of refractory and relapsed cases of multiple myelomaby Katedry i Kliniki Hematologii i Transplantacji Szpiku Kostnego Slaskiej Akademii Medycznej w Katowicach, found that the good tolerance of the drug, especially in lower doses, and lack of myelosuppression effect allows to expect, that the combination of thalidomide with other cytostatic drugs will improve the efficacy in patients with refractory or relapsed myeloma(59).
Other study in an assessment to compare the costs of two recent treatments (bortezomib (BORT) and lenalidomide plus dexamethasone (LEN/DEX)) for relapsed/refractory multiple myeloma (rrMM), from the perspective of a United States (US) payer, found that drug costs for the treatments were very similar, differing by under $10 per day. Medical and AE management costs for BORT were higher by more than $40 per day. Treatment with BORT had annual excess total costs of >$17,000 compared with LEN/DEX. A cost advantage for LEN/DEX was maintained across a variety of sensitivity analyses. Total cost per month without progression was 11% lower with LEN/DEX. rrMM treatment with BORT and LEN/DEX had comparable drug costs, total treatment costs for BORT were higher due to ongoing direct medical and AE management costs. Total costs per outcome (a month without disease progression) were lower for LEN/DEX, according to the study by Cedars-Sinai Samuel Oschin Cancer Center(60).

A.4. Treatments of symptoms
1. Painful vertebral compression
Patients with painful vertebral compression fractures produced by multiple myeloma (MM) often experience reduction in pain after spinal augmentation with kyphoplasty or vertebroplasty. According to the study by The University of Texas MD Anderson Cancer Center, pain reduction after spinal augmentation with vertebroplasty or kyphoplasty was positively associated with reduction in other patient-reported cancer-related symptoms. Future studies of these augmentation procedures should measure multiple symptoms, in addition to pain and functional status(61). Patients of Multiple myeloma with common symptoms of back back may be prescribed by apin reliever or a back brace.

2. Infection
Multiple myeloma (MM) is a malignancy of clonal plasma cells, resulting in an increased production of ineffective immunoglobulins with suppression of non-involved immunoglobulins. According to the study by The Abbott Northwestern Hospital, Minneapolis, administering TMP-SMX for the first 2 months of initial chemotherapy is effective, inexpensive prophylaxis for early bacterial infection in multiple myeloma(62).
For parients of Mutliple myeloma with complication of infection, antibiotics may be necessary

3. Renal impairment
Renal impairment is a common complication of multiple myeloma (MM) and is supported in virtually all patients by a tubulointerstitial pathology that results from high serum concentrations of monoclonal free light chains (FLCs). According to the study by the UCL Centre for Nephrology, Royal Free Hospital, The mainstay of therapy is presently the removal of aggravating factors (dehydration, hypercalcaemia, nephrotoxic drugs) and the prompt institution of rapidly acting novel chemotherapy combinations. This approach allows the rescue of kidney function in more than two-thirds of patients. High cut-off haemodialysis dialysers may potentially add clinical benefits and the outcomes of controlled trials are eagerly awaited(63).
But other study indicated that if a patient with cast nephropathy and severe acute kidney injury remains dialysis-dependent, the prognosis is poor. A prompt diagnosis and commencement of effective chemotherapy is a critical determinant of renal recovery. A randomized controlled trial of high cut-off haemodialysis in patients with cast nephropathy, who all receive bortezomib-based chemotherapy, is underway(64).

4. Bone diseases
Bone disease associated with multiple myeloma(MM)is characterized by increased osteoclast activity and suppressed osteoclast function because of some factors produced by myeloma cells, leading to severe osteolytic lesions. According to the study by Tochigi Cancer Center, Tochigi, Japan, good control of MM itself is very important in order to manage bone lesions caused by MM. Bisphosphonate(BP), a potent inhibitor of osteoclast activity and function, should be used as adjunctive therapy for MM bone disease. Recently, the MRC Myeloma IX trial demonstrated improved survival and delayed disease progression with the use of an intravenous BP, zoledronate, in patients with newly diagnosed MM. Its results may lead to an alteration of guidelines for BP treatments of MM(65).
Other study also indicated that of treatment of bone diseases of which intravenous pamidronate and zoledronic acid are equally effective in reducing SREs, whereas zoledronic acid seems to offer survival benefits in symptomatic patients. Caution is needed to avoid adverse events, such as renal impairment and osteonecrosis of the jaw. Novel antiresorptive agents, such as denosumab, have given encouraging results, but further studies are needed before their approval for managing myeloma bone disease. Combination approaches with novel antimyeloma agents, such as bortezomib (which has anabolic effects on bone) with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents, antisclerostin drugs, or sotatercept, may favorably alter our way of managing myeloma bone disease in the near future(66).

5. Anemia
Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. According to the Department of Hematology and Immunology, Vrije Universiteit Brussel, Brussels, treatment options for anemic myeloma patients include red blood cell (RBC) transfusions and recombinant human erythropoietin (rHuEPO).
5.1. Red blood cell transfusions convey an immediate effect and rapidly increase the patient's hemoglobin level. Unfortunately, effects of RBC transfusions are only transient and can be associated with several risks, including infections and mild to even life-threatening immunologic reactions.

5.2. rHuEPO is biologically equivalent to the human endogenous hormone EPO, and its application leads to an increase of hemoglobin levels over an extended time without the risks of blood transfusions. Several studies reported a significant improvement of erythropoiesis, reduction in transfusion need, and improved quality of life by using rHuEPO as long-term treatment of myeloma-associated anemia. Recently, an international expert panel recommended the use of rHuEPO for anemic myeloma patients where other possible causes of anemia have been eliminated(67).


B. In Herbal medicine perspective
1. Grape seed and skin
In the study to investigate whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma (MM) cells by interfering with NF-kappaB and STAT3 pathways, showed that resveratrol inhibited the proliferation of human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT(68).

2. Cayenne
Capsaicin is a constituent of green and red peppers inhibited constitutive activation of STAT3 in multiple myeloma cells in a dose- and time-dependent manner, with minimum effect on STAT5. Capsaicin also inhibited the interleukin-6-induced STAT3 activation. The activation of Janus-activated kinase 1 and c-Src, implicated in STAT3 activation, was also inhibited by the vanilloid, with no effect on extracellular signal-regulated kinase 1/2 activation. Pervanadate reversed the capsaicin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Capsaicin down-regulated the expression of the STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, and vascular endothelial growth factor. Finally, capsaicin induced the accumulation of cells in G(1) phase, inhibited proliferation, and induced apoptosis, as indicated by caspase activation. Capsaicin also significantly potentiated the apoptotic effects of Velcade and thalidomide in multiple myeloma cells. When administered i.p., capsaicin inhibited the growth of human multiple myeloma xenograft tumors in male athymic nu/nu mice, according to the study by The University of Texas M. D. Anderson Cancer Center(69).

3. Tripterygium Wilfordi (Thunder of God vine) and Celastrus Regelii
Celastrola, is a remedial ingredient isolated from the root extracts of Tripterygium Wilfordi (Thunder of God vine) and Celastrus Regelii. According to the study by the National University of Singapore, celastrol inhibited the proliferation of MM cell lines regardless of whether they were sensitive or resistant to bortezomib and other conventional chemotherapeutic drugs. It also synergistically enhanced the apoptotic effects of thalidomide and bortezomib. This correlated with the down-regulation of various proliferative and anti-apoptotic gene products including cyclin D1, Bcl-2, Bcl-xL, survivin, XIAP and Mcl-1. These effects of celastrol were mediated through suppression of constitutively active NF-κB induced by inhibition of IκBα kinase activation; and the phosphorylation of IκBα and of p65. Celastrol also inhibited both the constitutive and IL6-induced activation of STAT3, which induced apoptosis as indicated by an increase in the accumulation of cells in the sub-G1 phase, an increase in the expression of pro-apoptotic proteins and activation of caspase-3(70).

4. Nigella sativa
Thymoquinone(TQ), is a phytochemical compound of the plant Nigella sativa. According to the study by the National University of Singapore, TQ inhibited both constitutive and IL-6-inducible STAT3 phosphorylation which correlated with the inhibition of c-Src and JAK2 activation. Vanadate reversed the TQ-induced down-regulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that TQ can induce the expression of Src homology-2 phosphatase 2 that correlated with suppression of STAT3 activation. TQ also down-regulated the expression of STAT3-regulated gene products, such as cyclin D1, Bcl-2, Bcl-xL, survivin, Mcl-1 and vascular endothelial growth factor. Finally, TQ induced the accumulation of cells in sub-G1 phase, inhibited proliferation and induced apoptosis, as indicated by poly ADP ribose polymerase cleavage. TQ also significantly potentiated the apoptotic effects of thalidomide and bortezomib in MM cells.(71)

C. In traditional Chinese medicine perspective
A number of natural products isolated from Chinese herbs have been found to inhibit proliferation, induce apoptosis, suppress angiogenesis, retard metastasis and enhance chemotherapy, exhibiting anti-cancer potential both in vitro and in vivo, including flavonoids (gambogic acid, curcumin, wogonin and silibinin), alkaloids (berberine), terpenes (artemisinin, β-elemene, oridonin, triptolide, and ursolic acid), quinones (shikonin and emodin) and saponins (ginsenoside Rg3), which are isolated from Chinese medicinal herbs(72).
1. Sophora roots
Multiple myeloma (MM) is a hematological malignancy characterized by the uncontrolled proliferation of clonal plasma cells in bone marrow in the elderly. Matrine, a main alkaloid if Sophora roots, has been shown to inhibit cellular proliferation and induce apoptosis of various cancer cells. According to the study by the First Affiliated Hospital of Wenzhou Medical College, matrine could exert antiproliferative effects on myeloma cells and induce apoptosis of myeloma cells in vitro. The induction of apoptosis appeared to proceed via the mitochondrial pathway, including down-regulation of Bcl-2/Bax ratio, loss of Deltapsim, release of cyt c from mitochondria to cytosol, and activation of caspase-3(73).

2. the root and rhizomes of Rheum palmatum L.
Emodin is an active component of a traditional Chinese and Japanese medicine isolated from the root and rhizomes of Rheum palmatum L. According to the study by the Faculty of Pharmaceutical Sciences, Hoshi University, emodin significantly induces cytotoxicity in the human myeloma cells through the elimination of myeloid cell leukemia 1 (Mcl-1). Emodin inhibited interleukin-6-induced activation of Janus-activated kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3), followed by the decreased expression of Mcl-1. Activation of caspase-3 and caspase-9 was triggered by emodin, but the expression of other antiapoptotic Bcl-2 family members, except Mcl-1, did not change in the presence of emodin(74).

3. Scutellaria radix
In the study to investigate the effects of the traditional Chinese herbal medicines Huang-Lian-Jie-Du-Tang (HLJDT), Gui-Zhi-Fu-Ling-Wan (GZFLW), and Huang-Lian-Tang (HLT) on the proliferation and apoptosis of myeloma cells by the Yamaguchi University, indicated that HLJDT inhibited the proliferation of myeloma cell lines and the survival of primary myeloma cells, especially MPC-1- immature myeloma cells, and induced apoptosis in myeloma cell lines via a mitochondria-mediated pathway by reducing mitochondrial membrane potential and activating caspase-9 and caspase-3. Further experiments confirmed that Scutellaria radix was responsible for the suppressive effect of HLJDT on myeloma cell proliferation, and the baicalein in Scutellaria radix showed strong growth inhibition and induction of apoptosis in comparison with baicalin or wogonin(75).

4. Cantharidin (CTD)
Cantharidin (CTD) a vesicant produced by beetles in the order Coleoptera has a long history in both folk and traditional medicine. In the study to investigate the possibility of CTD as a novel therapeutic agent for the patients with multiple myeloma, showed that CTD inhibited the cellular growth of human myeloma cell lines as well as freshly isolated myeloma cells in patients. Cultivation with CTD induced apoptosis of myeloma cells in a cell-cycle-independent manner. Treatment with CTD induced caspase-3, -8, and -9 activities, and it was completely blocked by each caspase inhibitor. We further examined the effect of CTD on the IL-6 signaling pathway in myeloma cells, and found that CTD inhibited phosphorylation of STAT3 at tyrosine 705 residue as early as 1 h after treatment and down-regulated the expression of the antiapoptotic bcl-xL protein. STAT3 directly bound and activated the transcription of bcl-xL gene promoter, resulting in the induction of the expression of bcl-xL in myeloma cells(76).
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