Multiple myeloma

The homogeneous immunoglobulin is identified in the blood is often referred to as a M component. In approximately 60% of patients the M component is IgG, in 20% - 24%, IgA,; rarely it is IgM, IgD, or IgE. In the remaining 15% - 20% of cases, the plasma cells produce only kappa or lambda light chains, which because of their low molecular weight, are readily excreted in the urine, where they are termed as Bence Jones proteins. In these patients, BJ proteinuria without serum M component is present (light chain disease). However, in up to 80% of patients, the malignant plasma cells synthesize complex immunoglobulin molecules as well as excess light chains, therefore, both BJ proteins and serum M component are present.

M components may be indicative of B cell malignancy, it should be remembered that M components are also seen in otherwise normal elderly persons, a condition called monoclonal gammopathy of undetermined significance.

Variants: Plasma cell dyscrasias can be divided into 6 major variants:

1. Multiple myleoma

   1. Localized plamacytoma

      • Single lesion in the skeleton or in the soft tissues.

      • Tumors in the sinuses, nasopharynx, and larynx.

      • Modest elevations of M protein.

      • Solitary skeletal myelomas usually have occult lesions elsewhere.

      • Stable for several years, but after a lapse of 5 - 10 years, most develop disseminated disease.

      • Cured by local resection. Spread is less common.

   2. Lymphoplasmacytic lymphoma

      • Mixed proliferation of B cells ranging from small round lymphocytes to plasmacytic lymphocytes (so called plymphocytes) to plasma cells.

      • Associated with chromosomal translocations involving the IgH locus on chromosome 14 and the PAX5 gene on chromosome 9, which encodes a transcription factor that normally regulates B-cell differentiation.

      • M component is IgM, with IgA and IgG in few.

        • IgM because of its size and excess results in hyperviscosity syndrome - Waldenstrom macroglobulinemia.

      • Diffuse infiltration of lymphoid organs.

      • Lytic bone lesion are not seen, unlike myeloma

      • Affects older persons (60 - 70 years).

   3. Heavy-chain disease

      • Heavy chain disease is a group of very rare plasma lymphocytic malignancies characterized by production of paraproteins that consists solely of the heavy chain moiety of immunoglobulins.

      • Heavy chains of IgA, IgG, and IgM constitute the paraprotein which serves as a marker for 3 distinct plasmalymphocytic malignancies associated with different clinical manifestations.

        • IgA subtype: The IgA subtype is a form of GI mucosa associated lymphoid tissue MALT lymphoma.

        • IgG subtype, known as Franklin's disease, is a lymphoproliferative disease with systemic symptoms and palatal and uvula edema from involvement of the Waldemyer's ring pharyngeal lymphoid tissue.

        • IgM subtype resembles CLL.

   4. Primary or immunoctye-associated amyloidosis

      • Monoclonal proliferation of plasma cells withe excessive production of light chains.

      • The amyloid deposit type (AL type) consist of degraded light chains.

2. Monoclonal gammopathy of undetermined significance (MGUS).

   2. • M proteins can be detected in the serum of 1% - 3% of asymptomatic, healthy persons older than age 50 years.

      • No associated disease

      • Approximately 20% of patients with MGUS develop a well-defined plasma cell dyscrasia (myeloma, lymphoplasmacytic lymphoma, or amyloidosis) over a period of 10 to 15 years.

      • Dx of MGUS must be made with caution and after careful exclusion of all other specific forms of monoclonal gammopathies.

      • MGUS patients have < 3 g/dL, of monoclonal protein in the serum and no BJ proteinuria.

Benign monoclonal proteins were first described by Dr. Jan Waldenström in 1960 after he detected abnormal narrow hypergammaglobulinemia bands in serum protein electrophoresis (SPEP) samples from healthy individuals.1 The term monoclonal gammopathy of undetermined significance (MGUS) was coined by Dr. Robert Kyle in 1978 to describe an asymptomatic plasma cell dyscrasia characterized by a monoclonal protein of <3 gm/dL, bone marrow plasma cells <10 percent and the absence of end-organ damage commonly associated with multiple myeloma.2 MGUS is a relatively common condition with a prevalence of three to five percent in the adult population over the age of 50 years.3 SPEP is a frequently performed laboratory test ordered by primary-care physicians evaluating patients with anemia, by nephrologists evaluating patients with renal insufficiency (possibly with associated proteinuria), and by neurologists evaluating patients with peripheral neuropathy. When the SPEP reveals a monoclonal protein, referral to a hematologist usually follows. Therefore, it is part of routine practice for hematologists to see patients with monoclonal proteins that are initially identified as the result of screening assessments. The hematologist must then decide which additional diagnostic studies are warranted, and based upon those results, develop management and follow-up plans.

Although it accounts for only 15 to 20 percent of MGUS cases (that also includes IgG-MGUS, IgA-MGUS and light chain-MGUS), IgM-MGUS poses a unique diagnostic challenge because of the association of monoclonal IgM proteins with B cell lymphoproliferative disorders (particularly Waldenström’s macroglobulinemia, WM), amyloidosis and peripheral neuropathy.

Three distinct classes of MGUS are recognized: Non-IgM-MGUS (essentially IgG-MGUS or IgA-MGUS as both IgD-MGUS and IgE-MGUS are fleetingly rare), light chain-MGUS, and IgM-MGUS.5, 6 (Table) Distinguishing among these sub-groups is important as doing so directs both the diagnostic plan and the follow-up recommendations; facilitates identification of diseases associated with MGUS; and impacts on management recommendations and prognosis. Although the majority of patients with IgM-MGUS will have a benign course, it is critical for the clinician to rule out a concurrent associated disease and to monitor for progression or transformation into a distinct entity that requires specific therapy.

The Risk of MGUS Progression

Unstratified, patients with non-IgM MGUS have approximately a one percent per year risk of their disease transforming into multiple myeloma; however, the risk of transformation is double in patients with IgM MGUS. Risk for transformation can be more precisely stratified based on three parameters: IgG subtype vs. non-IgG subtype; M protein concentration <1.5 gm/dL vs. ≥1.5 gm/dL; and normal vs. abnormal serum free light chain ratio.7 Stratification of risk can help guide the diagnostic evaluation and follow-up recommendations.

IgM MGUS not only has a higher risk of transformation than non-IgM MGUS, but also the spectrum of diseases associated with IgM MGUS transformation is broader than that of non-IgM MGUS. Whereas non-IgM MGUS can progress into smoldering and active MM and AL amyloidosis, IgM MGUS can transform into WM, AL amyloidosis, and less commonly, IgM smoldering myeloma or IgM multiple myeloma.8 For this reason, patients with IgM MGUS require closer follow-up than patients with non-IgM MGUS, and from a conceptual perspective, IgM-MGUS can be thought of as a “lymphoproliferative” MGUS while non-IgM MGUS behaves as a “plasma cell proliferative” MGUS.

Special Concerns for IgM: MGUS

Neurologists routinely screen patients with peripheral neuropathy for the presence of a monoclonal protein, and approximately five to 10 percent of such patients will be found to have an M protein by SPEP. A causal relationship between MGUS and peripheral neuropathy is supported by association of peripheral neuropathy with other plasma cell dyscrasias including WM, MM, AL amyloid and POEMS (polyneuropathy, organomegaly, endoocrinopathy, monoclonal gammopathy, skin changes). The peripheral neuropathy of MGUS is classically bilateral, peripheral and sensory with electrophysiologic studies showing a demyelinating pattern; and in patients with progressive, debilitating disease, biopsy may reveal axonal loss. Although peripheral neuropathy can occur with all forms of MGUS, it is most commonly associated with IgM-MGUS. Demonstration of IgM anti-myelin-associated glycoprotein (MAG) antibodies supports a causal relationship between IgM-MGUS and polyneuropathy but is not essential for the diagnosis. Because peripheral neuropathy can be caused by other processes that may co-exist with IgM-MGUS, the clinician is often faced with the dilemma of whether to assign the neuropathy to MGUS, and if so, what to do about it. The decision can be guided by the observations that the neuropathy associated with IgM-MGUS is characteristically a relatively benign, slowly progressive sensory process (although some cases can be severe and debilitating). Management is challenging as effective therapy is lacking. A minority of patients respond to rituximab and other immunomodulatory treatments are generally ineffective.9 As is the case with other plasma cell dyscrasia-associated neuropathies, the M protein concentration in IgM-MGUS-associated peripheral neuropathy does not correlate with disease severity, arguing against the use of myeloma-directed therapy to reduce the plasma cell burden as a treatment strategy for the neuropathy of IgM-MGUS.

Association with AL amyloid: This complex disease can be associated with any form of myeloma, although usually one of the two processes dominates the clinical picture. That is to say that patients typically have either a myeloma-phenotype manifested by some combination of hypercalcemia, renal insufficiency, anemia, and skeletal involvement or an amyloid phenotype characterized by organ (liver, heart, kidney) infiltration by the pathologic immunoglobulin light chain. AL amyloid is more commonly associated with IgM-MGUS than other forms of MGUS. Thus, it is imperative that AL amyloid be carefully considered when evaluating patients with an IgM monoclonal protein.

Association with Waldenstrom's Macroglobulinemia: Classified as a lymphoplasmacytic lymphoma that originates from the lymphocytes in the bone marrow. It iis associated with an IgM paraprotein that increases the serum viscosity. The hallmark of this disease is an IgM monoclonal protein, lymphoadenopathy, hepatosplenomegally, and bone marrow involvement by plasmacytoid lymphocytes. Frank disease may be preceded by a relatively asymptomatic smoldering phase in which IgM MGUS is the only apparent clinical manifestation. ESR is very high because rouleaux formation is excessive in the face of IgM paraprotein. The symptoms of hyperviscosity include headache, confusion, mucosal bleeding, hypoxia from sludging of blood, tissue ischemia, and interference with platelet function. Hepatosplenomegaly may occur along with peripheral neuropathy but bone disease and renal disease are absent. Plasmapheresis is the usual treatment. Disease is indolent with a favorable prognosis.

Association with other B-cell lymphoproliferative disorders: Although IgM-MGUS is more commonly associated with WM, it can be observed in association with another B cell lymphoproliferative disease such as CLL or non-Hodgkin lymphoma. As indicated in the algorithm (Figure), determining if organ damage is attributable to the M protein is critical, as in most cases the monoclonal protein simply “co-exists” with the lymphoproliferative disorder. Although the M protein may be discovered first as part of a laboratory evaluation, it is not usually the presenting clinical manifestation of lymphoproliferative diseases other than WM.

Association with IgM MM: This is a rare form of myeloma that is genuinely distinct from WM. IgM MM is distinguished from WM primarily by skeletal involvement (lytic bone lesions) in the former, but genetic studies may also be informative [e.g., t(4:14) in IgM MM and somatic mutation of MYD88 in WM].

Suggested Approach to the Evaluation of Patients with an IgM M Protein.

The strategy that I use in the evaluation of patients with an IgM monoclonal protein is described below and illustrated in the figure.

1. History – This remains a critical aspect of the evaluation, as symptoms elicited from a careful history focus attention on specific issues that require further investigation. Indeed, even subtle symptoms become important when the differential diagnosis includes such a wide spectrum of disorders as amyloidosis, POEMS, multiple myeloma, and lymphoma. Key symptoms to address include the following:◦Constitutional (weight loss, extreme fatigue) – Such symptoms suggest AL amyloid or lymphoma.

◦Gastrointestinal – Upper GI bleeding, early satiety, and chronic diarrhea raise the possibility of GI amyloid.

◦Cardiac – Progressive shortness of breath, presyncope/syncope and chest pain are consistent with cardiac amyloid.

◦Neurological – Bilateral, sensory neuropathy is consistent with the neuropathy associated with plasma cell dyscrasias; and vision changes, headache, vertigo or dizziness raise the possibility of hyperviscosity associated with WM.

◦Skeletal pain – This symptom suggests IgM myeloma.

◦Skin – Urticarial rash raises the possibility of Schnitzler syndrome.

2. Physical Exam – The physical exam can be informative as patients with an IgM M protein and WM or other non-Hodgkins lymphoma may present with lymphadenopathy and heptosplenomegaly. Patients with concurrent AL amyloid may have hepatosplenomegally or macroglossia, while patients with IgM myeloma may have discrete sites of skeletal pain. A careful neurological exam is essential for identifying and characterizing a concurrent neuropathy.

3. Labs: The following lab studies should be obtained:◾CBC, serum calcium, creatinine, β-2-microglobulin, LDH, liver enzymes

◾Serum protein electrophoresis with immunofixation electrophoresis

◾Serum free light chain assay

◾Quantitative immunoglobulins

◾Spot urine sample for protein quantitation, protein electrophoresis and immunofixation electrophoresis. For patients with significant proteinuria and patients with a monoclonal light chain (Bence Jones protein) detected in the spot urine, a 24-hour urine sample should be collected to quantitate total protein and light chain excretion.

Other laboratory tests that should be considered based on the clinical circumstances:◾Cardiac function biomarkers (NT-proBNP and troponin) for suspected amyloid

◾Anti-MAG antibodies in patients with a sensory neuropathy

◾Peripheral blood flow cytometry for suspected CLL

4. Radiologic and Other Diagnostic Testing: Skeletal survey (radiographic or MRI myeloma protocol) is recommended for patients with bone pain and for patients in whom IgM MM is a consideration.

◦Others diagnostic studies that may be considered based on clinical circumstances:◾Abdominal US to assess for hepatic amyloid

◾Echocardiogram and ECG to assess for cardiac amyloid

◾Abdominal/pelvic CT to assess for non-Hodgkin’s lymphoma including WM

◾PET scan to assess for lymphoma

5. Bone marrow evaluation – Although many patients with MGUS do not require this procedure, in higher-risk cases (M-protein concentration >1.5 gm/dL and IgM-MGUS), bone marrow aspirate and biopsy is recommended and may also include cytogenetic, myeloma FISH, and flow cytometric analyses and targeted gene sequencing. Bone marrow analysis is deferred in the very elderly, in those in whom the M protein concentration is low (less than 0.5 gm/dL), and in patients with an inflammatory condition. Myeloma FISH and targeted gene sequencing – Recommended if marrow findings are consistent with MM or lymphoma. Finding t(11;14) by cytogenetics or FISH suggests IgM MM, and mutant MYD88 supports a diagnosis of WM.

Flow cytometry – This analysis is informative in patients suspected of having a B cell lymphoproliferative disorder including CLL, non-Hodgkin lymphoma or WM.

6. Fatpad aspirate – I do not routinely subject patients to this procedure, however, if there is clinical suspicion of AL amyloid, fat pad aspirate with congo red staining is an excellent screening tool. I have a slightly higher index of suspicion for AL amyloid when the IgM M protein is lambda-restricted. If the fat pad aspirate is negative for AL amyloid but suspicion remains high, target organ biopsy with congo red staining is warranted.

Follow-Up

If after the initial evaluation a patient is diagnosed with IgM MGUS, regular surveillance is imperative as risk of progression/transformation is a continuous variable. I recommend that patients be seen twice annually with a clinical assessment, along with the following laboratory studies: CBC, comprehensive metabolic panel, SPEP, serum-free light chain assay, and quantitative immunoglobulins.14 I do not recommend repeat imaging or bone marrow analysis unless there is suspicion of progression.

Free light chains:

• Kappa Free, Serum 0.33 - 1.94 mg/dL

• Lambda Free, Serum 0.57 - 2.63 mg/dL

• K/L FLC Ratio 0.26 - 1.65

Free light chains are fragments from immunoglobulins (also known as antibodies) are normal constituents of the blood. In some conditions, an excess of one of the types of light chains can occur, and this can lead to an abnormal ratio. In general, if this ratio is below 4.0, patients tend to do well and it is just a lab finding. Recheck in 6 months for borderline case.

Conclusion

Monoclonal IgM is associated with a diverse set of diseases that range from a generally benign process requiring no specific therapy (IgM-MGUS) to overt disease requiring a specific management plan. Approaching the initial evaluation systematically and comprehensively will enable the clinician to accurately characterize the disease process.

Etiology: unknown, exposure to ionizing radiation. Seen commonly in farmers, wood workers, leather worker, and those exposed to petroleum products.

Incidence and prevalence: Increases with age. Median age at Dx ~65 years. Uncommon <40 years. Males > Females. Blacks twice than whites. 10% are Asx.

Pathology:

• • Proliferation of neoplastic plasma cells, a.k.a myeloma cells in the bone marrow is stimulated by cytokine IL-6, produced by fibroblasts and macrophages in the bone marrow stroma.

  • Most common translocations are t(11;14)(q13;q32) and t(4;14)(p16;q32).

  • Chromosomal abnormalities found in patients with myeloma: 13q14 deletions, 17p13 deletions, and 11q abnormalities predominate.

  • Errors in switch recombination - genetic mechanism to switch antibody heavy chain istoype.

  • Overexpression in myc or ras genes.

  • Mutations in p53 and Rb-1.

Clinical features:

• • Bone pain is the most common symptom - 70%. Involves back and ribs. Pain increases on movement. Persistent localized pain signifies pathological fracture. Bone lesions is caused by proliferation of myeloma cells, activation of osteoclasts and suppression of osteoblasts. Myeloma produces OAF (osteoclast activating factor). OAF activity on osteoclast is mediated by cytokines, IL-1, lymphotoxin, VEGF, RANK ligand, MIP-1 alpha, TNF. Glucocorticoids and IFN-alpha inhibit production of these cytokines. Bone lesions are lytic and rarely associated with osteoblastic new bone formation. Thus radioisotope bone scan is less useful than plain X-rays. Bone lysis causes hypercalcemia. Occasionally, bone lesions are palpable when they expand, involves skull, clavicles, sternum. Vertebral collapse leading to spinal cord compression.

  • Hypercalcemia, osteoporosis, pathologic fractures, multiple lytic bone lesions throughout the skeletal system, bone pain: Tumor expansion, production of osteoclast activating factor by tumor cells, osteoblast inhibitory factors.

  • Renal failure: Hypercalcemia, light chain (kappa and lamba - a.k.a Bence-Jones proteins) deposition, amyloidosis, urate nephropathy, drug toxicity (NSAID, biphosphonates), contrast dye.Chromosomal translocations involving the IgG locus on chromosome 14.

  • Incurable, but Tx can induce remission

  • Easy fatigue - anemia: Bone marrow infiltration, production of inhibitory factors, hemolysis, decreased red cell production, decreased eythropoietin levels.

  • Recurrent infections: Susceptibility to infection is the 2nd most common problem in MM. Bacterial pneumonia and pyelonephritis are very common. Why do Pt. have high incidence of infection? Hypogammaglobulinemia, low CD4 count, decreased neutrophil migration. If the M component is excluded due to decreased production and increased destruction of normal antibodies. In some cases, there is also a population of circulating regulatory cells suppress normal antibody synthesis. Poor antibody response to bacterial polysaccharide antigen in bacterial cell walls. There is abnormalities in complement fixation, granulocyte lysozyme function and granulocyte migration is slow. Dexamethasone, all add up to produce immunosuppressed state, leading to increased susceptibility to infection.

    • Pneumonia and pyelonephritis are the most common infections.

    • Most frequent pathogens:

      • Lungs - S. pneumoniae, S.aureus, and K. penumoniae

      • Urinary tract - E. coli, and other gram negative organisms. ~25% have recurrent infections.

    • >75% of patients of MM will have a serious infection at some time.

  • Neurologic symptoms: Hyperviscosity, cryoglobulinemia, amyloid deposits, hypercalcemia, nerve compression, anti-neuronal antibody, POEMS (Polyneuropathy, organomegaly, endocrinopathy, multiple myeloma and skin changes) syndrome, therapy-related toxicity. CTS from infiltration of peripheral nerves by amyloid. Also Bortezomib and thalidomide therapy results in sensory neuropathy.

  • Nausea and vomiting: Renal failure, hypercalcemia

  • Bleeding/clotting disorder: Interference with clotting factors, antibody to clotting factors, amyloid damage of endothelium, platelet dysfunction, antibody coating of platelet, therapy-related hypercoagulable defects.

  • Pain of multiple myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture.

Dx:

• • Triad of myeloma: Plamacytosis (>10%), lytic bone lesion, and serum and/or urine M component.

  • Monoclonal protein in blood or urine: MGUS or multiple myeloma. MGUS is more prevalent in general population than multiple myeloma.

  • MGUS don't require Tx but needs monitoring with routine blood and urine tests. Rate of conversion of MGUS to MM 1% per year.

  • Majority of pt with multiple myeloma typically have excess IgG or IgA. The presence of IgM monoclonal protein is usually a sign of Waldenstrom's macroglobulinemia, a low grade lymphoproliferative d/o. IgD and IgE are subtypes that are rare, 2% of cases. 20% of Pts. secrete monoclonal protein only in the form of light chains in the urine, commonly referred to as Bence Jones proteins. 3% are non-secretors and do not secrete anything detectable in the blood or urine. They have immunoglobulins within the plasma cell masses.

  • Pts. secreting lambda light chains have significantly shorter overall survival than Pts secreting kappa light chains. Lambda light chains is more likely to cause renal damage and form amyloid than are kappa light chains.

  • Hyperviscosity syndromes common in IgM paraproteinemia and IgG myeloma, subclass IgG3.

  • Plasma cell infiltration: Lytic bone lesions, osteoporosis, hypercalcemia, anemia, plamacytomas.

  • Paraprotein: Depression of normal immunoglobulins leads to infections; excess protein may cause rental tubular disease, amyloidosis, or narrowed anion gap (due to positively charged paraproteins).

  • Hepatomegaly, splenomegaly seen sometimes. Palpable plasmacytomas in skull.

Diagnostic Criteria For Multiple Myeloma, Myeloma Variants, and MGUS

• MGUS

  • • M protein in serum <30 g/L

    • Bone marrow clonal plasma cells <10%

    • No evidence of other B cell proliferative disorders

    • No myeloma-related organ or tissue impairment (no end organ damage, including bone lesions).

• Asymptomatic myeloma (smoldering myeloma)

  • • M protein in serum >30 g/L or above, and/or

    • Bone marrow (clonal) plasma cells >10% or above

    • No myeloma-related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms.

• Symptomatic multiple myeloma

  • • M-protein in serum and/or urine

    • Bone marrow (clonal) plasma cells or plasmacytoma. Plasma cells are CD138+ and monoclonal.

    • Myeloma-related organ or tissue impairment (end-organ damage, including bone lesions)

• Nonsecretory myeloma

  • • No M protein in serum and/or urine with immunofixation

    • Bone marrow clonal plasmacytosis >10% or more or plamacytoma

    • Myeloma-related organ or tissue impairment (end organ damage, including bone lesions)

• Solitary plasmacytoma of bone

  • • No M protein in serum and/or urine

    • Single area of bone destruction due to clonal plasma cells

    • Bone marrow not consistent with multiple myeloma. No marrow plasmacytosis.

    • Normal skeletal survey (and MRI of spine and pelvis if done)

    • No related organ or tissue impairment (no end organ damage other than solitary bone lesion)

    • Responds to radiation therapy.

Extramedullary plamacytomas usually involve submucosal lymphoid tissue of the nasopharyngx or paranasal sinuses without marrow plamacytosis. Response to local radiation Tx is good.

Myeloma-related organ or tissue impairment (end organ damage) (ROTI):

• • • Calcium level is increased: Sr. Ca: >0.25 mmol/L above UNL or >2.75 mmol/L

    • Renal insufficiency: Sr. Cr: >173 mmol/L

    • Anemia

    • Hb 2 g/dL below LLN or Hb <10 g/dL

    • Bone lesions: lytic lesions or osteoporosis with compression fractures (MRI or CT)

    • Others: Sx hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episode in 12 months).

Most important DDx in Pts with MM is MGUS. MGUS is more common than myeloma, occurring in 1% of the population over age 50 and in up to 10% individuals over age 75.

When bone marrow cells are exposed to radioactive thymidine in order to quantitate dividing cells, patients with MGUS always have a labelling index <1%; Pts with myeloma always have a labeling index > 1%. With long-term f/up ~1% of MGUS Pts go on to develop MM. Non IgG subtype, abnormal kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5 g/dL) are associated with higher incidence of progression of MGUS to myeloma. MGUS Pt. need no Tx.

Labs:

• • CBC with diff, BUN, Cr, albumin, lytes, ESR, CRP, Sr. Uric acid, SPEP with immunofixation electrophoresis (IFE), Beta-2 microglobulin, IgG (53%), IgM, IgA (25%), IgD (1%). BC x 2, Sr. alk. phosphatase, AST, ALT, Bili (total, direct), LDH.

  • Serum soluble IL-6 rcp levels and CRP.

  • UA complete, 24-h urine for Bence-Jones (light-chain) proteins, UPEP with immunofixation to identify M spike.

  • Serum free light chain assay.

  • Skeletal bone plain film suvery: Lytic lesions are seen in 60% - 90% of patients.

  • Myeloma is purely osteolytic lesion, so bone scan is negative and alkaline phosphatase is normal.

  • X-ray: CXR, head x 2 views, spine, hip and pelvis, bone denistometry, PET/CT

  • Bone marrow bx and aspirate will determine presence of plasmacytosis. FISH (fluorescent insitu hybridization) and cytogenetic studies. Del[13]; and t[4;14] are associated with worse prognosis.

  • Features not seen in MM include elevated alkaline phosphatase, positive bone scan, and splenomegaly. M spike may not be seen on UPEP or SPEP-obtain IFE if you still suspect myeloma.

Criteria for diagnosis of active multiple myeloma:

• • Monoclonal plasma cells in the bone marrow 10% or more, and/or Bx proven plasmacytoma

  • Monoclonal protein present in blood and/or urine

  • Myeloma-related organ dysfunction, also known as CRAB criteria

    • Calcium elevation: Sr. Ca: >10.5 mg/dL

    • Renal insufficiency: Sr. Cr: >2 mg/dL

    • Anemia: Hb <10 g/dL or 2 g < normal

    • Bone damage: lytic lesions or osteoporosis on skeletal survey

Tx:

• • Incurable. Remission with relapse.

  • Multiple myleoma: median survival ranges 2 - 4 years. In lymphoplasmacytic lymphoma it is somewhat longer, in the range of 4 - 5 years.

  • About 10% of patients with myeloma have an indolent course with very slow progression of disease over many years.

    • Antitumor therapy only if disease becomes symptomatic:

      • anemia, hypercalcemia, progressive lytic bone lesion (vertebral compression Fx), progressive rise in serum myeloma protein levels and/or BJ proteinuria, or recurrent infections.

  • Solitary bone plasmacytomas and extramedullary plamacytomas respond to local radiation therapy to a dose of around 40 Gy. If bone marrow involvement serum M component returns. Give chemotherapy.

  • Pts with symptomatic and/or progressive meyloma need systemic therapy to control progression of MM and symptomatic supportive therapy to prevent serious morbidity from complication of the disease.

  • After Dx, determine if Pt. is candidate for high-dose chemotherapy and autologous stem cell transplantation.

  • For Pts <65 yo, and older Pts with few comorbidities and good performance status, the standard of therapy is high dose corticosteroid regimen (dexamethasone 40 mg for 4 days q2 weeks), or in combination with VAD chemotherapy (vincristine, 0.4 mg/day x 4 day continuous infusion; doxorubicin, 9 mg/m2 daily in a 4-day continuous infusion; dexamethasone 40 mg daily x 4 days qwk for 3 weeks. This is for initial cytoreduction. OR

  • Thalidomide 200 mg PO qhs + dexamethasone 40 mg x 4 days, q2 wks for newly diagnosed patients. Standard therapy for new diagnosed patients without compromising collection of stem cells for transplantation.

  • For Pts. who are not candidates for stem cell transplantation, standard frontline regimen intermittent pulses of an alkylating agent, L-phenylalanine mustard (L-PAM, oral melphalan) and prednisone for 4-7 days q4-6 wks. The usual dose of MP regimen is melphalan, 8 mg/m2 daily, and prednisone, 25-60 mg/m2 daily x 4 days. Pt. responding to Tx have less bone pain, hypercalcemia resolves, less infections.

  • In patients >65 years and not transplant candidates, combining MP regimen with thalidomide is standard therapy.

  • High dose melphalan therapy (HDT) has higher overal response rates and prolonged progression-free and overall survival

  • Pt who have a relapse of disease following initial Tx should receive additional Tx, including lenalidomide and/or bortezomib. These agents not only target the tumor cells but also the tumor cell-bone marrow interaction and the bone marrow milleu.

  • Thalidomide: can cause peripheral neuropathy, constipation, fatigue, and hypotension, DVT risk increased especially when taken with corticosteroids. Pt. should get DVT prophylaxis.

  • Bortezomib: protease inhibitor - arrests cell cycle and apoptosis, as well as other pathways needed for cancer growth and survival. SE: thrombocytopenia, n/d, and peripheral neuropathy.

  • Lenalidomide is a thalidomide analogue, taken with dexamethasone causes better remission. SE: neutropenia, thrombocytopenia, DVT when combined with steroids.

  • Supportive care: biphosphonates: pamidronate and zolendronic acid. Inhibit osteoclast activity and have been shown to reduce the risk of skeletal complications. SE: renal insufficiency, hypocalcemia, and osteonecrosis of jaw (ONJ).

    • Hypercalcemia: biphosphonates, glucocorticoid therapy, hydration, and natriuresis. Calcitonin if needed.

      • Pamidronate 90 mg or zolendronate 4 mg once a month.

    • In the event of acute renal failure: IVF, plasmapheresis.

    • Treat UTI early and aggressively.

    • Hyperviscosity syndromes: plasmapheresis

    • Treat recurrent serious infections with prophylactic administration of IV gamma globulin preparations.

    • Cord compression symptoms need MRI stat, and radiation therapy for palliation.

    • Anemia may respond to EPO + iron + folate + vitamin B12.

  • Pt. have median survival of 5 years or more. Eventually die of complications like ARF, inf, and H'ge. Acute leukemia or myelodysplasia.

  • For refractory or relapsing cases carfilzomib (Kyprolis) Check resource.

IMWG