Multiple myeloma is a cancer of plasma cells that usually makes IgG or IgA (or light chains alone) and damages bone and kidney, producing the CRAB pattern of hypercalcemia, renal failure, anemia, and lytic bone lesions. Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma that makes IgM, spares the bones, and causes hyperviscosity, lymphadenopathy, and hepatosplenomegaly. On boards, three findings separate them: the heavy chain on immunofixation, the skeletal survey, and the bone marrow (CD138-positive plasma cells in myeloma vs CD20-positive lymphoplasmacytic cells with the MYD88 L265P mutation in Waldenstrom).

Why do boards pair multiple myeloma with Waldenstrom macroglobulinemia?

Both diseases make a monoclonal protein. Both show an M spike on serum protein electrophoresis, both cause anemia and fatigue in an older adult, and both can show rouleaux on the peripheral smear. A stem that only says "elderly patient, anemia, M spike" hasn't given you enough to choose.

The difference is the cell of origin. Myeloma is a neoplasm of fully differentiated plasma cells that live in the bone marrow. Waldenstrom is a B-cell lymphoma made of cells caught between a small lymphocyte and a plasma cell, which is why pathologists call it lymphoplasmacytic. That one fact drives almost every board clue.

Plasma cells in the marrow activate osteoclasts, so myeloma breaks bone. Lymphoma cells travel to lymph nodes, liver, and spleen, so Waldenstrom enlarges organs. The protein each one makes then adds its own damage. Light chains clog the kidney in myeloma. IgM, a giant pentamer, thickens the blood in Waldenstrom.

Which immunoglobulin does each disease make?

Start here, because the stem often hands it to you. Immunofixation names the heavy chain and the light chain in the spike.

Myeloma makes IgG in about half of cases and IgA in about a fifth. Roughly 15% to 20% of patients make only free light chains, called Bence Jones proteins when they show up in urine. IgM myeloma exists but is well under 1% of cases, so on a board question an IgM spike means Waldenstrom until proven otherwise.

Waldenstrom makes IgM by definition. The name says it: macroglobulin is the old term for IgM, the largest immunoglobulin. A Waldenstrom stem with an IgG spike is not a Waldenstrom stem.

This rule handles most questions on its own. The remaining questions hide the heavy chain and make you work from the organ damage, which is what the next sections cover.

Multiple myeloma: plasma cells, bone, and kidney

Who gets it

Myeloma is a disease of older adults, with most patients diagnosed after age 60. It's about twice as common in Black Americans as in white Americans, and boards like to put that demographic in the stem. Nearly all cases arise from a precursor called monoclonal gammopathy of undetermined significance (MGUS).

The classic presentation is an older adult with back pain, fatigue, and recurrent infections. Labs show anemia, a high calcium, a rising creatinine, and a high total protein with a normal or low albumin.

CRAB and the IMWG criteria

The International Myeloma Working Group (IMWG) defines myeloma as at least 10% clonal plasma cells in the marrow (or a biopsy-proven plasmacytoma) plus at least one myeloma-defining event. The CRAB events are:

  • C, calcium: above 11 mg/dL, or more than 1 mg/dL above the upper limit of normal
  • R, renal: creatinine above 2 mg/dL or creatinine clearance below 40 mL/min
  • A, anemia: hemoglobin below 10 g/dL, or more than 2 g/dL below the lower limit of normal
  • B, bone: one or more lytic lesions on skeletal radiography, CT, or PET-CT

The 2014 update added three biomarkers that count even without CRAB damage. They are 60% or more clonal plasma cells in the marrow, an involved to uninvolved serum free light chain ratio of 100 or more, and more than one focal lesion on MRI. You don't need these thresholds for most Level 1 or Step 1 questions, but they show up on Level 2 and Step 2 CK.

Why the bones break

Myeloma cells raise RANKL signaling and suppress osteoprotegerin, which turns osteoclasts on. They also release DKK1, which shuts osteoblasts off. Bone is chewed away and never rebuilt.

That imbalance creates three board findings. X-rays show "punched-out" lytic lesions, classically in the skull, spine, ribs, and pelvis. Pathologic fractures and vertebral compression fractures cause the back pain. Calcium released from bone causes hypercalcemia, with confusion, constipation, and polyuria.

The pearl students miss is the bone scan. A technetium bone scan detects osteoblast activity, and myeloma suppresses osteoblasts, so the scan can be falsely negative. Alkaline phosphatase is usually normal for the same reason. Imaging for myeloma uses a skeletal survey, whole-body low-dose CT, PET-CT, or MRI.

What myeloma does to the kidney

Kidney injury in myeloma has several causes, and boards test each one.

Cast nephropathy ("myeloma kidney") is the most common. Filtered free light chains bind Tamm-Horsfall protein (uromodulin) in the distal tubule and form waxy, fractured casts that block the tubule. Dehydration, NSAIDs, and IV contrast make it worse.

Hypercalcemia causes vasoconstriction, volume depletion, and nephrogenic diabetes insipidus. If the stem pairs myeloma with polyuria and dilute urine, calcium is the link. The central vs nephrogenic diabetes insipidus guide covers that mechanism.

AL amyloidosis occurs when light chains (more often lambda) fold into amyloid fibrils. In the kidney this causes nephrotic-range proteinuria. Elsewhere it causes macroglossia, restrictive cardiomyopathy, and apple-green birefringence with Congo red stain under polarized light.

Light chain proximal tubulopathy can cause an acquired Fanconi syndrome, with glucosuria, aminoaciduria, and phosphaturia.

A urine dipstick pearl ties this together. The dipstick mainly detects albumin, so it can read negative or trace while the urine is full of light chains. The sulfosalicylic acid test, urine protein electrophoresis, and urine immunofixation all detect them.

Other labs worth knowing

  • Rouleaux on the smear, from the positively charged protein reducing the normal repulsion between red cells
  • High ESR for the same reason
  • Protein gap between total protein and albumin, because the M protein adds to total protein
  • Low anion gap, because IgG is positively charged at physiologic pH and stands in for unmeasured cations
  • Recurrent infections with encapsulated bacteria such as Streptococcus pneumoniae, because the normal polyclonal antibodies are suppressed even when total immunoglobulin is high

On the marrow, plasma cells have an eccentric nucleus, "clock-face" chromatin, and a pale perinuclear hof where the Golgi apparatus sits. They stain for CD138 and CD38. Cytoplasmic immunoglobulin inclusions are called Russell bodies.

Treatment at board depth

Most patients get a triplet such as bortezomib, lenalidomide, and dexamethasone, and eligible patients go on to autologous stem cell transplant. Each drug has a classic board association.

  • Bortezomib is a proteasome inhibitor. Misfolded immunoglobulin builds up and triggers apoptosis. It causes peripheral neuropathy and herpes zoster reactivation, so patients get acyclovir prophylaxis.
  • Lenalidomide and thalidomide are immunomodulatory drugs. They're teratogenic and raise the risk of venous thromboembolism, so patients need thromboprophylaxis.
  • Daratumumab is a monoclonal antibody against CD38. CD38 is also on red cells, so it interferes with blood bank crossmatching.
  • Zoledronic acid or denosumab protects bone. Both can cause osteonecrosis of the jaw.

Waldenstrom macroglobulinemia: IgM and hyperviscosity

Who gets it

Waldenstrom is an indolent B-cell non-Hodgkin lymphoma, classified as lymphoplasmacytic lymphoma with an IgM paraprotein. It occurs mostly in older white men. It arises from IgM MGUS, not from the IgG or IgA MGUS that leads to myeloma.

The presentation is slower and less violent than myeloma. Patients have fatigue from anemia, weight loss, night sweats, and on exam, lymphadenopathy and hepatosplenomegaly. If you want a refresher on where Waldenstrom sits among the lymphomas, the Hodgkin vs non-Hodgkin lymphoma guide covers the broader categories.

Why IgM thickens the blood

IgM circulates as a pentamer, five antibody units joined by a J chain. It's large and mostly stays inside blood vessels. As the concentration rises, serum viscosity climbs steeply.

Normal serum viscosity is about 1.4 to 1.8 centipoise. Symptoms usually appear once it passes about 4. That's why hyperviscosity is the defining emergency of Waldenstrom and an uncommon feature of myeloma. When myeloma does cause it, the culprit is usually IgA, which can form dimers and larger polymers.

Hyperviscosity syndrome

Thick blood flows poorly through small vessels in the eye, brain, and mucosa. The classic triad is:

  1. Mucosal bleeding: nosebleeds and gum bleeding, because IgM coats platelets and interferes with clotting factors
  2. Visual changes: blurred vision, with dilated, tortuous retinal veins described as "sausage links" or "boxcars," plus retinal hemorrhages and sometimes papilledema
  3. Neurologic symptoms: headache, dizziness, vertigo, hearing loss, confusion, and in severe cases stupor or coma

Heart failure can also follow, because the expanded plasma volume and thick blood strain the heart.

The emergency treatment is plasmapheresis. Because most IgM stays in the vessels, removing plasma lowers IgM and viscosity quickly. Avoid transfusing red cells before plasmapheresis when you can, because adding cells to thick blood raises viscosity further.

Other things IgM does

IgM causes problems beyond viscosity, and each one has a board hook.

  • Peripheral neuropathy: IgM can target myelin-associated glycoprotein (anti-MAG), causing a distal, symmetric, mostly sensory demyelinating neuropathy with gait ataxia.
  • Type I cryoglobulinemia: the monoclonal IgM precipitates in the cold, causing Raynaud phenomenon, acrocyanosis, and skin ulcers.
  • Cold agglutinin disease: IgM against the I antigen on red cells causes complement-mediated hemolysis in the cold. The warm vs cold autoimmune hemolytic anemia guide covers that pattern.
  • AL amyloidosis: less common than in myeloma but still possible.

Diagnosis and the MYD88 mutation

Diagnosis needs an IgM monoclonal protein plus marrow infiltration by lymphoplasmacytic cells. The cells are a mix of small lymphocytes, plasmacytoid lymphocytes, and plasma cells. They express CD19, CD20, and surface IgM, and they're usually negative for CD5 and CD10. Dutcher bodies, which are PAS-positive immunoglobulin inclusions that appear to sit inside the nucleus, are the classic morphologic association.

The MYD88 L265P mutation is present in more than 90% of Waldenstrom cases. It activates NF-kappa-B signaling through Bruton tyrosine kinase (BTK), which is why BTK inhibitors work. Myeloma, including the rare IgM type, almost never carries this mutation, so it's the cleanest molecular separator between the two.

Lytic bone lesions, hypercalcemia, and cast nephropathy are rare in Waldenstrom. If a stem with an IgM spike gives you punched-out skull lesions, think about IgM myeloma, but that's a deliberate trick question and an uncommon one.

Treatment

Patients without symptoms are watched, and a high IgM alone is not a reason to treat. Symptomatic patients get rituximab-based regimens (such as bendamustine plus rituximab) or a BTK inhibitor such as ibrutinib or zanubrutinib.

One trap is the rituximab "IgM flare." Rituximab can briefly raise IgM and tip a borderline patient into hyperviscosity, so patients with very high IgM often get plasmapheresis first.

Multiple myeloma vs Waldenstrom macroglobulinemia side by side

Feature Multiple myeloma Waldenstrom macroglobulinemia
Cell of origin Clonal plasma cell Lymphoplasmacytic B cell
Immunoglobulin IgG (about half), IgA (about a fifth), light chain only (15% to 20%) IgM
Precursor Non-IgM MGUS IgM MGUS
Bone Lytic "punched-out" lesions, fractures Usually spared
Calcium Often high Usually normal
Kidney Cast nephropathy, hypercalcemia, AL amyloid, Fanconi Uncommon
Hyperviscosity Uncommon (IgA when it occurs) Defining feature
Lymph nodes, liver, spleen Usually normal Often enlarged
Neuropathy Bortezomib-induced, amyloid Anti-MAG demyelinating neuropathy
Smear Rouleaux Rouleaux
Marrow cell markers CD138, CD38 CD19, CD20, surface IgM
Inclusion bodies Russell bodies Dutcher bodies
Key mutation Varied, including t(11;14) and t(4;14) MYD88 L265P (over 90%)
Emergency Hypercalcemia, cord compression, renal failure Hyperviscosity, treated with plasmapheresis
Core drugs Bortezomib, lenalidomide, dexamethasone, daratumumab Rituximab, bendamustine, BTK inhibitors

Which tests separate plasma-cell from lymphoplasmacytic disease?

Here's the order I'd work through on a board question, from cheapest to most definitive.

Serum protein electrophoresis finds the M spike but doesn't tell you which immunoglobulin it is. Both diseases are positive. Students lose points by stopping here.

Immunofixation names the heavy chain. IgG or IgA points to myeloma. IgM points to Waldenstrom.

Serum free light chains measure kappa and lambda and their ratio. A very abnormal ratio supports myeloma, and it's the key test in light chain only myeloma, where the SPEP can look nearly normal.

Calcium, creatinine, and a skeletal survey look for CRAB damage. Positive findings strongly favor myeloma.

Serum viscosity and a fundoscopic exam look for hyperviscosity. Positive findings strongly favor Waldenstrom.

Bone marrow biopsy with flow cytometry settles it. CD138-positive plasma cells point to myeloma, while CD20-positive lymphoplasmacytic cells with surface IgM point to Waldenstrom. Testing for MYD88 L265P confirms Waldenstrom.

MGUS, smoldering myeloma, and other distractors

Answer choices usually include the precursor states and a few look-alikes.

MGUS has an M protein under 3 g/dL, fewer than 10% clonal plasma cells, and no end-organ damage. It progresses at about 1% per year. The board answer for MGUS is monitoring, not chemotherapy.

Smoldering myeloma sits between MGUS and myeloma. It has an M protein of 3 g/dL or more (or 10% to 60% marrow plasma cells) but no myeloma-defining event.

Solitary plasmacytoma is a single plasma cell tumor in bone or soft tissue with a normal marrow, treated with radiation.

Chronic lymphocytic leukemia can produce a small IgM spike, but it has an absolute lymphocytosis, smudge cells on the smear, and CD5 and CD23 positivity.

Primary AL amyloidosis has a small clonal plasma cell population and organ damage from amyloid deposits rather than from the tumor mass. The giveaway is nephrotic syndrome, macroglossia, or a restrictive heart in a patient with a modest M spike. The nephritic vs nephrotic syndrome guide covers where amyloid fits among the nephrotic causes.

Three paraprotein stems: working the split

Here are three example stems built to show the split.

Patient 1. A 68-year-old Black man has three months of low back pain and fatigue. He's been treated twice this year for pneumonia. Calcium is 12.4 mg/dL, creatinine is 2.3 mg/dL, and hemoglobin is 8.9 g/dL. Total protein is 9.8 g/dL with an albumin of 3.1 g/dL. Lateral skull film shows multiple small round lucencies.

Every CRAB letter is present, along with a protein gap, encapsulated infections, and punched-out skull lesions. This is multiple myeloma. Immunofixation will most likely show IgG or IgA, and the marrow will show CD138-positive plasma cells.

Patient 2. A 72-year-old white man has two weeks of headache, blurred vision, and recurrent nosebleeds. Exam shows cervical lymphadenopathy and a palpable spleen. Fundoscopy shows dilated, segmented retinal veins with flame hemorrhages. Calcium and creatinine are normal. SPEP shows an M spike, and immunofixation shows IgM kappa.

Hyperviscosity, organomegaly, an IgM spike, and normal calcium and creatinine make this Waldenstrom macroglobulinemia. The next step is urgent plasmapheresis. Marrow testing will show CD20-positive lymphoplasmacytic cells, and MYD88 L265P will very likely be positive.

Patient 3. A 64-year-old woman has numb feet and an unsteady gait that have worsened over a year. Exam shows symmetric loss of vibration and position sense in the feet. Nerve conduction studies show a demyelinating pattern. SPEP shows a small IgM spike, and anti-MAG antibodies are positive.

This is an IgM paraproteinemic neuropathy. The anti-MAG antibody tells you the IgM itself is attacking myelin. The workup then decides between IgM MGUS and Waldenstrom by looking for marrow involvement and organomegaly.

Stem clues that crack these questions fast

The clues I look for in every question are age, acuity, unusual findings, matching timelines, laterality, labs and imaging, and the question part. Here's how they apply to paraproteins.

  1. Age and demographics. Both diseases are rare before 40. A Black patient in his late 60s with bone pain tilts toward myeloma. An older white man with big nodes tilts toward Waldenstrom.
  2. Acuity. Hyperviscosity symptoms develop over days to weeks and are an emergency. Back pain with a new neurologic deficit in a myeloma patient means cord compression, which is also an emergency.
  3. Unusual findings. A stem rarely mentions a low anion gap, retinal vein shape, or a negative bone scan by accident. Each one points to a specific disease.
  4. Matching timelines. Kidney failure that follows a CT with IV contrast or a course of NSAIDs in a myeloma patient points to cast nephropathy.
  5. Laterality. Hyperviscosity, cryoglobulin, and anti-MAG findings are bilateral and symmetric. A single focal bone lesion with a normal marrow points to solitary plasmacytoma.
  6. Labs are king. Immunofixation and calcium together decide most questions. IgM with normal calcium is Waldenstrom, and IgG or IgA with high calcium is myeloma.
  7. The question part. "Most likely finding on bone marrow biopsy," "most appropriate next step," and "mechanism of the drug" each ask for something different. Read the last sentence before you commit.

When two answers both look right on a heme/onc question, the guide to choosing between two answers on COMLEX walks through how to break the tie.

Common board pitfalls and how to avoid them

Stopping at "M spike." An SPEP result alone can't separate the two diseases. Look for the heavy chain, the calcium, and the bones.

Ordering a bone scan for myeloma. The bone scan relies on osteoblasts, which myeloma suppresses. The correct imaging is a skeletal survey, low-dose whole-body CT, PET-CT, or MRI.

Trusting a negative urine dipstick. The dipstick misses light chains. Urine protein electrophoresis or immunofixation catches them.

Calling hyperviscosity a myeloma emergency first. It can occur in IgA myeloma, but the board default for hyperviscosity with an M spike is Waldenstrom.

Transfusing before plasmapheresis. Extra red cells make thick blood thicker. Lower the viscosity first.

Treating MGUS or asymptomatic Waldenstrom. Neither gets chemotherapy. Monitoring is the answer until end-organ damage or symptoms appear.

Forgetting the infection risk in myeloma. A total globulin that's high doesn't mean immunity is intact. The functional antibodies are suppressed, so encapsulated bacterial infections are common.

Frequently asked questions about multiple myeloma vs Waldenstrom macroglobulinemia

What is the main difference between multiple myeloma and Waldenstrom macroglobulinemia?

Multiple myeloma is a cancer of plasma cells that usually makes IgG, IgA, or free light chains and causes lytic bone lesions, hypercalcemia, kidney injury, and anemia. Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma that makes IgM and causes hyperviscosity, lymphadenopathy, and hepatosplenomegaly while usually sparing the bones and kidneys. The heavy chain on immunofixation is the fastest way to tell them apart.

Why does Waldenstrom cause hyperviscosity more often than myeloma?

IgM is a pentamer, the largest immunoglobulin, and most of it stays inside blood vessels. As IgM levels rise, serum viscosity climbs steeply. IgG is much smaller and spreads into tissues, so it rarely thickens blood enough to cause symptoms. When myeloma does cause hyperviscosity, it is usually IgA myeloma, because IgA can form dimers and larger polymers.

Does Waldenstrom macroglobulinemia cause lytic bone lesions?

Rarely. Lytic lesions, hypercalcemia, and cast nephropathy are hallmarks of multiple myeloma, not Waldenstrom. If a stem describes an IgM spike with punched-out bone lesions, consider the rare IgM subtype of myeloma, which lacks the MYD88 L265P mutation.

What test confirms Waldenstrom macroglobulinemia vs multiple myeloma?

Bone marrow biopsy with flow cytometry is the confirmatory test. Myeloma shows clonal plasma cells that are CD138 and CD38 positive. Waldenstrom shows lymphoplasmacytic cells that are CD19 and CD20 positive with surface IgM. The MYD88 L265P mutation is present in more than 90% of Waldenstrom cases and supports that diagnosis.

Why is the bone scan negative in multiple myeloma?

A technetium bone scan detects osteoblast activity. Myeloma activates osteoclasts and suppresses osteoblasts, so bone is destroyed without new bone formation, and the scan can miss the lesions. Alkaline phosphatase is usually normal for the same reason. Myeloma is imaged with a skeletal survey, low-dose whole-body CT, PET-CT, or MRI.

What is the treatment for hyperviscosity syndrome?

Plasmapheresis is the emergency treatment. It removes the plasma that holds the excess immunoglobulin, and it works especially well in Waldenstrom because most IgM stays inside blood vessels. Red cell transfusion is avoided until viscosity is lowered. Treatment of the underlying disease, such as rituximab or a BTK inhibitor in Waldenstrom, then controls the protein production.

Get more clinical breakdowns like this in the free Skool community

The Premeducated free Skool community has a 100-plus video library of question breakdowns, weekly office hours with physician tutors, and cloze-deletion Anki cards transcribed directly from Lucas's video library. Free, no upgrade required.

Join the free Skool community

Related guides