Eduovisual
Blood & Lymphoreticular
Multiple myeloma: CRAB criteria and management
— Median age at diagnosis ~69; African American patients have 2× incidence and earlier onset
— Male predominance; risk factors: obesity, prior MGUS/smoldering myeloma, ionizing radiation, certain pesticides
— Arises from post-germinal center plasma cells; nearly always preceded by MGUS → smoldering myeloma → active MM
— Cytokine-driven (IL-6, RANKL) osteoclast activation produces purely lytic lesions without compensatory osteoblastic activity → low alk phos despite extensive bone disease
— Older patient with unexplained back/rib pain + anemia + elevated total protein-albumin gap ("globulin gap" >4 g/dL)
— New AKI with bland urinalysis but heavy proteinuria on 24-hour collection (light chains miss the dipstick, which detects albumin)
— Pathologic fracture, vertebral compression, or hypercalcemia in a non-immobilized outpatient
— Recurrent encapsulated organism infections (functional hypogammaglobulinemia despite high total protein)
— Incidental rouleaux on peripheral smear or markedly elevated ESR (>100)
— Persistent unexplained anemia in adults >50
— Osteoporosis disproportionate to age/sex with lytic features
— Peripheral neuropathy + monoclonal gammopathy (POEMS, AL amyloid overlap)
Board pearl: A normal urine dipstick does not exclude myeloma kidney — the dipstick detects albumin, but cast nephropathy is driven by filtered light chains. Always order UPEP with immunofixation + serum free light chain ratio when myeloma is on the differential, not just a spot protein/creatinine.
Step 3 management: Suspected MM in clinic → simultaneously order CBC, CMP, calcium, SPEP/UPEP with immunofixation, serum free light chains, and whole-body low-dose CT or PET-CT; refer to heme-onc before bone marrow biopsy if access is limited.
— Bone pain (60%): insidious low back or rib pain worsened by movement, relieved by rest; sudden severe pain suggests pathologic fracture or vertebral collapse
— Fatigue from anemia (70%): normocytic, normochromic; rouleaux on smear
— Renal symptoms: foamy urine, edema, nocturia, or asymptomatic AKI found on routine labs
— Hypercalcemia symptoms: "stones, bones, groans, psychiatric overtones" — polyuria, constipation, confusion, nausea
— Infection (I): recurrent pneumococcal pneumonia, sinusitis, UTI from functional hypogammaglobulinemia
— Spinal cord compression: saddle anesthesia, urinary retention, bilateral leg weakness — neurologic emergency
— Hyperviscosity syndrome (more typical of Waldenström but seen with IgA/IgG3 myeloma): headache, blurred vision, mucosal bleeding, retinal "sausage-link" veins
— AL amyloidosis overlap: macroglossia, periorbital purpura ("raccoon eyes"), restrictive cardiomyopathy, nephrotic syndrome, carpal tunnel
— POEMS syndrome: Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, Skin changes
— Duration and progression of back pain; night pain or pain unrelieved by position
— Weight loss, night sweats (less prominent than in lymphoma but possible)
— Prior MGUS diagnosis — 1% per year progression risk
— Family history (2–4× risk in first-degree relatives)
— Medication review: bisphosphonate use may mask hypercalcemia
— Critical because it drives transplant eligibility and regimen intensity
— Use IMWG frailty score (age, comorbidities, ADL/IADL) in outpatient workup
Key distinction: MGUS = M-protein <3 g/dL, marrow plasma cells <10%, no CRAB. Smoldering myeloma = M-protein ≥3 g/dL or marrow plasma cells 10–60%, still no CRAB. Active MM requires CRAB or a SLiM criterion (covered later). Misclassifying smoldering as active triggers unnecessary toxic therapy.
— Pallor (anemia), cachexia in advanced disease, antalgic gait from vertebral pain
— Volume status assessment is critical: hypercalcemia → polyuria → hypovolemia, while cast nephropathy can present euvolemic or hypervolemic if oligoanuric
— Tachycardia from anemia or sepsis (functional hypogammaglobulinemia)
— Orthostatic hypotension from dehydration (hypercalcemia) or autonomic neuropathy of AL amyloid
— Hypertension uncommon at presentation; if present consider amyloid cardiomyopathy with preserved filling pressures
— Point tenderness over thoracic/lumbar spine or ribs; percussion tenderness over vertebral body suggests compression fracture
— Loss of height >4 cm or new kyphosis
— Range-of-motion limitation from compression deformity
— Saddle sensation, anal tone, post-void residual — screen for cauda equina/cord compression
— Symmetric distal sensory loss (stocking-glove) suggests amyloid or POEMS-related neuropathy
— Cranial nerve palsies from skull base plasmacytoma (rare but tested)
— Periorbital purpura ("pinch purpura" after Valsalva) → AL amyloid until proven otherwise
— Macroglossia with lateral tooth indentations → amyloid
— Soft-tissue plasmacytomas: firm subcutaneous nodules over ribs/sternum
— Elevated JVP, S3, hepatomegaly → amyloid cardiomyopathy
— Pleural effusions from amyloid or volume overload
— Funduscopy: dilated tortuous "sausage-link" retinal veins with hyperviscosity
— Mucosal bleeding (gingival, epistaxis) from platelet dysfunction or acquired vWF inactivation
Board pearl: Macroglossia + periorbital purpura + nephrotic-range proteinuria in a patient with M-protein = AL amyloidosis — get a fat pad biopsy with Congo red staining (apple-green birefringence) before assuming pure myeloma.
— CBC with differential and peripheral smear: normocytic anemia, rouleaux formation, occasional circulating plasma cells (plasma cell leukemia if >2×10⁹/L or >20%)
— CMP: elevated calcium (correct for albumin), creatinine for AKI, total protein vs albumin gap
— LDH: elevated reflects high tumor burden, included in R-ISS staging
— Beta-2 microglobulin and albumin: drive ISS staging (I: B2M <3.5 + alb ≥3.5; II: intermediate; III: B2M ≥5.5)
— Uric acid, phosphate: tumor lysis risk at treatment initiation
— SPEP: identifies M-spike, quantifies monoclonal protein
— Serum immunofixation (IFE): identifies heavy and light chain isotype (IgG > IgA > light chain only > IgD > IgM)
— 24-hour UPEP with immunofixation: detects Bence Jones proteinuria
— Serum free light chain (FLC) assay with kappa/lambda ratio: most sensitive; abnormal ratio (<0.26 or >1.65) is required for diagnosis in light chain–only disease and used in SLiM criteria
— Whole-body low-dose CT (preferred) or whole-body MRI/PET-CT; plain skeletal survey is obsolete per IMWG 2014
— MRI for suspected cord compression or to evaluate smoldering myeloma (>1 focal lesion ≥5 mm = active MM)
— Dipstick may be falsely negative; order sulfosalicylic acid (SSA) test or quantitative protein to detect light chains
— Quantitative immunoglobulins (suppressed uninvolved isotypes), viral hepatitis screen, HIV (before therapy), TSH, vitamin D
Step 3 management: Triad to order on the same visit when MM is suspected: SPEP + serum IFE + serum FLC ratio, plus 24-hour urine for UPEP + urine IFE. Skipping FLC misses ~20% of light chain–only or non-secretory myelomas.
— Quantify clonal plasma cells (kappa or lambda restriction by flow/IHC)
— Send for cytogenetics (FISH): t(4;14), t(14;16), t(14;20), del(17p), gain/amp 1q21 = high risk; t(11;14), hyperdiploidy = standard risk
— Optional: gene expression profiling, minimal residual disease (MRD) flow at 10⁻⁵ or NGS at 10⁻⁶ for response assessment later
— Clonal bone marrow plasma cells ≥10% OR biopsy-proven plasmacytoma, PLUS
— At least one myeloma-defining event:
— MGUS: <10% plasma cells, <3 g/dL M-protein, no CRAB/SLiM
— Smoldering MM: ≥10% plasma cells OR ≥3 g/dL M-protein, no CRAB/SLiM
— Solitary plasmacytoma: single bone/soft tissue lesion, normal marrow, no CRAB
— Plasma cell leukemia: circulating plasma cells >5% (revised) — aggressive
— Fat pad aspirate or organ biopsy with Congo red (apple-green birefringence under polarized light)
— Mass spectrometry typing distinguishes AL from ATTR
— Cardiac: troponin, NT-proBNP, ECG (low voltage), echo (speckled myocardium, preserved EF with diastolic dysfunction)
Board pearl: SLiM-CRAB expanded the definition so high-risk smoldering patients can be treated before end-organ damage. A patient with 65% marrow plasma cells but normal calcium, kidney, Hgb, and bones is active MM by the "S" criterion — don't wait for a fracture.
— Stage I: ISS I + standard-risk cytogenetics + normal LDH (median OS not reached)
— Stage II: neither I nor III
— Stage III: ISS III + (high-risk FISH OR elevated LDH) (median OS ~43 months historically, improving with new therapies)
— Transplant-eligible: typically age <70–75, good performance status, adequate organ function, no major comorbidities
— Transplant-ineligible: frail, significant cardiac/pulmonary disease, ECOG ≥3
— Age alone is not an absolute contraindication; functional age matters more than chronologic age
— Achieve deep response (≥VGPR, ideally MRD-negative CR)
— Prolong progression-free and overall survival
— Preserve organ function and quality of life
— Baseline echocardiogram (especially before anthracycline-containing or carfilzomib regimens)
— Hepatitis B/C, HIV serologies
— Vaccinations: pneumococcal (PCV20 or PCV15→PPSV23), influenza annually, shingles recombinant (RZV), COVID-19; avoid live vaccines on therapy
— VTE risk assessment (IMPEDE-VTE or SAVED score) before starting IMiDs
— Dental evaluation before bisphosphonates/denosumab (ONJ prevention)
— Fertility counseling in younger patients
— Bone-modifying agent (zoledronic acid monthly or denosumab) for ALL patients with bone disease
— Hydration and avoidance of nephrotoxins (NSAIDs, IV contrast when possible)
— IVIG only for recurrent infections with documented hypogammaglobulinemia
Step 3 management: Before the first dose of induction therapy, document: echo, HBV/HCV/HIV, dental clearance for bisphosphonate, VTE prophylaxis plan (aspirin 81 mg if low risk, DOAC/LMWH if high risk on IMiD), and updated vaccinations.
— Dara-VRd: daratumumab + bortezomib + lenalidomide + dexamethasone × 4–6 cycles
— Triplet alternative: VRd (bortezomib/lenalidomide/dex) if daratumumab unavailable
— Followed by autologous stem cell transplant (ASCT) with melphalan 200 mg/m² conditioning
— Then lenalidomide maintenance until progression (improves OS)
— Dara-Rd (daratumumab + lenalidomide + dex) — MAIA trial standard
— VRd-lite with dose-reduced bortezomib/lenalidomide for frail patients
— Continuous therapy until progression or intolerance
— Proteasome inhibitors (PIs): bortezomib (SC preferred over IV to reduce neuropathy), carfilzomib (cardiotoxicity, HTN), ixazomib (oral)
— Immunomodulatory drugs (IMiDs): lenalidomide, pomalidomide, thalidomide
— Anti-CD38 monoclonal antibodies: daratumumab, isatuximab
— Corticosteroids (dex): hyperglycemia, insomnia, infection risk, myopathy
— Acyclovir/valacyclovir prophylaxis (HSV/VZV) while on PI or daratumumab
— PJP prophylaxis (TMP-SMX) if high-dose steroids prolonged
— Bisphosphonate or denosumab monthly × 2 years, then reassess
Board pearl: A patient on daratumumab who needs an urgent transfusion may have a panreactive antibody screen — this is anti-CD38 binding reagent RBCs, not a true alloantibody. Use DTT-treated cells or phenotypically matched units.
— Standard of care for eligible patients after induction
— Stem cell mobilization with G-CSF ± plerixafor (avoid prolonged lenalidomide before collection — stem cell toxicity)
— Conditioning: high-dose melphalan 200 mg/m²
— Engraftment ~10–14 days; isolation precautions, growth factor support
— Tandem ASCT considered for high-risk cytogenetics (del 17p, t(4;14))
— Rarely used; reserved for young high-risk or relapsed patients in clinical trials due to high TRM (~15–30%)
— BCMA-directed CAR-T: idecabtagene vicleucel, ciltacabtagene autoleucel — durable responses after ≥3–4 prior lines
— Bispecific antibodies: teclistamab (BCMA×CD3), talquetamab (GPRC5D×CD3), elranatamab
— Toxicities: cytokine release syndrome (CRS), ICANS neurotoxicity, prolonged cytopenias, hypogammaglobulinemia, infection
— Indication: symptomatic hyperviscosity (headache, visual changes, mucosal bleeding) — temporizing measure
— Does not treat cast nephropathy effectively in most data (limited role)
— Localized palliative XRT for: painful bone lesions unresponsive to systemic therapy, impending pathologic fracture, spinal cord compression, solitary plasmacytoma (curative-intent 40–50 Gy)
— Vertebroplasty/kyphoplasty for painful vertebral compression fractures
— Orthopedic stabilization for long-bone lesions with >50% cortical involvement or Mirels score ≥9
— Decompressive laminectomy for cord compression refractory to steroids/radiation
CCS pearl: Patient presents with new bilateral leg weakness and urinary retention + back pain + M-protein. Sequence of CCS orders: IV dexamethasone immediately → STAT MRI total spine → neurosurgery consult + radiation oncology consult. Do not wait for biopsy confirmation to start steroids when cord compression is suspected.
— Use IMWG frailty score (age >75, ADL/IADL deficits, Charlson comorbidities) to stratify fit/intermediate/frail
— Frail patients: dose-reduced Dara-Rd or VRd-lite, weekly bortezomib (not twice weekly), dex 20 mg weekly (not 40)
— Avoid high-dose melphalan/ASCT; consider attenuated melphalan if used
— Monitor for falls, polypharmacy, delirium during steroid pulses
— Causes: light chain cast nephropathy (most common), AL amyloidosis, hypercalcemia, hyperuricemia, NSAID/contrast injury
— Bortezomib-based regimens are preferred — rapid light chain reduction can reverse AKI; no dose adjustment for bortezomib in renal failure
— Lenalidomide requires renal dose adjustment: 10 mg daily if CrCl 30–60; 15 mg every other day if <30; further reduction on dialysis
— Daratumumab: no renal dose adjustment
— Avoid: bisphosphonates if CrCl <30 (use denosumab instead — no renal adjustment but monitor calcium, supplement Ca/vitamin D aggressively to prevent hypocalcemia)
— Aggressive hydration, avoid IV contrast and NSAIDs
— Hemodialysis may be needed; high-cutoff dialysis for light chain removal is investigational, not standard
— Bortezomib: reduce dose if bilirubin >1.5× ULN
— Lenalidomide: limited data, use cautiously
— Daratumumab: no adjustment for mild-moderate impairment
— Cardiac disease: avoid carfilzomib if EF reduced or uncontrolled HTN; baseline and serial echos
— Diabetes: dex worsens hyperglycemia — adjust insulin proactively; consider dex-sparing regimens
— Prior VTE: full anticoagulation (DOAC or LMWH), not aspirin, during IMiD therapy
Step 3 management: Newly diagnosed MM with Cr 3.5 and 50% marrow plasmacytosis → start bortezomib-based induction urgently (often with dex and cyclophosphamide initially, VCd), aggressive IV hydration, hold bisphosphonates until CrCl improves, use denosumab for bone protection.
— MM in pregnancy is exceedingly rare (median dx age ~69)
— Lenalidomide, pomalidomide, thalidomide are absolutely contraindicated (severe teratogens — phocomelia); REMS program mandates two contraception methods and monthly pregnancy tests in reproductive-age patients
— Bortezomib: limited data, generally avoided in first trimester
— Daratumumab: avoid (IgG crosses placenta, neonatal cytopenias possible)
— If diagnosed during pregnancy: multidisciplinary management; deliver when feasible, then initiate standard therapy
— Workup family history (rare familial clusters)
— Discuss fertility preservation before therapy: sperm banking, oocyte/embryo cryopreservation
— More aggressive intent: tandem ASCT considered, clinical trial enrollment encouraged
— Long-term survivorship issues: second primary malignancies (AML/MDS from melphalan, lenalidomide), cardiovascular disease, osteoporosis
— Multiple myeloma is essentially nonexistent in children; a pediatric "myeloma-like" presentation should prompt evaluation for lymphoma, leukemia, or Langerhans cell histiocytosis instead
— 2× incidence, earlier onset, higher MGUS prevalence
— Equal or better outcomes when given equivalent access to triplet/quadruplet therapy and ASCT — but historically undertreated
— Higher prevalence of t(11;14) (standard risk); may benefit from venetoclax-based regimens in relapse
— Lower lenalidomide tolerance reported; monitor cytopenias closely
— MM therapy is expensive; oral parity laws and patient assistance programs are often needed
— Geriatric assessment in community oncology improves outcome equity
Key distinction: Don't reflexively assume MM in a young adult with bone lesions and M-protein — consider POEMS, AL amyloidosis, plasmablastic lymphoma (HIV-associated), or monoclonal gammopathy of renal/clinical significance (MGRS/MGCS) before committing to myeloma therapy.
— Mechanism: osteoclast activation (RANKL, MIP-1α), not PTHrP
— Treatment: IV normal saline 200–300 mL/hr first, then IV bisphosphonate (zoledronic acid 4 mg, dose-adjust for renal function) or denosumab if AKI; calcitonin for rapid but transient effect; avoid loop diuretics unless volume overloaded
— Hydration, stop nephrotoxins, urgent anti-myeloma therapy (bortezomib-based) is the most effective renal rescue
— Dialysis if uremic, hyperkalemic, or volume overloaded
— Pathologic fractures, vertebral compression, spinal cord compression
— Prevention: monthly bisphosphonate × 2 years, then reassess; calcium + vitamin D supplementation
— Osteonecrosis of the jaw (ONJ): 1–4% risk with prolonged bisphosphonate/denosumab — dental clearance before initiation, avoid invasive dental work during therapy
— Functional hypogammaglobulinemia + treatment-related neutropenia
— Encapsulated organisms early (S. pneumoniae, H. influenzae); later: HSV/VZV reactivation, PJP, fungal
— IVIG replacement (400 mg/kg q4 weeks) for recurrent serious infections + IgG <400
— IMiD + dex confers 10–20% risk untreated; prophylaxis mandatory
— Bortezomib (sensory > motor, painful); reduce dose or switch to weekly SC; gabapentin/duloxetine for pain
— Carfilzomib: HF, HTN, pulmonary HTN, MI; monitor BP, weight, symptoms
— Lenalidomide maintenance increases AML/MDS and solid tumor risk (~5–8%); benefit still favors maintenance for OS
— Mucosal bleeding, retinopathy, neurologic symptoms; emergent plasmapheresis
Board pearl: New atrial fibrillation, HTN urgency, or dyspnea in a patient on carfilzomib = cardiotoxicity. Hold the drug, obtain echo and troponin/BNP, and involve cardio-oncology before resuming.
— Spinal cord compression with neurologic deficits → inpatient: high-dose dex, MRI, neurosurgery + radiation oncology
— Hypercalcemic crisis (Ca >14 or symptomatic with confusion/arrhythmia) → IV fluids, telemetry
— AKI requiring urgent dialysis or rapidly rising creatinine
— Symptomatic hyperviscosity → emergent plasmapheresis
— Tumor lysis syndrome at treatment initiation (uncommon but possible with high tumor burden) → IV fluids, allopurinol or rasburicase, telemetry
— Febrile neutropenia → broad-spectrum antibiotics within 1 hour (cefepime or pip-tazo), admit
— Sepsis from encapsulated organism
— CRS/ICANS after CAR-T or bispecific therapy → tocilizumab, steroids, ICU per grading
— Hematology-oncology: all new diagnoses
— Nephrology: AKI, cast nephropathy, dialysis planning
— Radiation oncology: cord compression, painful lesions, plasmacytoma
— Orthopedic surgery: impending or actual pathologic fractures, Mirels ≥9
— Neurosurgery: cord compression with structural instability
— Cardiology / cardio-oncology: baseline echo, carfilzomib monitoring, amyloid evaluation
— Infectious disease: opportunistic infections, complex prophylaxis
— Palliative care: early integration improves quality and survival
— Refer to academic center for ASCT, CAR-T, bispecifics, clinical trial enrollment
— Document transfer rationale, medication list, dental clearance, recent imaging
— New back pain with weakness or bladder dysfunction
— Confusion + known hypercalcemia
— Fever on chemotherapy
— Acute dyspnea or chest pain on carfilzomib
CCS pearl: On CCS, a myeloma patient with new lower extremity weakness — do not order plain films first. The correct sequence: IV access → dexamethasone 10 mg IV → MRI thoracolumbar spine STAT → consult radiation oncology and neurosurgery → admit to monitored bed.
— M-protein <3 g/dL, marrow plasma cells <10%, no CRAB/SLiM
— Progression to MM: ~1%/year (lifetime)
— Surveillance: SPEP, CBC, CMP, calcium at 6 months then annually if low-risk
— Low-risk MGUS (IgG, M <1.5 g/dL, normal FLC ratio): annual labs only, no imaging
— Asymptomatic but higher burden; risk-stratify with 20/2/20 (M-protein >2 g/dL, marrow plasma cells >20%, FLC ratio >20)
— High-risk smoldering: consider clinical trial enrollment or lenalidomide-based therapy
— IgM monoclonal gammopathy, MYD88 L265P mutation
— Symptoms: hyperviscosity, lymphadenopathy, hepatosplenomegaly, anemia
— No lytic bone lesions — key distinguishing feature
— Treatment: BTK inhibitors (ibrutinib, zanubrutinib), rituximab-based regimens, plasmapheresis for hyperviscosity
— Low-burden plasma cell clone (often <10% marrow) producing toxic light chains
— Organ-specific: nephrotic-range proteinuria, restrictive cardiomyopathy, neuropathy, macroglossia, hepatomegaly
— Diagnosis requires tissue biopsy with Congo red + mass spec typing
— Treatment: daratumumab-CyBorD (DaraCyBorD) per ANDROMEDA trial
— Polyneuropathy + Organomegaly + Endocrinopathy + Monoclonal protein (usually lambda) + Skin changes
— Often with osteosclerotic (not lytic) bone lesions, elevated VEGF
— Treatment: radiation for solitary lesions, ASCT for disseminated disease
— Circulating clonal plasma cells >5% (revised); aggressive, poor prognosis
— Single lesion, normal marrow; treated with localized radiation, curative intent
Key distinction: IgM M-protein + lymphadenopathy + hyperviscosity = Waldenström, not myeloma. No lytic lesions in Waldenström — if you see lytic bone disease with IgM, think IgM myeloma (rare) instead.
— Breast, lung, prostate, renal, thyroid; usually mixed lytic-blastic or purely blastic (prostate)
— Tip-off: known primary, organ-specific symptoms, elevated alk phos (osteoblastic activity — contrast with MM's typically normal alk phos)
— Workup: CT chest/abdomen/pelvis, mammography, PSA, age-appropriate cancer screening
— Lymphoma of bone, osteosarcoma (young), Ewing sarcoma — biopsy distinguishes
— Common in elderly; no M-protein, normal calcium and renal function
— DEXA scan, vitamin D, secondary osteoporosis workup (TSH, testosterone, celiac, etc.)
— Hypercalcemia + bone disease — but elevated PTH and lytic lesions of "brown tumors" rather than diffuse myeloma lesions
— PTH is suppressed in MM-related hypercalcemia
— Sarcoidosis, TB → 1,25-OH vitamin D-mediated hypercalcemia; PTH suppressed
— Anemia + bone pain + elevated creatinine can mimic MM
— CKD anemia is hypoproliferative with appropriate EPO deficiency; no M-protein
— Chronic infection (HIV, hepatitis), autoimmune disease (RA, SLE), liver disease
— SPEP shows broad-based polyclonal band, no discrete M-spike; immunofixation negative
— Normocytic, low-normal MCV, elevated ferritin, low TIBC; no M-protein
— Infection, drug reaction, autoimmune; polyclonal marrow plasma cells by flow/IHC
— Squamous cell, renal cell carcinoma; check PTHrP if no M-protein and hypercalcemia
— Lytic lesions but with elevated inflammatory markers and infectious context
Board pearl: "Older patient with hypercalcemia, bone pain, anemia, and AKI" sounds like MM but always check PTH first — primary hyperparathyroidism is far more common and curable with parathyroidectomy.
— Lenalidomide 10–15 mg daily continuous until progression — improves PFS and OS
— High-risk cytogenetics: bortezomib + lenalidomide maintenance or carfilzomib-based maintenance
— Monitor CBC, CMP every 1–3 months; dose-adjust for cytopenias and renal function
— Counsel on secondary malignancy risk (AML/MDS, skin cancers) — annual dermatologic exam
— Zoledronic acid or denosumab monthly × 2 years, then reassess; some continue lower-frequency dosing
— Calcium 1000–1200 mg/day + vitamin D 1000–2000 IU/day
— Avoid invasive dental procedures; annual dental cleaning and exam
— DEXA scan baseline and every 2 years
— Acyclovir/valacyclovir prophylaxis throughout PI or daratumumab therapy
— TMP-SMX for PJP if on high-dose dex or daratumumab + high-risk
— Annual influenza, COVID-19 boosters, PCV20 or PCV15→PPSV23, RZV (Shingrix)
— No live vaccines (MMR, varicella, yellow fever, live zoster, oral polio) during therapy
— IVIG for recurrent infections with IgG <400 mg/dL
— Statin per ASCVD risk; control BP and DM
— Monitor for steroid-induced hyperglycemia, osteoporosis, cataracts
— Aspirin 81 mg daily if low risk; DOAC if prior VTE or high risk
— Labs (CBC, CMP, calcium, SPEP, IFE, FLC) every 1–3 months on therapy
— Imaging if clinical concern for new lesions or biochemical progression
— Address fatigue, sexual health, mental health, financial toxicity
— Advance care planning conversations early — MM remains incurable
Step 3 management: At every maintenance visit, document: M-protein and FLC trend, calcium and creatinine, evidence of new bone pain (low threshold for imaging), vaccination status, dental check, and contraception/REMS compliance if on IMiD.
— Stringent CR: normal FLC ratio, no clonal plasma cells on IHC
— Complete response (CR): negative IFE in serum and urine, <5% marrow plasma cells, no soft tissue plasmacytomas
— VGPR: ≥90% reduction in serum M-protein + urine <100 mg/24h
— Partial response (PR): ≥50% reduction in serum M-protein
— MRD assessment: by NGS or flow at 10⁻⁵ to 10⁻⁶ sensitivity; MRD-negative status correlates with PFS/OS
— Active treatment: labs every cycle (2–4 weeks); SPEP/FLC every 1–3 months
— Maintenance: every 1–3 months
— Smoldering MM: every 3–6 months
— MGUS: every 6–12 months based on risk
— Repeat whole-body CT or PET-CT at suspected progression, new bone pain, or biochemical relapse
— Routine surveillance imaging not recommended in asymptomatic responders
— Biochemical: rising M-protein or FLC without CRAB
— Clinical relapse: new CRAB features → triggers next line of therapy
— Physical therapy for deconditioning, gait training after vertebral fractures
— Occupational therapy for ADL adaptation
— Nutrition: adequate protein, calcium, vitamin D; manage steroid-related weight gain
— Smoking cessation, moderate exercise (resistance + aerobic) per tolerance
— Pain management: combine pharmacologic (acetaminophen, gabapentinoids, opioids judiciously) with radiation for focal pain; avoid NSAIDs (renal toxicity)
— Mental health: depression/anxiety common; screen with PHQ-9
— Financial counseling: copay assistance programs, oral parity laws
— Reconcile medications carefully — chemotherapy holds during admissions, prophylactic antimicrobials, anticoagulation
— Communicate plan with PCP at every transition
Board pearl: A patient with previously stable MM presents with new fatigue and Cr increase from 1.1 to 1.8. Order SPEP, FLC, calcium, CBC same day — biochemical relapse with cast nephropathy is the most likely scenario, and delay risks irreversible renal damage.
— Discuss with patients that MM is incurable but treatable; long-term remission is realistic but cure is not guaranteed
— Quadruplet and CAR-T therapies carry substantial toxicity; ensure understanding of CRS, neurotoxicity, second malignancies
— Document goals of care early — many patients prioritize quality over duration
— Lenalidomide, pomalidomide, thalidomide REMS mandates:
— Prescriber and pharmacy certification
— Two forms of contraception for reproductive-age patients (or sterilization/abstinence)
— Monthly pregnancy tests
— Patient agreement forms signed at each refill
— Legal liability if not followed; teratogenicity is severe and litigated
— Cancer registry reporting is required in all US states
— Genetic information (cytogenetics, secondary malignancy risk) — counsel about implications, GINA protections
— Daratumumab interference with blood bank typing — always document in chart and notify blood bank before transfusion
— Acyclovir prophylaxis often dropped at discharge — explicit reconciliation prevents zoster reactivation
— Bisphosphonate dosing missed during hospitalizations — clarify outpatient schedule
— Document code status, healthcare proxy, advance directive at diagnosis and update at progression
— Discuss palliative care integration early — improves QoL and may improve survival
— Hospice referral at end-of-life when therapy goals shift
— Spinal cord compression: delays cause irreversible paraplegia — escalate within hours, not days
— Hypercalcemia: do not give IV bisphosphonate without checking renal function; use denosumab if CrCl <30
— Vaccination errors: live vaccines to immunosuppressed patient = catastrophic; verify vaccine type
— Drug-drug interactions: warfarin + dex (INR fluctuations), lenalidomide + erythropoietin (VTE risk)
— African American patients historically undertreated; ensure equitable access to ASCT, CAR-T, and clinical trials
— Cost barriers — assess insurance status, copay assistance enrollment proactively
Step 3 management: On every admission for an MM patient on daratumumab, write a clear order: "Anti-CD38 monoclonal antibody — notify blood bank before any crossmatch; use DTT-treated or antigen-matched RBCs." This single line prevents transfusion delays.
— Rouleaux formation on peripheral smear
— Total protein – albumin gap >4 g/dL ("globulin gap")
— ESR >100 without obvious infection
— Low anion gap (cationic IgG paraprotein)
— Normal alkaline phosphatase despite extensive lytic bone disease (no osteoblast activity)
— Bence Jones proteinuria = urinary free light chains (heat-precipitable at 40–60°C, redissolves at 100°C)
— Dipstick-negative proteinuria despite heavy quantitative protein (light chains miss albumin-detecting dipstick)
— Punched-out lytic lesions on skull films (classic but obsolete imaging)
— Pepper-pot skull appearance
— t(11;14): standard risk, venetoclax-sensitive
— t(4;14), t(14;16), t(14;20), del(17p), 1q gain: high risk
— Hyperdiploidy: standard risk, generally favorable
— Bortezomib: SC > IV (less neuropathy), HSV prophylaxis mandatory
— Carfilzomib: cardiotoxicity, HTN, pulmonary HTN
— Lenalidomide: VTE, secondary AML/MDS, renal dose adjustment
— Daratumumab: blood bank interference (anti-CD38)
— Melphalan: stem cell toxic — avoid prolonged use before ASCT collection
— Amyloid AL: macroglossia, periorbital purpura, restrictive CM, nephrotic syndrome, carpal tunnel
— POEMS: polyneuropathy + organomegaly + endocrinopathy + M-protein + skin
— Schnitzler syndrome: IgM gammopathy + chronic urticaria + fever
— Cryoglobulinemia: Type I (myeloma/Waldenström), Type II (HCV)
— "Foamy urine in older patient with anemia and back pain"
— "AKI with bland urinalysis but heavy proteinuria"
— "Recurrent pneumococcal pneumonia in adult"
— "Pathologic fracture without trauma + hypercalcemia"
— "Periorbital purpura after coughing"
Board pearl: A low anion gap in an older patient with anemia is a free, classic clue for IgG multiple myeloma — cationic paraproteins falsely lower the calculated anion gap. Order SPEP.
— 68-year-old with 3 months of back pain, fatigue, and recent foamy urine. Labs: Hgb 8.2, Cr 2.4, Ca 11.6, total protein 9.8, albumin 3.4
— Next best step: SPEP, serum FLC, 24-hour UPEP, whole-body CT
— Diagnosis: Multiple myeloma
— Known MM patient with new bilateral leg weakness, urinary retention, saddle anesthesia
— Next best step: IV dexamethasone immediately, then STAT MRI total spine, then radiation oncology and neurosurgery consult
— Patient on daratumumab needs transfusion; type-and-screen shows panreactive antibody
— Answer: anti-CD38 interference; use DTT-treated cells or phenotypically matched units
— MM patient with Ca 14.5, confusion, dehydration
— Next step: IV normal saline first, then IV bisphosphonate (or denosumab if AKI), calcitonin for rapid effect
— Incidental M-protein 1.2 g/dL IgG kappa, normal CBC/CMP, normal FLC ratio in 65-year-old
— Answer: low-risk MGUS — annual SPEP, CBC, CMP, calcium; no imaging needed
— Marrow with 65% plasma cells, normal Ca/Cr/Hgb, no bone lesions
— Answer: This is active myeloma (SLiM criterion "S" = ≥60% plasma cells); treat as MM
— New MM with Cr 3.0
— Answer: Bortezomib-based regimen (rapid light chain reduction), denosumab for bones (not bisphosphonate at this GFR), aggressive hydration
— 55-year-old woman starting lenalidomide
— Answer: two forms of contraception, monthly pregnancy tests, REMS enrollment
— MM patient with periorbital purpura, macroglossia, restrictive cardiomyopathy
— Answer: AL amyloidosis — fat pad biopsy with Congo red, treat with daratumumab-CyBorD
— Patient on lenalidomide maintenance asks about vaccines
— Answer: inactivated vaccines OK (flu, COVID, PCV20, RZV); no live vaccines (MMR, varicella, live zoster, yellow fever)
Key distinction: If the stem describes "IgM M-protein + lymphadenopathy + hyperviscosity + no lytic lesions" — it is Waldenström, not MM. Treatment is BTK inhibitor (ibrutinib), not bortezomib/lenalidomide.
Multiple myeloma is a clonal plasma cell malignancy diagnosed by ≥10% marrow plasma cells (or biopsy-proven plasmacytoma) plus a CRAB or SLiM myeloma-defining event, managed with daratumumab-based triplet/quadruplet induction, autologous stem cell transplant in eligible patients, lenalidomide maintenance, and lifelong bone, infection, and renal protective care.
— Order SPEP + serum IFE + serum FLC ratio + 24-hour UPEP together; dipstick will miss light chains
— Confirm with bone marrow biopsy (≥10% clonal plasma cells) + FISH for risk stratification
— Imaging: whole-body low-dose CT, PET-CT, or whole-body MRI — plain skeletal survey is obsolete
— CRAB = Calcium >11, Renal Cr >2 or CrCl <40, Anemia Hgb <10, ≥1 lytic Bone lesion; SLiM = ≥60% plasma cells, FLC ratio ≥100, MRI focal lesion >5 mm
— Transplant-eligible: Dara-VRd induction → ASCT → lenalidomide maintenance
— Transplant-ineligible: Dara-Rd until progression
— Renal failure: bortezomib-based (no dose adjustment), avoid bisphosphonate if CrCl <30 (use denosumab)
— Cord compression: IV dex → STAT MRI → radiation/neurosurgery
— Acyclovir prophylaxis on proteasome inhibitor or daratumumab
— VTE prophylaxis (ASA or DOAC) on IMiDs
— REMS compliance for lenalidomide/pomalidomide/thalidomide
— Bisphosphonate or denosumab × 2 years; dental clearance first
— Daratumumab interferes with blood bank — communicate before transfusion
— Vaccinations: PCV20, RZV, flu, COVID; no live vaccines
— Monitor SPEP, FLC, CBC, CMP, calcium every 1–3 months
— Imaging at biochemical/clinical relapse
— Integrate palliative care early, document advance directives, screen for depression and financial toxicity
Board pearl: When a Step 3 stem mentions back pain + anemia + AKI + hypercalcemia in an older adult, the diagnostic move is always the SPEP/FLC/UPEP triad first, then bone marrow biopsy — and the management move is always bortezomib-based therapy as the renal-safest, fastest-acting backbone.