2. DEFINITION:
• MM represents a malignant proliferation of plasma cells derived
from a single clone.
• Myeloma cells produce monoclonal immunoglobulins - produce
symptoms
3. ETIOLOGY
• Cause not known.
• High risk-
• exposed to petroleum products, farmers, wood workers, leather workers, radiation
exposure
• Chromosomal alterations have been found in patients with myeloma:
• hyperdiploidy, 13q14 deletions, translocations t(11;14)(q13;q32), t(4;14)(p16;q32),
and t(14;16), 1q amplification or 1p deletion, and 17p13 deletions.
• N-ras, K-ras, and B-raf mutations are most common
4. INCIDENCE AND PREVALENCE:
• Increases in incidence with age.
• Median age at diagnosis - 69 years
• uncommon under age 40.
• Males are more commonly affected than females, and
• blacks have nearly twice the incidence of whites.
• Accounts for 1.3% of all malignancies in whites and 2% in blacks
• 13% of all hematologic cancers in whites and 33% in blacks.
5. GLOBAL CONSIDERATIONS
• Developing countries including Asia – lowest incidence.
• Higher incidence in more developed countries
• combination of a longer life expectancy
• more frequent medical surveillance.
• Despite these differences in prevalence
• characteristics, response to therapy, and prognosis of myeloma are similar
worldwide.
6. PATHOGENESIS
• The cause of myeloma is not known.
• Following factors and abnormalities have been implicated:
1. Radiation exposure.
2. Epidemiologic factors.
3. Karyotypic abnormalities.
4. Oncogenes-antioncogenes.
7.
8.
9. 1. Multiple myeloma (MM) cells bind via cell-surface adhesion molecules
to bone marrow stromal cells(BMSC) & extracellular matrix (ECM)
2. This triggers multiple myeloma cell growth, survival,
drug resistance, & migration in the bone marrow milieu.
3. Growth, drug resistance, and migration are
mediated via Ras/Raf/mitogen-activated protein
kinase, PI3-K/Akt, and protein kinase C signaling
cascades, respectively
11. BONE LESIONS
• Bone pain most common symptom (70%).
• Persistent localized pain usually signifies a pathologic fracture.
• The bone lesions are lytic in nature.
• radioisotopic bone scanning is less useful than plain radiography.
• Bony lysis results in substantial mobilization of calcium from bone
• Localized bone lesions -collapse of vertebrae leading to spinal cord
compression.
12. • PATHOGENESIS
• Proliferation of tumor cells,
activation of osteoclasts that
destroy bone, and suppression of
osteoblasts .
• Increased osteoclast activity -
osteoclast activating factors (OAFs)
produced by the myeloma cells
mediated by several cytokines.
• Osteoblastic new bone formation
RARE due to their suppression by
dickhoff-1 (DKK-1).
13. INFECTIONS
• The 2ND most common clinical problem in patients is susceptibility to bacterial
infections
• Most common infections are pneumonias and pyelonephritis,
• most frequent pathogens Streptococcus pneumoniae, Staphylococcus aureus, and
Klebsiella pneumoniae in the lungs and
• Escherichia coli and other gram-negative organisms in the urinary tract.
• Recurrent infections ~25%
• >75% of patients will have a serious infection at some time in their course.
14. Susceptibility to infection several contributing
causes-
• Diffuse hypogammaglobulinemia (both decreased production and increased
destruction of normal antibodies).
• The large M component - fractional catabolic rates of 8–16% instead of the normal
2%.
• Circulating regulatory cells .
• Very poor antibody responses.
• Therapeutic agents.
• Granulocyte migration is not as rapid as normal in patients.
• Abnormality in complement system.
15. RENAL FAILURE (25%)
• Hypercalcemia is the most common cause of renal failure.
• OTHER CAUSES
• Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of NSAIDS for pain
control, use of iodinated contrast dye for imaging, bisphosphonate use, and occasional infiltration of the
kidney by myeloma cells all may contribute to renal dysfunction.
• Tubular damage associated with the excretion of light chains is almost always
present.
• Normally filtered, reabsorbed in the tubules, and catabolized.
• Increasing light chains presented to the tubule, the tubular cells become overloaded
• either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal
enzymes.
• Adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis),
• Proteinuria without hypertension
16. ANEMIA
• Normocytic and normochromic anemia occurs in ~80% of myeloma
patients.
• replacement of normal marrow
• inhibition of hematopoiesis by factors made by the tumor, to reduced production
of erythropoietin by the kidney, and
• effects of long-term therapy.
• Megaloblastic anemia due to either folate or vitamin B12 deficiency.
• Granulocytopenia and thrombocytopenia are rare
• except when therapy-induced.
17. OTHER MANIFESTATIONS
• Pseudohyponatremia
• As each volume of serum has less water as a result of the increased protein.
• Clotting abnormalities
• failure of antibody-coated platelets to function properly;
• interaction of the M component with clotting factors I, II, V, VII, or VIII; antibody to
clotting factors; or amyloid damage of endothelium.
• Deep venous thrombosis-
• with use of thalidomide, lenalidomide, or pomalidomide in combination with
dexamethasone.
18. • Raynaud’s phenomenon and impaired circulation
• may result if the M component forms cryoglobulins, and
• Hyperviscosity syndromes may develop depending on the physical properties of the M
component (most common with IgM, IgG3, and IgA paraproteins).
• Hyperviscosity is defined based on the relative viscosity of serum as
compared with water.
• i.e., serum is normally almost twice as viscous as water.
• Hyperviscosity syndrome( normal relative serum viscosity is 1.8)
• IgM > IgA/IgG(IgG3 max)
• Encephalopathy
• Headache , visual disturbances, ataxia, vertigo, retinopathy
• Shortness of breath
• Chest pain
• Vaso-occlusion, exacerbation or precipitation of heart failure
19. Neurologic Symptoms (less common)
• Hypercalcemia
• lethargy, weakness, depression, and confusion.
• Hyperviscosity
• headache, fatigue, shortness of breath, exacerbation or precipitation of heart failure, visual
disturbances, ataxia, vertigo, retinopathy, somnolence, and coma.
• Bony damage and collapse
• cord compression, radicular pain, and loss of bowel and bladder control
• Peripheral neuropathy
• Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and
other sensorimotor mono- and polyneuropathies.
20. • Sensory neuropathy more common
• associated with IgM more than other isotypes.
• Sensory neuropathy is also a side effect of therapy,
• specifically thalidomide and bortezomib.
• Cord compression, pathologic fractures, hyperviscosity, sepsis, and
hypercalcemia
• present as medical emergencies.
• Tumor expansion is dominantly within bone and bone marrow and, for
reasons unknown,
• rarely causes enlargement of spleen, lymph nodes, or gut-associated lymphatic
tissue.
21.
22. WHEN TO SUSPECT
• Disease of elderly
• Patient of advanced age(average 69 years) with bone pain and pathological fractures at unusual
sites not associated with trauma and which does not improve with treatment, bone pain with lytic
lesions discovered on routine skeletal films or other imaging modalities.
• An increased total serum protein concentration and/or the presence of a monoclonal(M) protein in
the serum and urine.
• Unexplained anemia, with no history of blood loss/hemolysis/anemia of chronic disease, with
normal vitB12 and folate and iron studies.
• Hypercalcemia, which is either symptomatic or discovered incidentally, with normal vitamin and
history of malignancy sarcoidosis or use of medications such thiazides.
• Renal impairment- no clear explanation including pre-renal causes, primary renal disorders or
obstructive conditions
23. INVESTIGATIONS
• CBC- Anemia, Leukopenia, Thrombocytopenia, Raised ESR(often>100)
• values correlate neither with tumor burden nor with treatment response
• Hence its importance is uncertain.
• Peripheral smear
• Rouleaux formation
• Pancytopenia
• Monoclonal plasma cells can be seen
• > 2000/mm3 S/O Plasma cell leukemia
• SPEP/UPEP
• Serum & urine Immunofixation
• Free light chain assay
24.
25.
26. • Urinalysis
• Protein- near all light chains initially-Bence Jones proteinuria
• After glomerular involvement
• non selective proteinuria
• Albumin
• Casts
• RFTs
• Elevated urea / creatinine
• Serum calcium- raised
• Serum uric acid- raised
28. • IMAGING – may reveal punched out lytic lesions/ diffuse
osteopenia/collapsed vertebrae
• CT - bone abnormalities
• PET/CT - Most sensitive for extramedullary disease
• MRI - Most sensitive for bone lesions
• For patients with suspected multiple myeloma, cross-sectional imaging (low-
dose CT, PET/CT, or MRI scan), rather than a skeletal survey, as the imaging
modality to detect bone involvement.
• Accumulating data suggest that patients who previously would have met criteria
for smoldering myeloma based on negative skeletal surveys, but who have
lesions detected by one of these modalities, have a shorter time to progression
than similar patients with negative cross-sectional imaging
29. • Bone marrow examination
• Percent monoclonal plasma cells = >10 %
• Morphology
• Oval with abundant basophilic cytoplasm
• Nucleus is round and eccentrically located
• Perinuclear halo
• "clock-face" or "spoke wheel" chromatin without nucleoli
• Cytoplasmic immunoglobulin inclusions -Mott cells, Morula cells, Russell bodies, Flame cells
• Immunophenotype – Flow cytometry or immunohistochemistry
• Cytogenetics
30.
31. PROGNOSIS
• Serum β2-microglobulin - the
single most powerful predictor
of survival and staging.
• Three-stage International
Staging System (ISS) that
predicts survival.
• Combination of serum β2-
microglobulin and albumin levels
32. DIAGNOSIS
The diagnosis of myeloma is made by classic triad of features:
1. Marrow plasmacytosis of more than 10%
2. Radiologic evidence of lytic bony lesions
3. Demonstration of serum and/or urine M component.
35. TREATMENT
For management patient may be divided under following category
1. Inactive Disease- UNDER CLINICAL OBSERVATION
2. Active Disease
-Non-transplant Candidates
-Transplant Candidates
3. Relapsed or Refractory Disease
• Therapy can significantly prolong survival and improve the quality of life for myeloma
patients.
• The therapy of myeloma includes an initial induction regimen followed by
consolidation and/or maintenance therapy and, on subsequent progression,
management of relapsed disease.
36. TREATMENT: MGUS
• No specific intervention
• Follow-up once a year or less frequently
• Exception: higher risk MGUS
• Serum protein electrophoresis
• Complete blood count
• Creatinine
• Calcium
should be repeated every 6 months.
• MGUS and severe polyneuropathy is considered for therapeutic intervention
• absence of any other potential causes for neuropathy.
• plasmapheresis and occasionally rituximab in patients with IgM MGUS
• myeloma-like therapy in those with IgG or IgA disease
37. • SMM only require antitumor therapy when myeloma defining events
are identified.
• SPEP, CBC, Serum calcium, KFT, UPEP, IMMUNOFIXATION to be performed at
diagnosis and in 2-3 months repeat---if stable---4-6 months for 1 year…..then every
6-12 months.
• TREATMENT: Solitary plasmacytoma
• Local Radiotherapy
• Prolonged disease-free survival after local radiation therapy at a dose of around 40
Gy.
38. TREATMENT: Symptomtic myeloma(standard
Risk)
• Determine HCT eligibility
• All patients need to be assessed to determine eligibility for autologous
hematopoietic cell transplantation (HCT)
• Age >70 years, significant cardiopulmonary problems, or other comorbid
illnesses
• Induction therapy
• Patients eligible for HCT = Induction therapy - HCT - Maintenance
• Patients ineligible for HCT = Induction - Maintenance chemo
39. HCT eligible
• Induction regimens
• Lenalidomide plus dexamethasone (Rd)
• Bortezomib, lenalidomide, dexamethasone (VRd)- SUPERIOR
• Bortezomib, cyclophosphamide, dexamethasone (VCd)
• Bortezomib, melphalan, prednisone (VMP) three to four months prior to stem
cell collection.
40. HCT eligible
• Following induction therapy and stem cell collection
• Early transplant strategy –
• Proceed with autologous HCT (single or double) directly after recovery from stem cell collection
• at least two years of maintenance therapy post-transplant
• Delayed transplant strategy –
• Continued therapy, usually with the same regimen used for induction, reserving autologous HCT until
first relapse
• Allogeneic HCT
• complete a total of 8 to 12 cycles of triplet therapy followed by lenalidomide based maintenance
until relapse
• early or delayed autologous HCT > either chemotherapy alone or allogeneic HCT
41. Maintenance after HCT
• Virtually all patients eventually develop relapsed disease even after HCT.
• For standard risk = Lenalidomide
• For high risk = Bortezomib
• Rx continued until the patient reaches a plateau phase (usually 12 to 18
months), which is defined as a stable level of M-protein
42. HCT ineligible
• Bortezomib-based triplet regimen for 8 to 12 cycles followed by
lenalidomide-based maintenance therapy.
• In patients who are frail and are not felt to be candidates for triplet therapy
• doublet therapy with lenalidomide and low dose dexamethasone until progression.
• Maintenance therapy prolongs progression-free survival
• Lenalidomide maintenance
• Lenalidomide plus dexamethasone (Rd) - SUPERIOR
43. HIGH RISK MYELOMA
• Do poorly with all conventional treatment options
• Should be encouraged to enroll in a clinical trial investigating novel
therapeutic strategies
• For transplant-eligible patients
• triplet-based induction therapy followed by early autologous HCT and proteasome-
inhibitor-based maintenance .
• Transplant-ineligible patients
• 8 to 12 cycles of triplet-based induction therapy followed by proteasome inhibitor-
based maintenance
44. EVALUATING RESPONSE TO TREATMENT
• Should be evaluated before each treatment cycle to determine how
their disease is responding to therapy and to assess for potential
treatment-related and disease-related complications.
• Measurement of M protein in serum and urine
• FLC assay
• Patients without measureable M-protein or abnormal FLC
• Periodic bone marrow aspirates and biopsies
• Whole body PET/CT
47. RELAPSED DISEASE
• Almost all patients with MM who survive initial treatment will eventually relapse
• Relapsed or refractory MM is usually identified on routine surveillance
• Therapy for relapsed disease is indicated if there is a clinical relapse or a rapid rise in
paraproteins
• Options-
• HCT
• a rechallenge of the previous chemotherapy regimen
• a trial of a new regimen
• Multiple regimens
• Daratumumab, lenalidomide, dexamethasone (DRd)
• Elotuzumab, lenalidomide, dexamethasone(Erd)
• Daratumumab, bortezomib, dexamethasone (DVd)
• Bortezomib, lenalidomide, dexamethasone (VRd)
• Bortezomib, cyclophosphamide, dexamethasone (VCD)
• Ixazomib, lenalidomide, dexamethasone (IRd)
• Panobinostat, bortezomib, dexamethasone
48. Figure 3. Proposed Mechanism of Action of Drugs to
Target the Myeloma Cell and Components of the Bone
Marrow Microenvironment.
In myeloma cells, alkylating agents, corticosteroids, and
bortezomib inhibit cell growth and induce apoptosis.
• The effect of bortezomib on myeloma cells is mediated
in part by the inhibition of nuclear factor-κB.
• Thalidomide and bortezomib inhibit the interaction
between myeloma cells and stromal cells as well as
the production of cytokines such as tumor necrosis
factor α and interleukin-6.
• Thalidomide inhibits angiogenesis and stimulates the
immune-surveillance properties of T cells and
natural killer cells.
• Solid arrows indicate stimulation or secretion and
dashed arrows inhibition.
49. • Bortezomib
• Herpes zoster prophylaxis is indicated and
• neuropathy can be decreased both – sc and administration on a weekly schedule.
• Lenalidomide
• prophylaxis for deep-vein thrombosis (DVT)
• either aspirin or if patients are at a greater risk of DVT, warfarin or low-molecular-
weight heparin.
• stem cells should be collected within 6 months may compromise the ability to collect
adequate numbers of stem cells.
• Initial therapy continued until maximal cytoreduction.
50.
51.
52. Supportive Care
• Directed to anticipated complications of the disease
• Hypercalcemia :
• Bisphosphonates, glucocorticoid therapy
• Hydration, and natriuresis, and rarely requires calcitonin as well.
• Bisphosphonates e.g., pamidronate 90 mg or zoledronate 4 mg once a month
• Plasmapheresis may be the treatment of choice for hyperviscosity
syndromes
• Prophylactic administration of intravenous γ globulin preparations is used in
• recurrent serious infections
53. Supportive Care
• Kyphoplasty or vertebroplasty
• painful collapsed vertebra
• Most bone lesions respond to analgesics and systemic therapy,
• certain painful lesions may respond most promptly to localized radiation.
• Anemia a/w myeloma
• may respond to erythropoietin along with hematinics (iron, folate, cobalamin).
• Worsening of renal function may be prevented by
• maintaining a high fluid intake to prevent dehydration and enhance excretion of light
chains and calcium.
54. TAKE HOME MESSAGE
• Disease of elderly
• Should suspect when-elderly patient present with bone pain or with symptoms
that are often non-specific, such as nausea, vomiting, malaise, weakness,
recurrent infections, and weight loss.
• cross-sectional imaging > conventional skeletal survey
• Survival in the older increased due to availability of non-transplant options.
• Remains incurable.
Bone pain or fracture, renal failure, susceptibility to infection, anemia, hypercalcemia, and occasionally clotting abnormalities, neurologic symptoms, and manifestations of hyperviscosity.
tumor, its products, and the host response.
Evidence is strong that errors in switch recombination—the genetic mechanism to change antibody heavy chain isotype—participate in the early transformation process.
However, no single common molecular pathogenetic pathway has yet emerged.
Genome sequencing studies have failed to identify any recurrent mutation with frequency >20%; N-ras, K-ras, and B-raf mutations are most common and combined occur in >40% of patients.
Evidence of complex clusters of subclonal variants is present at diagnosis, acquires additional mutations over time, indicative of genomic evolution that may drive disease progression.
It remains difficult to distinguish benign from malignant plasma cells based on morphologic criteria in all but a few cases (Fig. 107-3).
Myeloma occurred with increased frequency in those exposed to the radiation of nuclear warheads in World War II after a 20-year latency.
Interleukin (IL) 6 may play a role in driving myeloma cell proliferation.
An estimated 30,280 new cases of myeloma were diagnosed in 2017, and 12,590 people died from the disease in the United States. Myeloma
The incidence of myeloma is highest in African Americans and Pacific Islanders; intermediate in Europeans and North American whites; and
Incidence of MM in other ethnic groups including native Hawaiians, female Hispanics, American Indians from New Mexico, and Alaskan natives is higher relative to U.S. whites in the same geographic area.
Chinese and Japanese populations have a lower incidence than whites.
Immunoproliferative small-intestinal disease (IPSID) with alpha heavy chain disease is most prevalent in the Mediterranean area.
Oncogenes-antioncogenes. Overexpresion and mutations in following genes have been noted in proliferation of tumour cells in myeloma: i) Overexpression of MYC and RAS growth promoting oncogenes in some cases. ii) Mutation in p53 and RB growth-suppressing antioncogene in some cases A variety of chromosomal alterations with prognostic significance has been found in patients with myeloma 13q14 deletions, 17p13 deletions, and translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) predominate.
These effects are due both to direct multiple myeloma cell– bone marrow stromal cells binding and to induction of various cytokines, including IL-6, insulin-like growth factor type I (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell–derived growth factor (SDF)-1.
MM cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSCs) and extracellular matrix (ECM),
which triggers MM cell growth, survival, drug resistance, and migration in the bone marrow milieu .
These effects are due both to direct MM cell–BMSC binding via adhesion molecules and to induction of various cytokines,
including IL-6, insulin-like growth factor type I (IGF-I), vascular endothelial growth factor (VEGF), and stromal cell–derived growth factor (SDF)-1α.
Growth, drug resistance, and migration are mediated via Ras/Raf/mitogen-activated protein kinase, PI3K/Akt, and protein kinase C signaling cascades, respectively.
The increased osteoclast activity - osteoclast activating factors (OAFs) produced by the myeloma cells (mediated by several cytokines, including IL-1, lymphotoxin, VEGF, receptor activator of NF-κB [RANK] ligand, macrophage inhibitory factor [MIP]-1α, and tumor necrosis factor [TNF]).
First, patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded.
Various abnormalities in T-cell function are also observed including decreased Th1 response, increase in Th17 cells producing proinflammatory cytokines, and aberrant Treg cell function.
Renal failure occurs in nearly 25% of myeloma patients, and some renal pathology is noted in >50%.
Proteinuria without hypertension, and the protein is nearly all light chains.
Generally, very little albumin is in the urine because glomerular function is usually normal.
When the glomeruli are involved, nonselective proteinuria is also observed.
Patients with myeloma also have a decreased anion gap [i.e., Na+ – (Cl− + HCO3−)] because the M component is cationic, resulting in retention of chloride.
Renal dysfunction due to light chain deposition disease, light chain cast nephropathy, and amyloidosis is partially reversible with effective therapy.
Myeloma patients are susceptible to developing acute renal failure if they become dehydrated.
Adult Fanconi’s syndrome (a type 2 proximal renal tubular acidosis),
with loss of glucose and amino acids & loss in the ability of the kidney to acidify and concentrate the urine.
In addition, mild hemolysis may contribute to the anemia.
Symptoms of hyperviscosity occur at a level greater than 4 centipoise (cP), which is usually reached at paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA; however, depending on chemical and physical properties of the paraprotein molecule, it can occasionally be observed at lower levels.
In >50% of patients with neuropathy, the IgM monoclonal protein is directed against myelin-associated globulin (MAG).
Anion gap decreased- M component and calcium ---unmeasured cations.
Bone marrow examination
Immunophenotype – Flow cytometry or immunohistochemistry
The normal kappa/lambda ratio in the bone marrow is 2:1. A ratio of more than 4:1 or less than 1:2 is considered to meet the definition of kappa or lambda monoclonality, respectively.
CD79a, VS38c, CD138, and CD38 +ve
CD19 -ve
Chromosome 13q deletion, previously thought to predict poor outcome, is not a predictor following the use of newer agents.
Microarray profiling has formed the basis for RNA-based prognostic staging systems.
Genome sequencing efforts have allowed for characterization of critical genes, pathways, and clonal heterogeneity in myeloma.
The median number of mutations per transcribed genome in myeloma is around 58.
A very heterogeneous mutational landscape with no unifying mutation has been observed.
The ISS system, along with cytogenetic changes, is the most widely used method for assessing prognosis (Table 107-3).
The most frequently mutated genes are KRAS and NRAS (about 20% each), followed by TP53, DIS3, FAM46C, and BRAF, all mutated in 5–10% of the patients.
All other mutations were observed in <5% of the patients.
These results are now being applied to develop new targeted personalized therapies in myeloma.
With the use of highdose therapy and the newer agents, the Durie-Salmon staging system is unable to predict outcome and thus is no longer used.
β2-Microglobulin is the light chain of the class I major histocompatibility antigens (HLA-A, -B, -C) on the surface of every cell.
Daratumumab is a monoclonal antibody targeted against CD38
Elotuzumab is a humanized monoclonal antibody targeted against SLAMF7, a glycoprotein expressed on MM and natural killer cells
Panobinostat — Panobinostat is a histone deacetylase (HDAC) inhibitor
The pneumococcal conjugate vaccines may be more protective.
pneumococcal polysaccharide vaccines may not elicit an antibody response.
Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control
may need emergency MRI and local radiation therapy and
glucocorticoids if cord compression is identified.
In patients in whom neurologic deficit is increasing or substantial, emergent surgical decompression may be necessary.
