Wednesday, April 7, 2010

April 6th - LBJ - Multiple Myeloma/Amyloid

Today at Morning Report a Case of Multiple Myeloma was Presented. Here is a brief overview of the disease and what you'll need to know for boards regarding plasma cell disorders and amyloidosis

Multiple Myeloma is the most common malignant plasma cell dyscrasia. There are many other malignant and secondary plasma cell disorders, most of which are beyond what you'll need for boards.  Also keep in mind there are various subsets of non-malignant plasma cell disorders (i.e. MGUS) which you should be aware of

Multiple Myeloma - Presenting Symptoms/Physical Exam
General - Fatigue and Weight Loss are Common
Anemia - Pallor is the most common finding on examination
Bone Pain, Osteopenia and Pathologic Fractures - From Osteoclast activity and Lytic Lesions
Renal Failure - Symptoms of azotemia from light chain deposition or calcium impairment of renal perfusion
Nephrotic Syndrome - Can present with edema, increased risk of thrombosis
Hypercalcemia - Can present as various symptoms (i.e. confusion, renal stones, constipation etc)
Recurrent Infections - Due to Immunglobulin Disease
Bleeding Tendancy - Platelet and Coagulation Dysfunction
Neurologic Complications - Radiculopathy, Cord Compression, Polyneuropathy
Leukostasis - Uncommon, but with a very high plasma cell burden - patients can get Blurred Vision/Headache/Heart Failure/Dyspnea.

Always think of Myeloma in a patient (especially elderly) with anemia, renal failure and hypercalcemia

Lab Findings/Workup/Diagnosis:
In General, to diagnose Multiple Myeloma we use the Working Group Criteria or the WHO Criteria. Although there are other lab findings that are not specific parts of the diagnostic criteria. In general, the WHO criteria are a bit more pathology based, and the Working Group is more clinically based.  I'll put both of them here so you are aware:

The diagnosis of multiple myeloma requires a minimum of one major Criterion  + one minor criterion OR
three minor criteria with bone marrow plasma cells >10% or a monoclonal protein

Major criteria
I Plasmacytoma on tissue biopsy
II Bone marrow plasmacytosis with > 30% plasma cells
III Monoclonal globulin spike on serum electrophoresis (> 3 g/dL for IgG, > 2 g/dL for IgA) or on concentrated urine electrophoresis (> 1g/24h of k or l light chains)

Minor criteria
Bone marrow plasmacytosis 10 to 30% plasma cells
Monoclonal globulin spike less than the level defined above
Lytic bone lesions
Residual normal IgM <0.05 g/gL, IgA < 0.1g/dL, IgG < 0.6g/dL

Working Group:
1 - Monoclonal Plasma Cells in Bone Marrow >10% OR a plasmocytoma on biopsy
2 - Monoclonal Protein in serum or urine (send SPEP and UPEP with IF and Serum Light Chain Analysis)
3 - Any one of the following organ related diseases:
     Calcium Elevated, Renal Insufficiency, Anemia, Lytic Bone Lesions or Osteopenia
Other Lab Findings in patients with myeloma:
BUN decreased
Negative anion Gap acidosis
Proteinuria of various severity on Ua
Globulin Gap
Alk Phos is NORMAL (remember this increases with blastic disease, not lytic disease)
Send LDH and B2 Microglobulin for staging and prognosis

The mainstay of treatment is supportive care: 
Transfusions for severe anemia and most patients should get EPO for anemia
Dialysis for Renal Failure
Bisphosphonates for lytic lesions
Saline and bisphosphonates for hypercalcemia
Prophylactic immunizations
Monthly Immune Globulin Infusion for recurrent infections
Radiation Therapy for Plasmacytomas or refractory bone pain

Remission is rare in patients, and is usually best achieved with autologous bone marrow transplantation. However, this is usually offered to patients that are <70 years old with good performance status - and unfortunately most patients with myeloma do not fit into this category

Positive Response to treatment is seen in about half of patients that recieve various combinations of treatment - including alkylating agents, steroids, anthracyclines and thalidomide.  Chemotherapy regimens including doxorubicin and vincristine are used with treatment failure. Lenalidomide, an analog of thalidomide, has less side effects (i.e. less fatigue) but also carries the risk of thromboembolic disease.  Bortezomib is a proteasome inhibitor that has been used as well. 

Non-Malignant Plasma Cell Disorders. Most are here to be completen, but you should really know MGUS for boards:
1) Monoclonal Gammopathy of Undetermined Signficiance - Less than 10% Plasma Cells with no symptoms or systemic complications.  This is present in about 2% of patients >50 years olf.  Annually, about 2% of patients transform into Myeloma - and about 20% will get myeloma during their lifetime. So, these patients need regular SPEP and UPEPs and physical exams/visits with clinicians to look out for progression to myeloma.  BM Bx will be needed in patients with MGUS that have concerning signs/symptoms that are a change from their regular status.  MGUS is seen in the general population, but is seen with increased incidence in those with autoimmune diseases, cirrhosis, and HIV

2) Smolering Myeloma - Plasma Cells greater than 10% but less than 30% without signs/symptoms

3) Indolent Myeloma - Plasma Cells greater than 10% but less than 30% with only mild anemia or <3 lytic lesions

Waldenstrom's Macroglobulinemia
This disease is causes by increased secretion of IgM paraprotein by plasma cells (as opposed to IgA or IgG in Myeloma.)  Can present very similar to MM, but these patients are at a higher risk of getting a hyperviscosity syndrome (CHF, AMS, MI, CVA, Retinal Complaints) and organomegaly is common. Treat hyperviscosity with plasmapheresis + Chemotherapy (agents used include rituximab, chlorambucil or fludarabine)


Think of AL Amyloidosis in a patient with any plasma cell dyscrasia that has a change in symptoms (especially CHF). There are multiple other forms of amyloid (i.e. AA and inflammatory conditions such as Familial Mediterranean Fever) 

There are multiple findings/clues for amyloid:

General: Constitutional Symptoms
Skin: Purpura around face, neck, eyelids, “Shoulder Pad Sign,” Nodules
CV: Congestive Heart Failure Symptoms, Conduction Blocks, Arrythmias
GI: Dysmotility, Obtruction, Organomegaly
Heme: Anemia, DIC, Bleeding
Nervous System: Paresthesias, syncope, changes in bowel movement, carpal tunnel
Other: Change in Voice/Macroglossia

Remember that CHF is the cause of Death in over half of patients with myeloma.  They will have a restrictive pattern of filling, and classic septal hypertrophy changes/"snowstorm" appearance of the septum:

Diagnosis of Amyloid: 
Biopsy of an affected site will give the best yield. So if there is renal failure you may consider renal biopsy.  This will have the highest yield, but of course risks vs benefits must be weighed.  Other less invasive ways to diagnose include: Abdominal Fat Pad or Rectal Biopsy for Congo red stain (looking for apple-green bifringence). These have a reported diagnostic yield of between 70-85%
Best survival with high-dose melphalan and stem cell transplant, but this is not offered to most patients

Images Courtesy of:
University of Virginina Dept of Heme/Onc & - information page on AL Amyloidosis

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