A. Characteristics

1. Cancer of immunoglobulin (Ig) producing plasma cells undergo clonal expansion
2. Part of a spectrum of plasma cell "dyscrasias" (abnormal growth)
3. Epidemiology
   1. Usually occurs in older persons: median age ~67 years
   2. Men > Women ~3:2
   3. Incidence ~14,600 new cases annually in USA (4 per 100,000 annually)
   4. Prevalence ~45,000 in USA
   5. Median lifespan ~33 months overall with current therapy
   6. Median lifespan of patients under 70 years is 4-5 years [1]
   7. ~10,800 deaths per year in USA
   8. Incidence in blacks ~2X that of whites
   9. Reduced incidence in Asians (<1 per 100,000 annually in China, Phillipines)
4. Overview of Plasma Cell Biology
   1. Plasma cells are fully differentiated B lymphocytes which secrete antibodies (Abs)
   2. Each plasma cell normally secretes a single monoclonal (Mc) Ig Ab molecule
   3. Normally, plasma cells cannot divide, and live 2-12 weeks
   4. Myeloma cells are immortal plasma cells that usually (>98%) secrete all or part of a Mc Ig
   5. Mc Igs in serum are called "paraproteins"
   6. Light chains from Ig molecules in urine are called "Bence-Jones' Proteins"

B. Classification of Plasma Cell Dyscrasias [13]

1. Multiple Myeloma / Plasma Cell Myeloma
   1. Myeloma cells divide slowly and relentlessly, overcrowding bone marrow
   2. Most myeloma cells secrete IgG (~70%); IgA (~20%) is next most common
   3. Light (L) chains of the kappa class in ~65% of cases
   4. Some myelomas secrete only light chains (>10%) and >2% are "non-secretors"
2. Solitary Plasmacytoma [10]
   1. Single isolated mass of plasma cells
   2. Usually found in bone
   3. May also form soft-tissue mass
3. Monoclonal Gammopathy of Undetermined Significance (MGUS) [4,7,36]
   1. MGUS is defined as serum monoclonal Ig <3.0gm/dL without end-organ damage
   2. Increasing numbers of persons found to have a monoclonal gammopathy for evaluation of raised Ig levels on serum chemistry
   3. Overall prevalence in age >50 years 3.2% (men 4.0%, women 2.7%)
   4. Overal prevalence age >70 5.3% and age >85 is 7.5%
   5. MGUS progresses to myeloma or related diseases ~1% per year
   6. About 3% of patients initially thought to have MGUS will a have single bony lesion ("plasmacytoma"); this qualifies as Stage I Myeloma (see below)
   7. Neuropathy and autoimmune phenomena can develop
   8. Symptomatology: crowding of marrow by tumor cells or bone fractures, bone pain
   9. Abnormal B cell population is monoclonal, CD38+, CD56+, CD19-
   10. Must rule out frank myeloma, including full chemistry panel, urinalysis, bone series
   11. In general, annual followup of patients with MGUS is recommended
4. Waldenstrom's Macroglobulinemia (WM)
   1. Due to IgM secreting malignant plasma cells
   2. Symptoms nearly always related to hyperviscosity associated with elevated IgM
   3. Lymphadenopathy, peripheral neuropthy, occlussive diseases observed
   4. Behaves more like indolent lymphoma than MM
5. Indolent Lymphomas and Related Disorders [13]
   1. Lymphocytoplasmic Lymphoma
   2. Splenic marginal zone lymphoma
   3. Heavy Chain Diseases
   4. Chronic lymphocytic leukemia (CLL)
6. Heavy (H-) Chain Diseases
   1. Rare variants of B-cell lymphomas which produce IgA > IgM > IgG
   2. IgA H-chain disease also called immunoproliferative small intestinal disease
   3. This is a form of mucosa associated lymphoid tumor (MALT lymphoma)
   4. Campylobacter jejuni infection implicated in IgA H-chain disease pathogenesis
   5. Early stages may respond to antibiotic treatment
   6. Gamma H-chain disease is often associated with systemic (lymphocytoplasmic) lymphoma
   7. Gamma H-chain disease with widespread involvement of bone marrow, spleen, lymph nodes
   8. Gamma H-chain disease with constitutional symptoms, anemia, eosinophilia, autoimmunity
   9. Mu H-chain disease is very rare and associtaed with CLL (small lymphocytic lymphoma)
   10. Mu H-chain disease with hepatosplenomegaly, vaculolated bone marrow, free urinary light chains in addition to abnormal serum mu chain
   11. Treatment with rituximab (Rituxan®) and/or chemotherapy
7. Multicentric Castleman's Disease
   1. Lymphoma variant, often with IgG or IgA, usually lambda light chain paraproteins
   2. Most cases due to human herpesvirus 8 (HHV8) infection, some due to HIV infection
   3. Generalized lymphadenopathy and splenomegaly
   4. Anemia, thrombocytosis, elevated ESR, polyclonal hypergammaglobulinemia

B. Pathogenesis

1. Unclear etiology
2. Develops from clonal population of plasma cells, probably as MGUS
3. Triggering factor leading to clonal outgrowth of plasma cells unknown
   1. Infection or inflammation has been suggested
   2. HIV infection increases risk of MM development ~4X
4. Gene Rearrangements in ~50%
   1. Translocations involving Ig genes are common and may be pathogenic
   2. Nearly all involve immunoglobulin heavy chain (IgH) locus on chrom 14q32
   3. t(11;14) involving IgH-cyclin D1 (bcl1, CCND1) fusion (chrom 11q13) - most common
   4. t(4;14) involving FGFR3-IgH and IgH-MMSET translocations (chrom 4p16.3)
   5. t(14;16) involving IgH-c-MAF (chrom 15q23)
   6. t(14;6) involving IgH-CCND3 (chrom 6p21)
5. Chrom 13 deletion - 40-50% of patients (poor prognostic factor)
6. Growth and Angiogenic Factors
   1. Myeloma cells utilize autocrine and bone marrow stromal paracrine factors to live
   2. Interaction of myeloma cell with bone marrow microenvironment critical
   3. Highly angiogenic tumor in bone marrow environment
   4. Interleukin 6 (IL6) is one of the major growth factor for plasma cell malignancies
   5. IL6 stimulates B cell (especially IgA) maturation and liver acute phase reactants
   6. IL6 is major contributor to systemic symptoms ("B" Symptoms)
   7. Insulin like growth factor 1 (IGF-1) also implicated in myeloma cell development
   8. Vascular endothelial growth factor (VEGF) and FGFß likely involved in angiogenesis
7. Effects on Bone [5]
   1. Most myeloma resides in bone
   2. Malignant cells cause "punched out" osteolytic lesions
   3. These cause bone pain, pathologic fractures, hypercalcemia
   4. Myeloma cells produce osteoclast stimulating factors
   5. These include IL6 and RANK ligand
   6. Myeloma cells destroy ostoprotegerin, an antagonist of RANK ligand
   7. Dickkopf1 (DKK1) is increased in myeloma patients with osteolytic lesions [6]
   8. DKK1 is an inhibitor of osteoblast differentiation

C. Presentation

1. About 20% of cases are now discovered incidently
   1. Often due to abnormal serum globulin level, low grade anemia, renal disease
   2. Monoclonal serum Ig (on serum protein electrophoresis, SPEP) is sometimes found
   3. Monoclonal Ig <3.0gm/dL without symptoms is MGUS (see above)
   4. 1-1.5% of patients with MGUS develop frank myeloma each year
   5. Smoldering Myeloma - asymtomatic (see below)
   6. Nonsecretory myeloma in ~7% of cases, often present with bone lesions [2,14]
2. Smoldering (Asymptomatic) Myeloma [39]
   1. No symptoms or end-organ damage present
   2. Serum monoclonal Ig >3gm/dL and bone marrow plasma cells >10%
   3. End-organ damage includes hypercalcemia, renal insufficiency, anemia, bone lesions, or recurrent bacterial infections
   4. Risk of progression to symptomatic myeloma is ~10%/year in first 5 years, then 3%/year thereafter, with 1%/year progression in last 10 years of study
   5. Risks at diagnosis for progression include IgA isotype, >20% plasma cells in bone marrow, serum monoclonal protein >4gmdL, lambda light chain in urine, reduced normal Igs
3. Common Symptoms
   1. Sweats (particularly at night)
   2. Myalgias, Fatigue, Weight Loss
   3. Anemia - due to bone marrow myeloma cell load and/or to inhibition of erythropoiesis
   4. Fever - may be low grade, unusual in most early stage patients
   5. Bone Pain
   6. Bone Fractures - particularly vertebral fractures and collapse; cord compression possible
   7. Infection - may be severe, including sepsis or pneumonia
   8. Renal failure ~15% present with acute renal failure (ARF) [32]
   9. Hyperviscosity
4. Physical Examination
   1. Neuropathy - including carpal tunnel syndrome, sensory abnormalities, pain
   2. Myopathy
   3. Lymphadenopathy
   4. Hepatosplenomegaly
5. Complications (see below)
   1. Bone Disease - fractures, lytic lesions, pain
   2. Resistant Anemia
   3. Recurrent (bacterial) infections (usually with reduced polyclonal immunoglobulins)
   4. Hypercalcemia
   5. Renal insufficiency or failure
   6. Amyloidosis (primary, now called AL type)
   7. Progressive neuropathies
   8. Hyperviscosity Syndrome - uncommon presentation of myeloma [8]

D. Evaluation

1. Often for Fever of Unknown Origin (FUO)
   1. Consider neoplasm, infection, collagen vascular disease (ESR often >100)
   2. Leukocyte count, ESR (often >100), Blood Smear (Rouleau Formation)
   3. Electrolytes, minerals (especially Ca2+), Liver and Renal Function, Serum Proteins
   4. Urinalysis - including sulfosalicylic acid precipitation (SSA), 24 hour urine for protein
   5. Tuburculosis Screening: PPD (+ control)
2. Bone Marrow Examination is helpful as well
   1. True multiple myeloma requires >5% plasma cells in bone marrow
   2. With <5% plasma cells in bone marrow, disease is called plasma cell dyscrasia
   3. If monoclonal gammopathy is present without true myeloma, diagnosis is MGUS
3. CT Scan of Abdomen and Chest
4. Serology for collagen vascular disease
5. Serum and Urine Protein Electrophoresis (SPEP and UPEP) [2]
   1. SPEP detects intact immunoclogulins (Igs), UPEP urinary free light (L) chains
   2. IgG most common (34% IgG kappa, 18% IgG lambda)
   3. IgA second most common (13% kappa, 8% lambda)
   4. IgM 0.5% (Waldenstrom's)
   5. IgD 2%
   6. Free kappa L chains 9%
   7. Free lambda L chains 7%
   8. Biclonal 2%
   9. Nonsecretory 7%
   10. Note: urinary Bence-Jones' Proteins are Light (L) Chains
   11. WM is due to plasma cells that secrete IgM and usually presents with hyperviscosity
   12. Nonsecretory myeloma will show no abnormalities on SPEP or UPEP [14]
6. Radiography
   1. Skeletal "survey" series for lytic lesions due to the myeloma
   2. Myeloma cells secrete osteoclast activating factors (OAF), increase bone destruction
   3. Note that nuclear medicine (technitium) bone scans are usually negative
   4. This negativity is because there is no osteoblast activity
   5. At presentation, 66% have lytic lesions, 26% have fractures [2]
7. Hyperparathyroidism (HPT) [12]
   1. ~10% of patients with primary HPT have a monoclonal gammopathy
   2. Of these, 20% had indolent myeloma
   3. 80% have monoclonal gammopathy of undetermined significance (MGUS)
   4. Serum protein electrophoresis should be performed on patients with primary HPT

E. Complications

1. Bone Disease
   1. Myeloma cells infiltrate bone and cause bone degradation (see above)
   2. Bone pain, often severe, is the immediate consequence
   3. Pathologic Bone Fractures - due to lytic lesions (non-blastic)
   4. Increased bone resorption leads to hypercalcemia
   5. Spinal Cord Compression
   6. Bone marrow infiltration by myeloma leads to cytopenias
   7. Bisphosphonates are very effective at attenuating bone pain, preventing hypercalcemia, reducing metastases (see below)
2. Hypercalcemia
   1. Due mainly to bone destruction by plasma cell infiltrates
   2. Causes, polyuria, polydipsia, muscle cramps, constipation
   3. Change in mental status occurs at very high calcium levels
   4. Much reduced incidence with use of bisphosphonates
3. Bacterial Infections
   1. Leading cause of death in patients with myeloma
   2. Highest risk is in first 2-3 months of chemotherapy
   3. Highest risk from Streptococcus pneumoniae, Haemophilus influenzae, herpes zoster
   4. May be reduced with IVIg infusion (as in CLL)
   5. Trimethoprim/Sulfamethoxazole (160mg/800mg) reduces infection risk during initial chemotherapy ~80% and should always be used with any DEX regimen
   6. Herpes zoster must be treated aggressively to prevent dissemination
4. Chronic Renal Failure (CRF)
   1. Renal insufficiency and CRF present in ~25% of patients with MM
   2. Presence of renal disease in MM is a poor prognostic marker
   3. "Myeloma kidney" is a syndrome with multiple etiologies
   4. Amyloidosis with light chains (AL type)
   5. Membranous nephritis / nephrotic syndrome
   6. Nephrocalcinosis (due to hypercalcemia)
   7. Recovery of renal function associated with lower creatinine levels and proteinuria
   8. Treatment of hypercalcemia and good response to chemotherapy help renal function
   9. Plasma exchange (5-7 sessions) does not significantly improve outcome in new MM patients presenting with ARF, but may reduce dependence on dialysis [32]
5. Amyloidosis [18]
   1. Primary systemic amyloidosis due to pure Ig light chain disease
   2. L chains of Abs deposit in liver and spleen, even in asymptomatic patients
   3. Major organ dysfunction can occur, mainly kidney, heart, peripheral neurons
   4. Renal dysfunction - proteinuria, azotemia
   5. Conduction anomalies and restrictive cardiomyopathy
   6. Cardiomyopathy may progress to heart failure [17]
   7. May contribute to peripheral neuropathy (mainly paresthesias and dysesthesias)
   8. Amyloid may infiltrate bone marrow leading to suppression
   9. Nuclear medicine scanning with 123-Iodinated-serum amyloid P detects disease
   10. This scan may also be used prognostically
   11. Severe organ dysfunction leads to poor prognosis [18]
6. Cytopenias
   1. Progressive infiltration of bone marrow inhibits normal hematopoiesis
   2. Anemia is probably most common
   3. Thrombocytopenia and neutropenia also occur
7. Hyperviscosity is more common with Waldenstrom's than myeloma [8]
8. Neuropathy - typically sensory (10-15% of patients)
9. Acquired Angioedema [15]
10. Systemic Capillary Leak Syndrome (SCLS)
    1. Very rare, chronic, intermittant capillary hyperpermeability
    2. Due to shift in fluid and protein from intravascular to interstitial space
    3. Result is anasarca, weight gain, and renal failure (due to hypoperfusion)
    4. Serum albumin drops and hematocrit increases
    5. Nearly all patients have a monoclonal gammopathy and some have frank myeloma
    6. No clear direct role for monoclonal component in pathogenesis of disease
    7. More likely that immune dysregulation with systemic lymphocyte activation is involved
    8. Interleukin 2 infusions can cause a similar syndrome
    9. Glucocorticoids, plasma exchange, intravenous immune globulin have been used
11. Necrobiotic Xanthogranuloma [11]
    1. Uncommon disease with granulomas affecting skin, heart, and/or lungs
    2. Often found with myelomas or monoclonal gammopathies
    3. Pathological classification includes giant cells
    4. May be mistaken for sarcoidosis
    5. Skin lesions are yellow papules, nodules, may be invasive
    6. Appear like xanthomas in many cases
    7. Includes childhood forms and Erdheim-Chester Syndrome
    8. Responds to glucocorticoids and may require low dose alkyling agents

E. Staging

1. Stage I
   1. Hemoglobin >10mg/dL
   2. Serum calcium value normal (<10mg/dL)
   3. Normal bone structure on radiography or solitary bone plasmacytoma only
   4. Low M-component: IgG <5gm/dL, IgA <3gmd/L, urine L chain M-component <4gm/24h
2. Stage II - not stage I or stage III
3. Stage III
   1. Hemoglobin value <8.5 gm/dL OR
   2. Serum calcium value >12mg/dL OR
   3. Advanced lytic bone lesions (scale 3) OR
   4. High M-component: IgG >7gm/dL, IgA >5gm/dL, urine L chain M-component >12gm/24h
4. Renal Subclassifications
   1. Subclassification A: renal function creatinine <2mg/dL
   2. Subclassification B: renal function creatinine >2mg/dL

G. Treatment [1,2,3]

1. Treatment is Given for Patients with Symptoms or Complications
   1. Early stage disease without symptoms - no therapy
   2. Smoldering myeloma following chemotherapy - no further therapy
   3. Single Bony lesion - 4500 cGy irradiation eradicates nearly all tumors
   4. Irradiation of single bony lesions provides good long term survival rates
   5. Major decision is whether patient is or will be candidate for stem cell transplant
   6. Regimens differ depending on whether tranpslant is anticipated [2]
2. Standard or High Dose Therapy [28]
   1. High dose therapy/stem cell transplant (HDT/SCT) recommended where acceptable
   2. HDT/SCT requires age <65 years in most centers and studies
   3. Good renal function, performance status, stable comorbidities also required
   4. Transplant is current recommended in ~40% of myeloma patients
   5. Transplant candidates are usually given VAD therapy initially to induce remission
   6. Median survival age <65 with standard chemotherapy ~42 months
   7. Median survival age <65 with HDT/SCT ~54 months
   8. Double autologous HDT/SCT appears superior to single transplantation [26]
   9. Autologous stem cell transplant following melphalan for AL amyloidosis associated with MM provides median survival 4.6 years [25]
   10. Allograft from HLA-identical sibling superior to autograft after initial autograft for primary treatment of MM with 80 versus 54 month overall survival [37]
3. Initial Chemotherapy
   1. Provides remission induction and potential for future HDT/SCT
   2. Provides relief of symptoms, hypercalcemia, renal dysfunction, other organ dysfunction
   3. Increasing number of agents with good activity are being used
   4. Vincristine / Adriamycin (doxorubicin) / Dexamethasone (VAD)
   5. Thalidomide (THAL) ± dexamethasone (DEX)
   6. Melphalan / Prednisone (MP) with thalidomide (MPT) now standard in elderly persons [16]
   7. Bortezomib (Velcade®)
   8. Combinations of bortezomib with older agents associated with >90% response rates
   9. Alkylating agents are avoided if SCT is being considered
4. VAD and other Parenteral Chemotherapies
   1. Usually used for patients <65 years
   2. Four to 6 cycles provides rapid reduction in M-protein and rapid symptom improvement
   3. Most activity likely due to DEX
   4. Overall response rate ~50% with <5% complete remissions
   5. VAD preferred over MP for patients who may undergo HDT/SCT
   6. VAD does not improve survival over MP but does allow stem cell mobilization
   7. VBMCP (vincristine, BCNU, melphalan, cylophosphamide, prednisone): ~65% response rate
   8. Other combinations may provide higher response rate but no greater survival than VAD
5. Thalidomide (THAL; Thalomid®) [3,20,27,29]
   1. Antiangiogenic oral agent, reduces TNFa, IL6, and IL10 levels
   2. Stimulates lymphocytes (both CD4 and CD8)
   3. Overall ~35% response rate (response = more than 25% paraprotein reduction)
   4. Duration of responses of single agent ~3-6 months second line
   5. THAL is useful in patients relapsing after initial therapy or in combination up front [33]
   6. THAL may be combined safely with MP or bortezomib (Velcade®)
   7. MP with thalidomide (MPT) now standard first line in >65 year old or poor performance patients with 51 month versus MP alone 33 month median morality [16]
   8. After stem cell transplantation reduces relapse risk but no effect on overall survival [9]
   9. Initial dose 100-200mg daily, maximal 400mg qpm but unclear dose-response
   10. Common side effects: fatigue, somnolence, constipation, weakness
   11. Side effects, particularly painful peripheral neuropathy, become limiting over time
   12. 30-50% of patients develop painful peripheral neuropathy with use >6 months
   13. Patients with neuropathy often improve with reduction in dose (or temporary cessation)
   14. THAL combined with chemotherapy has increased risk of venous thromboembolism (VTE)
   15. Anticoagulant prophylaxis for VTE reduces risk
   16. THAL combined with glucocorticoids has increased risk of side effects [29]
   17. Hypothyroidism occurs in ~10% of MM patients treated with thalidomide [21]
   18. Laxatives or stool softeners should be used to prevent severe constipation
6. Lenalidomide (Revlimid®) [2,27,34]
   1. Thalidomide derivative approved for MM and myelodysplastic syndrome (MDS)
   2. Oral agent with very good anti-myeloma activity when combined with dexamethasone (DEX)
   3. Lenalidomide plus DEX can give >90% responses front-line
   4. Lenalidomide plus DEX increased progression free survival (11.3 months) and overall survival (>29 months) versus DEX alone (4.7 and and 20 months) in relapsed MM [40,41]
   5. Early data on lenalidomide + bortezomib as initial therapy: 100% response rate and 35% complete response rate (full doses of each drug were used)
   6. Lenalidomide also approved for myelodysplastic syndromes (MDS) with chrom 5q- abnormality
   7. Main side effects are neutropenia, thrombocytopenia, VTE
   8. Diarrhea, rash, pruritus and fatigue also common
   9. Dose is 25mg qd for days 1-21 of 28 day cycle
   10. Combined with DEX given 10-40mg qd on days 1-4, 9-12, 17-20 of 28 day cycle
7. Bortezomib (PS-341, Velcade®) [1,3,23,24]
   1. Proteasome inhibitor that selectively blocks intracellular 26S proteasome [35]
   2. Directly toxic to myeloma cells and reduces myeloma-stromal interactions
   3. Response rate ~30% in highly refractory patients (4-5 prior lines of therapy)
   4. Disease control (response or stabilization) in ~60% of refractory patients
   5. Response rate ~38% in relapsed myeloma, superior mortality reduction versus DEX [30]
   6. Highly active in first and second line diseaes, alone or in combination
   7. Generally well tolerated with mild diarrhea, fatigue, thrombocytopenia
   8. Peripheral neuropathy may be exacerbated, primarily with pre-existing neuropathy
   9. Dose is 1.0-1.3mg/m2 twice weekly for 2 out of 3 weeks (one cycle)
   10. Effective at first relapse as well as in refractory disease
   11. FDA approved for relapsed and/or refractory myeloma
   12. May be combined with THAL, liposomal doxorubicin, DEX, MP, adriamycin
   13. First-line bortezomib is highly effective alone or with THAL and/or DEX or lenalidomide/DEX
8. High Dose DEX
   1. High dose DEX is very effective in inducing remission
   2. Response rate ~45% when used first line
   3. Response rate ~18% in relapsed MM [30]
   4. DEX is the most active agent in the VAD regimen and may be used alone prior to HDT/SCT
   5. Dose 40mg/d po on days 1-4, 9-12, 17-20 every 5 weeks
   6. No effect on stem cells so may be used prior to transplant
   7. THAL added to DEX has reported 64% response rate as initial therapy
   8. Bortezomib is superior to dexamethasone in response and mortality in relapsed MM [30]
   9. High risk of myopathy (proximal muscle weekness) and opportunistic infections
9. MP Regimens [33]
   1. Oral melphalan + prednisone (MP) had been standard for patients >60-65 years
   2. Melphalan 0.15mg/kg po + prednisone 60mg po qd each for 7 days every 6 weeks
   3. Alternative: melphalan 0.25mg/kg + prednisone 2mg/kg po qd each for 4 days q 6 weeks
   4. Treatment continued for up to 72 weeks or up to 6 months after plateau phase
   5. Response rate 50% with complete remissions <10% [16]
   6. Median surival ~3 years; 5 year survival ~25%
   7. Addition of thalidomide 100-400mg po qd to MP (MPT): 3 year survival 80% [16,33]
   8. MPT has median survival 51 months; now first line in 65-74 year olds [16]
   9. Bortezomib can also be added to MP with improvement in response rate, progression
   10. MP should not be used prior to HDT/SCT because of bone marrow suppression
10. HDT/SCT
    1. For patients <65 years, improves median survival to 54 months (versus 42 months) [28]
    2. Double transplant had 42% 7 year survival versus 21% with single transplant [26]
    3. Generally reserved for patients who have responded to induction chemotherapy
    4. Following VAD induction chemotherapy, stem cells mobilized with G-CSF
    5. Bone marrow then ablated with high dose melphalan IV (200mg/m2)
    6. Bone marrow may also be ablated with melphalan 140mg/m2 + total body irradiation
    7. Autologous stem cells are then reinfused with growth factor support
    8. Purging peripheral stem cells of myeloma cells or selecting CD34+ not beneficial
    9. Two consecutive (dual) stem cell transplantation may improve overall survival
    10. Response rate ~75%, complete remissions 20-30% (slightly higher with double transplant)
    11. 5-year survival 52% but drops off with single transplant
    12. Double transplant clearly superior to single particularly with poor initial response [26]
    13. Double transplant with allograft from HLA-identical sibling after initial autograft superior to two autografts [37]
    14. High dose melphalan with autologous stem cell support benefit MM component and renal disease in primary amyloidosis [19]
    15. Mortality ~4% with single transplant, ~6% for tandem transplants [26]
    16. Mortality much higher for patients with primary amyloidosis and organ dysfunction
11. Allogeneic Transplantation [1,3]
    1. Potential for graft versus myeloma effect
    2. No contamination of grafted cells with myeloma cells
    3. Possibly leads to cures in some patients
    4. Mortality rates as high as 30% reported (mainly graft versus host disease, GVHD)
    5. Mini-allogeneic transplants are being investigated (15-20% associated mortality)
    6. Allogeneic transplantation generally considered experimental
12. Interferon alpha [2]
    1. Main emphasis has been on improving duration of remission
    2. Maintenance therapy 2-3MU/m2 x 3 per week
    3. Some studies have shown benefit; others have not
    4. This agent is now rarely used and no longer recommended
    5. Pegylated INFa is now available, less toxic and may be more effective
13. Interleukin 6 Blockade
    1. High affinity anti-IL6 antibodies or receptor blockers have been used
    2. May provide some slow down of tumor growth in resistant disease
    3. Inhibitors of nuclear factor kappa B (such as proteasome inhibitors) also reduce IL6
14. Erythropoietin (Procrit®, Epoietin®, Aranesp®, others) [38]
    1. May decrease need for transfusion in selected patients
    2. Target hemoglobin (Hb) no higher than 12gm/dL
    3. Hb >12gm/dL associated with increased mortality rates

G. Treatment of Bone Disease [22]

1. Bisphosphonates are recommended for all patients with myeloma
   1. Pamidronate (Aredia®) 90mg q month x 9 infusions substantially reduced bone disease
   2. Infusion is given intravenously (IV) with fluid hydration over 2 hours
   3. Pamidronate reduced bone pain, hypercalcemia, and pathologic fractures
   4. Pamidronate effective whether patients were receiving first or second line therapy
   5. Zoledronate (Zometa®) is as effective than pamidronate and can be administered IV administered intravenously over 15 minutes [22]
   6. Clodronate (Lytos®) - 1040mg/day often used ex-US [16]
2. Kyphoplasty is a fracture-reduction technique where polymethylmethacrylate is injected into vertebral compression fractures; restores height and reduces pain [1]
3. Osteonecrosis of the Jaw [31]
   1. Increasing reports of association with certain bisphosphonates
   2. Zoledronic acid has increased risk of jaw osteonecrosis compared with pamidronate
   3. In myeloma patients on zolendronic acid, up to 10% develop jaw osteonecrosis in 3 years
   4. Glucocorticoid use did not appear to contribute to jaw osteonecrosis

H. Prognosis

1. Poor Prognostic Factors
   1. High Tumor Mass (replacement of bone marrow by tumor cells)
   2. Hypercalcemia
   3. Bence - Jones' Proteinemia - renal deposition, amyloidosis
   4. Renal dysfunction (creatinine >2mg/dL) at diagnosis
   5. Chrom 13 deletion
   6. IgA and Lambda type myeloma have the worst prognosis
   7. Elevated ß2-microglobulin levels at diagnosis also have poor prognosis
   8. High lactate dehydrogenase at baseline is poor prognosis
   9. Age is poor prognosis
2. Prognosis [1,2]
   1. Conventional Therapy - ~3 years overall survival, event free for <2 years
   2. Double HDT/SCT may provide ~50% 5 year survival and ~40% 7 year survival
   3. Serum amyloid P retention >50% has median survival ~11 months
   4. Serum amyloid P retention <50% has median survival 24 months
   5. Newer agents probably permit extension of median survival to >5 years overall
3. Necrobiotica xanthogranuloma has good prognosis with current therapy

Resources

Corrected Serum Calcium for Albumin

References

1. Sirohi B and Powles R. 2004. Lancet. 363(9412):875
2. Kyle RA and Rajkumar SV. 2008. Blood. 111(6):2962
3. Kyle RA and Rajkumar SV. 2004. NEJM. 351(18):1860
4. Kyle RA, Therneau TM, Rajkumar SV, et al. 2002. NEJM. 346(8):564
5. Glass DA II, Patel MS, Karsenty G. 2003. NEJM. 349(26):2479
6. Tian E, Zhan F, Walker R, et al. 2003. NEJM. 349(26):2483
7. Kyle RA, Therneau TM, Rajkumar SV, et al. 2006. NEJM. 354(13):1362
8. Weinstein R and Mahmood M. 2002. NEJM. 346(8):603 (Case Record)
9. Barlogie B, Tricot G, Anaissie E, et al. 2006. NEJM. 354(10):1021
10. Richardson PG, Kassarjian A, Jing W. 2004. NEJM. 351(25):2637 (Case Record)
11. Heald P and Duncan LM. 1998. NEJM. 338(16):1138
12. Arnulf B, Bengoufa D, Sarfati E, et al. 2002. Arch Intern Med. 162:464
13. Munshi NC, Digumarthy S, Rahemtullah A. 2008. NEJM. 358(17):1838 (Case Record)
14. Reilly BM, Clarke P, Nikolinakos P. 2003. NEJM. 348(1):59 (Case Discussion)
15. Fremeaux-Bacchi V, Guinnepain MT, Cacoub P, et al. 2002. Am J Med. 113(3):194
16. Facon T, Mary JY, Hulin C, et al. 2007. Lancet. 370(9594):1209
17. Sinha MK, Lachmann HJ, Kuriakose B, et al. 2001. Lancet. 357(9267):1498 (Case Report)
18. Gertz MA, Lacy MQ, Dispenzieri A, et al. 2002. Am J Med. 113(7):549
19. Dember LM, Sanchorawala V, Seldin DC, et al. 2001. Ann Intern Med. 134(9):746
20. Singhal S, Mehta J, Desikan R, et al. 1999. NEJM. 341(21):1565
21. Badros AZ, Siegel E, Bodenner D, et al. 2002. Am J Med. 112(5):412
22. Zoledronate. 2001. Med Let. 43(1120):110
23. Mitchell BS. 2003. NEJM. 348(26):2597
24. Richardson PG, Barlogie B, Berenson J, et al. 2003. NEJM. 348(26):2609
25. Skinner M, Sanchorawala V, Seldin DC, et al. 2003. Ann Intern Med. 140(2):85
26. Attal M, Harousseau JL, Facon T, et al. 2003. NEJM. 349(26):2495
27. Kumar S, Gertz MA, Dispenzieri A, et al. 2003. Mayo Clin Proc. 78(1):34
28. Child JA, Morgan GJ, Davies FE, et al. 2003. NEJM. 348(19):1875
29. Dimopoulos MA and Eleutherakis-Papaiakovou V. 2004. Am J Med. 117(7):508
30. Richardson PG, Sonneveld P, Schuster MW, et al. 2005. NEJM. 352(24):2487
31. Durie BGM, katz M, Crowley J. 2005. NEJM. 353(1):99
32. Clark WF, Stewart AK, Rock GA, et al. 2005. Ann Intern Med. 143(11):777
33. Palumbo A, Bringhen S, Caravita T, et al. 2006. Lancet. 367(9513):825
34. Lenalidomide. 2006. Med Let. 48(1232):31
35. Reinstein E and Ciechanover A. 2006. Ann Intern Med. 145(9):676
36. Blade J. 2006. NEJM. 355(26):2765
37. Bruno B, Rotta M, Patriarca F, et al. 2007. NEJM. 356(11):1110
38. Erythropoietin Safety Concerns. 2007. Med Let. 49(1260):37
39. Kyle RA, Remstein ED, Therneau TM, et al. 2007. NEJM. 356(25):2582
40. Dimopoulos M, Spencer A, Attal M, et al. 2007. NEJM. 357(21):2123
41. Weber DM, Chen C, Niesvizky R, et al. 2007. NEJM. 357(21):2133