Setting: office
CC: “I coughed, and my chest has been sore ever since.”
VS: BP: 112/76 mm Hg; P: 76 beats/minute; T: 98°F; R: 24 breaths/minute
HPI: A 64-year-old man comes to the office with pain on the right side of his chest after a coughing spell a few days ago. He went to his local ED last night and an x-ray showed two fractured ribs. He has had a few episodes of bronchitis and pneumonia in the last 2 years. Old x-rays are compared and definitely showed no lesions in the past.
PMHX:
Fatigue
Anemia
Nephrolithiasis earlier this year
“Pathologic” Fracture
• Break during normal use
ROS:
Losing height, 2 inches shorter than he was
Medications:
Vitamins
PE:
General: tired, in visible pain when he moves
Chest: focal tenderness over site where fractures were found
Cardiovascular: normal
Rectal: no masses
Initial Orders:
Chest x-ray
Rib x-ray
Vertebral and spine x-ray
Complete blood count (CBC)
Comprehensive metabolic panel (CHEM-20)
Acetaminophen
Look for vertebral compression fractures when looking for pathological fracture.
Prostate cancer likes to metastasize to the bone.
Reports:
Chest x-ray: no pneumothorax; no pneumonia
Rib x-ray: two fractures, three lytic lesions
Vertebral and spine x-ray: compression fracture T4, T5
CBC: hematocrit 32%; mean corpuscular volume (MCV) 86 fL
CHEM-20: high total protein; normal albumin; calcium 11.5 mg/dL (elevated)
What will a nuclear bone scan show in myeloma?
a. Increased uptake diffusely
b. Increased uptake at lytic lesion sites
c. No change in uptake
Answer c. No change in uptake
Nuclear bone scans do not pick up extra technetium isotope in myeloma. The lesions in myeloma are purely lytic (Figure 9-3). Nuclear bone scans show where there is blastic activity as well. Metastases are a mix of lytic and blastic activity and so is osteomyelitis.
Figure 9-3. Myeloma lesions: Radiolucent or darker areas represent lytic lesions. (Reproduced with permission from Kaushansky K, et al. Williams Hematology, 8th ed. New York: McGraw-Hill; 2010.)
Nuclear isotope is deposited by osteoblasts.
There is no specific therapy for rib fractures beyond analgesia. You want to reduce pain so the patient does not “splint” when there is pain, reduce breathing, and develop a pneumonia.
“Splinting”: reducing ventilation secondary to rib pain
Orders:
Bisphosphonates (pamidronate, alendronate)
Serum protein electrophoresis (SPEP)
Peripheral blood smear
Uric acid level
Urinalysis (UA)
Oncology evaluation
Bisphosphonate inhibits osteoclasts.
High Total Protein = SPEP
Report:
SPEP: monoclonal spike in immunoglobulin G (IgG) range
Smear: rouleaux formation
Uric acid: normal
UA: trace protein
Oncology evaluation: no specific recommendations
Rouleaux Formation
• Red blood cells (RBCs) appear in stacks or “rolls” on the smear.
• IgG on the RBC surface makes RBCs “stick” to each other.
• Rouleaux formation is clinically meaningless.
What is the single most specific test for myeloma?
a. SPEP
b. Bone marrow biopsy
c. Urine immunoelectrophoresis
d. Bence Jones protein
e. Peripheral blood smear
Answer b. Bone marrow biopsy
Looking for >10% plasma cells on bone marrow biopsy is the single most specific test for myeloma. When combined with a monoclonal spike on SPEP and lytic lesions, this establishes the diagnosis of myeloma (Figure 9-4). Some cancers can give lytic lesions. The monoclonal gammopathy of unknown significance (MGUS) accounts for 99% of IgG spikes on SPEP. You can have Bence Jones proteinuria alone without myeloma. The only thing that gives >10% plasma cells on bone marrow biopsy is myeloma.
Figure 9-4. Serum protein electrophoresis demonstrates an M-protein peak (left). Immunofixation electrophoresis confirms it to be monoclonal IgG lambda type. (Reproduced with permission from Katarjian HM, et al. The MD Anderson Manual of Medical Oncology, 2nd ed. New York: McGraw-Hill; 2011.)
MGUS = IgG spike
• No bone lesion
• No renal damage
• No infections
• Normal calcium level
• Normal uric acid level
Why do you get hyperuricemia in myeloma, but not in hemolysis?
a. RBCs have no nuclei.
b. Neutrophils function normally.
c. Renal insufficiency makes it accumulate.
d. Haptoglobin removes uric acid from circulation.
Answer a. RBCs have no nuclei.
Uric acid increases from increased destruction of cells that have nuclei. RBCs have no nuclei. Freshly and abnormally released purines and pyrimidines come out of the nuclei. The metabolic end product of purines and pyrimidines is uric acid. Hyperuricemia generally occurs with chemotherapy of hematologic malignancy. This is why it can be normal on initial diagnosis.
Nucleic acids are made into uric acid.
You explain to the patient that the lytic bone lesions, pathologic fractures, hypercalcemia, and hyperuricemia with a monoclonal IgG spike on SPEP likely indicate multiple myeloma.
Orders:
Bone marrow biopsy
Repeat calcium and uric acid levels
Urine immunoelectrophoresis
Beta-2-microglobulin
CBC
Basic metabolic panel (CHEM-7)
Beta-2-Microglobulin
• The level is elevated in myeloma.
• It is used as a marker of response to treatment.
Mechanism of Renal Injury in Myeloma
• IgG damages glomeruli.
• Uric acid and hypercalcemia damage tubules.
• Bence Jones proteins are toxic to the tubules.
• Amyloid accumulates.
The patient continues to be fatigued. He has a brief episode of pneumonia since the last time he saw you. He was treated with antibiotics and improved.
Reports:
Bone marrow biopsy: 24% plasma cells (Figure 9-5)
Calcium 11.2 mg/dL and uric acid normal
Urine immunoelectrophoresis: Bence Jones protein markedly elevated
Beta-2-microglobulin: elevated
CBC: hematocrit 29%
CHEM-7: creatinine 1.7 mg/dL
Figure 9-5. Multiple myeloma (marrow). The cells bear characteristic morphologic features of plasma cells, round or oval cells with an eccentric nucleus composed of coarsely clumped chromatin, a densely basophilic cytoplasm, and a perinuclear clear zone containing the Golgi apparatus. Binucleate and multinucleate malignant plasma cells can be seen. (Reproduced with permission from Longo DL, et al. Harrison’s Principles of Internal Medicine, 18th ed., Vol. 2. New York: McGraw-Hill; 2012.)
Bence Jones Protein
• Immunoglobulin fragment
• Kappa or lambda light chains
• Toxic to kidneys
• Not detected by UA
Protein Detected on UA = Albumin
Death in myeloma is from:
• Infection
• Renal failure
In myeloma, if there are excess plasma cells making excess immunoglobulins, what is the mechanism of increased infections?
a. Myeloma switches to IgA.
b. IgE is deficient.
c. Neutrophils do not work.
d. IgG in myeloma is not effective.
e. Urinary loss neutralizes excess production.
Answer d. IgG in myeloma is not effective.
Plasma cells are made in excess amounts in myeloma, but they are not useful in producing effective immunoglobulins. Plasma cells in myeloma make large amounts of ineffective IgG. They do not make the immunoglobulins that the patient needs to fight infection.
Bence Jones protein is not functional.
Myeloma
• IgG: 50%
• IgA: 20%
• Bence Jones alone: 20%
Plasma cells secrete humoral factors that destroy bone in myeloma.
The patient returns in a week after the oncologist evaluates him.
What is the best therapy for this patient?
a. Melphalan
b. Steroids
c. Autologous stem cell transplant (ASCT)
d. Allogeneic bone marrow transplant (BMT)
e. Observation
Answer c. Autologous stem cell transplant (ASCT)
Autologous BMT can be done in patients up to age 70 years. Allogeneic bone marrow from a related, matched donor should be avoided after age 50 years. Melphalan alone is inappropriate for this patient. Melphalan by itself is little better than palliation. It will not result in a sustained remission in anyone. Steroids do have a primary antileukemia effect, but they cannot be used alone.
Allogeneic BMT kills the patient from graft-versus-host disease and from graft rejection. ASCT cannot reject the patient, because it is the patient’s own marrow. Stem cell transplantation allow a shorter duration of neutropenia. The cells are already partially grown and differentiated. This allows a much shorter duration of neutropenia compared to allogeneic BMT.
Longer Duration of Neutropenia = Higher Death Rate
Allogeneic = More Chance of Cure + More Chance of Death
Autologous = Less Chance of Cure + Less Chance of Death
Collect stem cells tagged with CD34.
The patient undergoes ASCT. Move the clock forward 1 day at a time and check the CBC each day. When the patient eventually recovers his cell count, he can be sent home.
Complex cases like chemotherapy management in leukemia or myeloma are unlikely to occur as CCS cases. You will never be asked which of the chemotherapy combinations is best. It is just not clear.
As you move the clock forward, it will become clear from cell count and beta-2-microglobulin level whether the patient is recovering or needs additional chemotherapy. It is not clear which drug or set of drugs will be used for relapsed myeloma. All of the following in combination of two or three are possible:
Lenalidomide (or thalidomide)
Melphalan
Prednisone (or dexamethasone)
Bortezomib
Lenalidomide: TNF inhibitor
Bortezomib: proteosome inhibitor