A 72-year-old African American man presents with progressive fatigue, difficulty breathing on exertion, and lower extremity swelling for 3 months. The patient was seen at the emergency department 2 times before. The first time was because of back pain, and the second was because of fever and cough. He took medications at the emergency room, but he refused to do further tests recommended to him. He does not smoke or drink alcohol. His family history is irrelevant. His vital signs include a blood pressure of 110/80 mm Hg, temperature of 37.2°C (98.9°F), and regular radial pulse of 90/min. On physical examination, the patient looks pale, and his tongue is enlarged. Jugular veins become distended on inspiration. Pitting ankle edema is present on both sides. Bilateral basal crackles are audible on the chest auscultation. Hepatomegaly is present on abdominal palpation. Chest X-ray shows osteolytic lesions of the ribs. ECG shows low voltage waves and echocardiogram shows a speckled appearance of the myocardium with diastolic dysfunction and normal appearance of the pericardium. Which of the following best describes the mechanism of this patient’s illness?

Deposition of an extracellular fibrillar protein that stains positive for Congo red in the myocardium

Thickening of the parietal pericardium with dystrophic calcification

Calcification of the aortic valve orifice with obstruction of the left ventricular outflow tract

Concentric hypertrophy of the myocytes with thickening of the interventricular septum

Diastolic cardiac dysfunction with reciprocal variation in ventricular filling with respiration

A 73-year-old man comes to the physician because of progressive fatigue and shortness of breath on exertion for 3 weeks. He has swelling of his legs. He has not had nausea or vomiting. His symptoms began shortly after he returned from a trip to Cambodia. He occasionally takes ibuprofen for chronic back pain. He has a history of arterial hypertension and osteoarthritis of both knees. He had an episode of pneumonia 4 months ago. His current medications include lisinopril and hydrochlorothiazide. He has no history of drinking or smoking. His temperature is 37°C (98.6°F), pulse is 101/min, and blood pressure is 135/76 mm Hg. Examination shows pitting edema of the upper and lower extremities. Laboratory studies show: Hemoglobin 14.1 g/dL Leukocyte count 6,800/mm3 Platelet count 216,000/mm3 Serum Urea nitrogen 26 mg/dL Creatinine 2.9 mg/dL Albumin 1.6 g/dL Urine Blood negative Protein 4+ Glucose negative Renal biopsy with Congo red stain shows apple-green birefringence under polarized light. Further evaluation of this patient is most likely to show which of the following findings?

Rouleaux formation on peripheral smear

Positive interferon-γ release assay

Elevated anti-citrullinated peptide antibodies

A 67-year-old man presents to the emergency department with altered mental status. The patient is non-verbal at baseline, but his caretakers at the nursing home noticed he was particularly somnolent recently. The patient has a past medical history of diabetes and Alzheimer dementia. His temperature is 99.7°F (37.6°C), blood pressure is 157/98 mmHg, pulse is 150/min, respirations are 16/min, and oxygen saturation is 98% on room air. Laboratory values are obtained and shown below. Hemoglobin: 9 g/dL Hematocrit: 33% Leukocyte count: 8,500/mm^3 with normal differential Platelet count: 197,000/mm^3 Serum: Na+: 139 mEq/L Cl-: 102 mEq/L K+: 4.3 mEq/L HCO3-: 25 mEq/L BUN: 37 mg/dL Glucose: 99 mg/dL Creatinine: 2.4 mg/dL Ca2+: 12.2 mg/dL The patient has lost 20 pounds over the past month. His parathyroid hormone is within normal limits, and his urinary calcium is increased. Physical exam demonstrates discomfort when the patient's lower back and extremities are palpated. Which of the following is the most accurate diagnostic test for this patient's underlying diagnosis?

Urine, blood, and cerebrospinal fluid cultures

A 60-year-old woman comes to the physician because of lower back pain, generalized weakness, and weight loss that has occurred over the past 6 weeks. She also says that her urine has appeared foamy recently. Physical examination shows focal midline tenderness of the lumbar spine and conjunctival pallor. Her temperature is 100.5°F (38°C). A photomicrograph of a bone marrow biopsy specimen is shown. Further evaluation of this patient is most likely to show which of the following findings?

Grouped erythrocytes with stacked-coin appearance

Myeloblasts with needle-shaped cytoplasmic inclusions

Erythrocytes with cytoplasmic hemoglobin inclusions

Neutrophils with hypersegmented nuclear lobes

B-lymphocytes with radial cytoplasmic projections

A 62-year-old retired professor comes to the clinic with the complaints of back pain and increasing fatigue over the last 4 months. For the past week, his back pain seems to have worsened. It radiates to his legs and is burning in nature, 6/10 in intensity. There is no associated tingling sensation. He has lost 4.0 kg (8.8 lb) in the past 2 months. There is no history of trauma. He has hypertension which is well controlled with medications. Physical examination is normal. Laboratory studies show normocytic normochromic anemia. Serum calcium is 12.2 mg/dL and Serum total proteins is 8.8 gm/dL. A serum protein electrophoresis shows a monoclonal spike. X-ray of the spine shows osteolytic lesions over L2–L5 and right femur. A bone marrow biopsy reveals plasmacytosis. Which of the following is the most preferred treatment option?

Chemotherapy and autologous stem cell transplant

A previously healthy 68-year-old woman is brought to the emergency department because of a 3-day history of nausea, anorexia, polyuria, and confusion. Her only medication is acetaminophen, which she takes daily for back pain that started 6 weeks ago. Physical examination shows conjunctival pallor. She is oriented to person but not to time or place. Laboratory studies show a hemoglobin concentration of 9.3 g/dL, a serum calcium concentration of 13.8 mg/dL, and a serum creatinine concentration of 2.1 mg/dL. Her erythrocyte sedimentation rate is 65 mm/h. Which of the following is the most likely underlying cause of this patient's condition?

Overproliferation of plasma cells

Decreased renal excretion of calcium

Excess PTH secretion from parathyroid glands

Plasma cell disorders for USMLE Step 1: High-Yield Pathology Lessons

MGUS & Intro - The Quiet Spike

Monoclonal Gammopathy of Undetermined Significance (MGUS): Asymptomatic premalignant clonal plasma cell proliferation.
Key Criteria:
- Serum M-protein < 3 g/dL
- Clonal bone marrow plasma cells < 10%
- Absence of CRAB criteria (hypercalcemia, renal failure, anemia, bone lesions).

⭐ The vast majority of Multiple Myeloma cases are preceded by an MGUS stage.

Multiple Myeloma - CRAB's Bone Party

Malignant proliferation of plasma cells in bone marrow, producing monoclonal immunoglobulin (usually IgG > IgA).
Presents in elderly; most common primary tumor of bone.

Pathophysiology & Diagnosis

M-spike on serum protein electrophoresis (SPEP).
Bone marrow biopsy: >10% clonal plasma cells.
Peripheral smear: Rouleaux formation (RBCs stacked like coins).
Urine: Bence-Jones proteins (Ig light chains) → renal failure.

📌 CRAB Criteria for End-Organ Damage:

Calcium ↑ (Hypercalcemia)
Renal insufficiency
Anemia (normocytic, normochromic)
Bone lesions / Back pain
- Lytic, "punched-out" lesions on X-ray, especially in the skull and vertebral column.

Skull X-ray: Multiple Myeloma "Punched-Out" Lesions

⭐ Rouleaux formation is caused by decreased charge between RBCs due to increased serum protein (paraproteins).

Waldenström's - The IgM Giant

Lymphoplasmacytic lymphoma defined by a monoclonal IgM M-spike.
Causes hyperviscosity syndrome due to large IgM pentamers.
- Presents with blurry vision, headaches, vertigo, Raynaud phenomenon.
- Unlike Multiple Myeloma, no lytic bone lesions or hypercalcemia.
Diagnosis: Bone marrow biopsy shows >10% clonal lymphoplasmacytic cells.

⭐ Hyperviscosity syndrome (e.g., sausage-link retinal veins) is the classic presentation and a medical emergency requiring plasmapheresis.

Fundoscopy: Retinal Veins in Waldenstrom Macroglobulinemia

AL Amyloidosis - Misfolded Mayhem

Pathophysiology: Clonal plasma cells produce misfolded Ig light chains (λ > κ), forming insoluble β-pleated sheets that deposit in tissues.
Key Manifestations:
- Heart: Restrictive cardiomyopathy (primary cause of death).
- Kidney: Nephrotic syndrome.
- Classic Signs: Macroglossia, periorbital purpura ("raccoon eyes").
Diagnosis: Tissue biopsy showing apple-green birefringence with Congo red stain under polarized light.

AL Amyloidosis: Congo Red & Apple-Green Birefringence

⭐ Despite thickened ventricular walls on echocardiogram, the EKG in cardiac amyloidosis classically shows low voltage QRS complexes.

High‑Yield Points - ⚡ Biggest Takeaways

Multiple Myeloma presents with the CRAB criteria: Calcium ↑, Renal failure, Anemia, and lytic Bone lesions.

Diagnostics show a monoclonal M-protein spike (IgG > IgA) and Bence Jones light chains in the urine.

Peripheral smear classically shows Rouleaux formation (stacked RBCs).

Waldenström macroglobulinemia features an IgM spike, causing hyperviscosity syndrome but no lytic bone lesions.

MGUS is an asymptomatic precursor with a smaller M-spike and <10% bone marrow plasma cells.

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