Family Medicine Board Review · Case-Based · Difficult Level

Multiple Myeloma — Clinical Vignette MCQs

Board-style cases built from the myeloma summary — CRAB recognition, diagnostic pattern traps, MGUS vs. smoldering vs. active disease, and hyperviscosity. Tap "Reveal Answer" on each, then read the pearl.

10 Questions ●●●● Difficult Single Best Answer
Q1Presentation Frequency Trap●●●● Very Hard

A 71-year-old man presents with several months of progressive fatigue. Labs show hemoglobin 9.6 g/dL, calcium 9.4 mg/dL, and creatinine 1.0 mg/dL. He denies bone pain. A resident says myeloma is unlikely since he lacks the "classic" hypercalcemia and bone pain of CRAB. What is the most accurate response to the resident?

Reveal Answer

Correct answer: B

Anemia (hemoglobin <12 g/dL) is present in ~73% of patients at diagnosis — the single most common presenting finding, more frequent than bone pain (58%) or hypercalcemia (28%). Isolated unexplained anemia in an older adult should still prompt consideration of myeloma workup (SPEP, UPEP, free light chains).

Why the others are wrong A — dismisses the diagnosis based on a false premise that hypercalcemia/bone pain are required. C — CRAB criteria don't need to all be present simultaneously; any one CRAB feature attributable to the plasma cell disorder is sufficient for diagnosis of symptomatic disease. D — bone marrow biopsy is the confirmatory test, but the correct initial step is first pursuing screening labs (SPEP/UPEP/free light chains), not jumping straight to biopsy. E — hypercalcemia is actually one of the less common presenting findings (28%), not the most common.
Exam Pearl Don't let the CRAB mnemonic's ordering fool you into thinking C (hypercalcemia) is most common — anemia (A) is actually the most frequent presenting abnormality, occurring in nearly three-quarters of patients.
Q2Lab Pattern Recognition●●●●● Extreme

A 68-year-old woman has a routine comprehensive metabolic panel and LFTs drawn for a preoperative visit. Results show total protein 9.8 g/dL (elevated), albumin 2.9 g/dL (low), with the remainder of the LFT panel otherwise normal. What is the most appropriate next step?

Reveal Answer

Correct answer: B

High total protein with low albumin suggests an elevated globulin fraction. Calculating the A/G ratio — and finding it <1 — is a classic clue for a monoclonal gammopathy. This should prompt SPEP and UPEP to evaluate for an M spike and Bence Jones proteins, respectively.

Why the others are wrong A — this pattern is not a benign aging variant and warrants investigation. C — liver biopsy is not the next step; this lab pattern isn't primarily suggestive of intrinsic liver disease, and further noninvasive testing (SPEP/UPEP) should come first. D — a 1-year deferral risks missing an active plasma cell disorder that needs timely evaluation. E — albumin supplementation doesn't address the underlying cause and isn't indicated based on this finding alone.
Exam Pearl An incidental high total protein + low albumin combination on a routine panel is a classic "found on routine labs" myeloma setup. Reflexively calculate the A/G ratio — a ratio <1 should trigger SPEP/UPEP before assuming benign causes.
Q3Distinguishing Bone Disease●●●●● Extreme

A 73-year-old man presents with progressive lower back pain. Skeletal survey shows multiple punched-out lytic lesions in the skull and spine. Basic metabolic panel shows calcium 11.4 mg/dL. Which additional laboratory finding would be most consistent with multiple myeloma rather than an alternative cause of diffuse lytic bone disease (e.g., metastatic carcinoma or Paget disease)?

Reveal Answer

Correct answer: C

Despite the presence of lytic bone lesions, multiple myeloma classically presents with normal ALP and normal phosphate. This is a key distinguishing feature — other causes of lytic/destructive bone disease (e.g., osteoblastic metastases, Paget disease) often show elevated ALP due to increased osteoblastic bone turnover, which is comparatively absent in myeloma (predominantly osteoclastic-driven lysis with suppressed osteoblast activity).

Why the others are wrong A — elevated ALP would point away from myeloma toward another process with active osteoblastic turnover. B — phosphate is typically normal in myeloma, not elevated. D — myeloma classically causes hyper-, not hypo-, calcemia from bone resorption. E — LDH is often used as a prognostic/confirmatory marker and tends to be elevated, not low, in more advanced or aggressive myeloma.
Exam Pearl "Lytic lesions + normal ALP + normal phosphate" = myeloma until proven otherwise. This normal ALP finding despite active bony destruction is a frequently tested distinguishing lab pattern.
Q4MGUS vs. Smoldering vs. Active●●●●● Extreme

A 66-year-old woman is found to have an M spike on SPEP ordered for unrelated reasons. She is asymptomatic. Further workup shows no anemia, normal renal function, normal calcium, and no lytic lesions on skeletal survey. Bone marrow biopsy shows 8% clonal plasma cells. What is the most appropriate management?

Reveal Answer

Correct answer: C

An asymptomatic patient with a monoclonal protein but no CRAB features (no anemia, normal renal function, normal calcium, no lytic lesions) has either MGUS or smoldering multiple myeloma depending on the exact plasma cell percentage/protein level — both are managed with expectant management and regular follow-up, not active treatment.

Why the others are wrong A — chemotherapy is reserved for symptomatic (CRAB-positive) active multiple myeloma, not asymptomatic monoclonal gammopathy. B — no lytic lesions or fracture risk indication is described; radiotherapy isn't indicated. D — there are no signs or symptoms suggesting spinal cord compression. E — bisphosphonates are used in active myeloma with bone disease, not as first-line management of an asymptomatic finding.
Exam Pearl Finding an M spike does not equal a myeloma diagnosis requiring treatment. The presence or absence of CRAB features is what separates observation-only disease (MGUS, smoldering myeloma) from active multiple myeloma requiring oncology-directed therapy.
Q5Hyperviscosity Recognition●●●●● Extreme

A 74-year-old man with a known monoclonal gammopathy presents with new blurred vision, headache, and mucosal bleeding from his gums. Fundoscopic exam reveals retinal hemorrhages with dilated, segmented ("sausage-link") veins. What is the most likely underlying mechanism for this presentation?

Reveal Answer

Correct answer: B

This constellation — blurred vision, headache, mucosal bleeding, and retinal hemorrhage with sausage-link venous changes — is classic for hyperviscosity syndrome, driven by high levels of circulating monoclonal protein in myeloma. Other features can include dyspnea, transient ischemic attack, and deep venous thrombosis.

Why the others are wrong A — hypercalcemia causes different symptoms (confusion, constipation, polyuria, "bones, stones, groans, psychiatric overtones"), not this specific retinal/mucosal bleeding pattern. C — no history or evidence of vitamin K deficiency is given, and this doesn't explain the retinal vascular findings. D — DIC would show more diffuse coagulopathy with lab abnormalities (elevated D-dimer, low fibrinogen, thrombocytopenia), not this specific hyperviscosity-driven retinal picture. E — amyloid retinal infiltration isn't the classic mechanism for this presentation; hyperviscosity is.
Exam Pearl Hyperviscosity syndrome in myeloma = dyspnea, TIA, retinal hemorrhage, DVT — think "the blood is too thick to flow properly," causing both bleeding (mucosal, retinal) and thrombotic complications simultaneously.
Q6Diagnostic Test Selection●●●● Very Hard

A 69-year-old woman has an M spike identified on SPEP during workup for anemia and elevated total protein. Which test is required to confirm the diagnosis of multiple myeloma?

Reveal Answer

Correct answer: B

While SPEP identifying an M spike is highly suggestive, and peripheral smear may show supportive rouleaux formation, the diagnosis is confirmed with bone marrow aspiration and biopsy, which quantifies clonal plasma cells and allows cytogenetics, flow cytometry, FISH, and/or immunohistochemistry.

Why the others are wrong A — simply repeating SPEP delays definitive diagnosis without adding confirmatory information. C — peripheral smear (rouleaux) is suggestive but not confirmatory/diagnostic on its own. D — calcium is one CRAB criterion but doesn't confirm the underlying plasma cell disorder. E — chest x-ray isn't part of the core diagnostic confirmation pathway (skeletal survey, not chest x-ray specifically, is the standard bone imaging test).
Exam Pearl SPEP (M spike) and peripheral smear (rouleaux) are suggestive; bone marrow biopsy is confirmatory. Boards test this exact distinction — don't confuse a screening finding with the definitive diagnostic test.
Q7Renal Workup●●●○ Hard

A 70-year-old man presents with fatigue and new-onset renal insufficiency (creatinine 2.4 mg/dL, up from a baseline of 1.0 mg/dL six months ago). Urinalysis shows no significant proteinuria on standard dipstick. Given a suspicion for multiple myeloma, what is the most appropriate urine test to order?

Reveal Answer

Correct answer: B

Standard urine dipstick primarily detects albumin and can miss free light chains (Bence Jones proteins), which are common in myeloma-associated renal insufficiency. UPEP is specifically needed to detect these monoclonal light chains, which is part of the standard confirmatory workup alongside SPEP.

Why the others are wrong A — repeating the same insensitive test won't detect light chains that standard dipstick misses. C — there's no indication of infection here; urine culture doesn't address the myeloma workup. D — creatinine clearance assesses renal function but doesn't identify the underlying cause (light chain nephropathy). E — urine eosinophils are used to evaluate for interstitial nephritis, not myeloma-related renal disease.
Exam Pearl Standard urine dipstick is insensitive to light chains — a classic board trap. When myeloma-related renal insufficiency is suspected, order UPEP (± urine immunofixation) specifically, not just a routine dipstick.
Q8Urgent Referral Trigger●●●●● Extreme

A 72-year-old woman with known multiple myeloma develops acute-onset lower back pain radiating down both legs, along with new urinary retention and saddle anesthesia. What is the most appropriate immediate management?

Reveal Answer

Correct answer: B

New bilateral leg symptoms, urinary retention, and saddle anesthesia in a myeloma patient are red flags for malignant spinal cord compression — an oncologic emergency requiring urgent imaging and oncology referral for consideration of urgent radiotherapy or surgical decompression.

Why the others are wrong A — a 2-week delay risks permanent neurologic damage; this requires emergent, not routine outpatient, imaging. C — analgesics alone don't address the underlying compressive emergency and delay definitive care. D — skeletal survey isn't the appropriate emergent imaging modality for suspected cord compression; MRI (or PET/CT) is needed. E — physical therapy is contraindicated and inappropriate in the setting of concerning red-flag neurologic symptoms.
Exam Pearl In any known myeloma patient, new back pain with neurologic red flags (bilateral symptoms, bowel/bladder dysfunction, saddle anesthesia) = emergent spinal cord compression workup, mirroring the same urgency taught for malignant epidural spinal cord compression in lymphoma.
Q9Peripheral Smear Recognition●●●○ Hard

A 70-year-old man's peripheral blood smear is reviewed as part of a workup for unexplained anemia. The smear shows red blood cells stacked together in a linear, coin-like arrangement. Which underlying process best explains this peripheral smear finding?

Reveal Answer

Correct answer: A

"Stacked coin" RBC arrangement is rouleaux formation, classically caused by elevated serum protein/monoclonal immunoglobulin altering RBC surface charge and promoting aggregation — a characteristic finding in multiple myeloma.

Why the others are wrong B — iron deficiency classically shows microcytic, hypochromic cells, not rouleaux. C — microangiopathic hemolysis shows schistocytes/fragmented cells, not stacked RBCs. D — sickle cell disease shows sickled cells, not rouleaux. E — megaloblastic anemia shows macro-ovalocytes and hypersegmented neutrophils, not rouleaux.
Exam Pearl Rouleaux formation = think elevated serum protein (multiple myeloma being the classic cause). Pair this smear description with an older patient, anemia, and bone pain to trigger myeloma on your differential.
Q10Integrative — Workup Algorithm●●●●● Extreme

A 75-year-old man presents with fatigue, recurrent infections, and unexplained weight loss over 3 months — no bone pain, and no known thrombotic events. Initial labs (CBC, creatinine, calcium, albumin, total protein) and immunofixation are pending. According to a standard evaluation algorithm for suspected plasma cell disorder, what should happen if this initial workup returns abnormal?

Reveal Answer

Correct answer: B

Per the evaluation algorithm, nonspecific symptoms (fatigue, recurrent infections, weight loss) prompt initial labs/imaging; if the initial workup is abnormal, the next step is additional myeloma-directed testing — beta-2 microglobulin, LDH, serum free light chain assay, and skeletal survey — to further categorize the plasma cell disorder before oncology involvement and staging.

Why the others are wrong A — treatment should never begin before completing diagnostic workup and confirming an active, symptomatic disease process. C — abnormal labs shouldn't be dismissed as normal aging; further evaluation is warranted per the algorithm. D — age alone is not a reason to bypass diagnostic workup and move to hospice; this is not evidence of terminal, untreatable disease. E — chest CT isn't the directed next step in this algorithm; the specific myeloma-related tests listed are what's indicated.
Exam Pearl The evaluation pathway is stepwise: nonspecific symptoms → initial labs/imaging → if abnormal, myeloma-directed workup (beta-2 microglobulin, LDH, free light chains, skeletal survey) → bone marrow biopsy for confirmation → categorize as MGUS, smoldering, or active myeloma. Know this sequence, not just the individual tests in isolation.
Multiple Myeloma Board Review · Case-Based MCQ Set · 10/10 Questions