Multiple Myeloma
BASICS
Description
- Malignant proliferation of a single clone of plasma cells producing monoclonal protein (Ig)
- Characterized by bony lytic lesions, hypercalcemia, infection risk, renal impairment
- MGUS may progress to smoldering MM (SMM) or symptomatic MM (~1% per year)
EPIDEMIOLOGY
- Older adults (median age 65–74)
- ~2% of all cancers, 17% of hematologic malignancies (U.S.)
- African Americans: 2–3× higher risk than Caucasians; less common in Asians
- Incidence: 7/100,000/year in U.S.
- Prevalence: ~160,000 worldwide (2018)
ETIOLOGY & PATHOPHYSIOLOGY
- Genetic alterations: chromosomal abnormalities, sporadic mutations
- Common: Ig heavy chain translocations (e.g., t(11;14)), del(17p13)
- Pathogenic protein: paratarg-7 (rare familial form)
RISK FACTORS
- Old age, immunosuppression
- Exposure: chemicals, heavy metals, ionizing radiation
ASSOCIATED CONDITIONS
- Secondary amyloidosis
- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes)
DIAGNOSIS
History
- 34% asymptomatic at presentation
- Anemia (73%): most common
- Hypercalcemia (28%): anorexia, abdominal pain, polyuria, somnolence
- Renal impairment (48%)
- Bone pain/lesions (80%), pathologic fractures (26–34%), osteoporosis
- Other: fatigue, PN, weight loss, recurrent infections, hyperviscosity syndrome, spinal cord compression
Physical Exam
- Dehydration, pallor, bone tenderness
- Hyperviscosity: retinal hemorrhage, bleeding, neuro changes (7%)
- Extramedullary plasmacytomas: large, purple subcutaneous masses
- Amyloidosis: waxy papules/plaques (eyelids, neck, retroauricular, anogenital)
Differential Diagnosis
- Reactive plasmacytosis, MGUS, SMM
- Metastatic cancer (kidney, breast, lung)
- Waldenström macroglobulinemia, AL amyloidosis, solitary plasmacytoma, POEMS
Diagnostic Tests
- MM diagnosis: ≥10% plasma cells in BM or plasmacytoma + ≥1 myeloma-defining event (SLiM-CRAB):
- Hypercalcemia (>11 mg/dL)
- Renal insufficiency (Cr >2 mg/dL or clearance <40 mL/min)
- Anemia (Hb <10 g/dL or >2 g/dL below LLN)
- Bone lesions (≥1 lytic lesion)
- SLiM: BM plasma cells ≥60%, FLC ratio ≥100 or <0.01%, >1 focal lesion on MRI/PET-CT
Initial Labs
- CBC, BUN/Cr, electrolytes, Ca, albumin, LDH, β2-microglobulin
- SPEP/SIFE: M protein
- Quantitative IgG/IgA/IgM, FLC κ/λ, ESR, CRP
- Urine: 24-hr protein, UPEP/UIFE (Bence Jones)
- Imaging: Whole-body low-dose CT (preferred), MRI/PET, skeletal survey (if CT/MRI unavailable)
- BM biopsy: % plasma cells, IHC, flow, cytogenetics, FISH
Follow-Up
- MRI (SMM/spinal cord compression)
- PET/CT (extramedullary disease)
- Bone densitometry (as indicated)
- Serial SPEP, SIFE, FLC, Ig for response/progression
Staging
- ISS:
- I: albumin ≥3.5, β2-microglobulin <3.5
- II: neither I nor III
- III: β2-microglobulin ≥5.5
- R-ISS: includes ISS + chromosomal + LDH
- mSMART: stratifies cytogenetic risk
TREATMENT
General
- Consider cardiac, renal status, cytogenetics, transplant eligibility
- ASCT is standard for eligible; non-eligible: extended chemo/maintenance
Medications
- Three phases: Induction, consolidation (often ASCT), maintenance
- Induction: PIs, IMiDs, steroids, ± monoclonal Abs (e.g., bortezomib/lenalidomide/dex ± daratumumab)
- Maintenance: Lenalidomide preferred; trials ongoing for dual agents
First Line
- Proteasome inhibitors (PI): bortezomib (SC/IV), carfilzomib (IV), ixazomib (PO)
- AEs: PN, cytopenia, rash, GI, fever, cardiac, thrombocytopenia
- Acyclovir for HSV prophylaxis
- Alkylator: cyclophosphamide (AEs: cytopenia, lung, hemorrhagic cystitis, fertility)
- IMiDs: thalidomide, lenalidomide, pomalidomide (AEs: DVT, neuropathy, rash, bradycardia, teratogenic)
- Dexamethasone
- Daratumumab (anti-CD38 monoclonal Ab)
- Bisphosphonates: for bone protection (monitor for jaw osteonecrosis)
Second Line
- Relapse: adjust therapy based on prior response, clinical trial if possible
- Agents: pomalidomide, elotuzumab, venetoclax, selinexor, bispecific Abs, CAR-T (e.g., idecabtagene, ciltacabtagene)
REFERRAL
- Orthopedics: bone pathology/support
- Major center: after 3 lines, for clinical trial
ADDITIONAL THERAPIES
- Radiation for bone pain/plasmacytoma
- Pain management (avoid NSAIDs)
- Aspirin for DVT prophylaxis on IMiDs
- Erythropoietin for anemia
- IVIg for recurrent severe infection
- Vaccination: pneumococcus, flu, COVID-19 (no live virus vaccines)
- Kyphoplasty/vertebroplasty for compression fractures
INPATIENT/ADMISSION
- Indications: pain, infection, cytopenia, renal failure, bone complications, cord compression
- Hydration, nephrotoxin avoidance, manage hypercalcemia
ONGOING CARE
Patient Education
PROGNOSIS
- Median survival (R-ISS):
- Stage I: not reached
- Stage II: 83 months
- Stage III: 43 months
COMPLICATIONS
- Infections, pain, fractures, hypercalcemia, hyperuricemia
- Spinal cord compression, hyperviscosity, amyloidosis, dialysis
ICD-10
- C90.0: Multiple myeloma
- C90.00: MM, not in remission
- C90.01: MM, in remission
Clinical Pearls
- MM = plasma cell malignancy with end-organ damage (“CRAB”)
- Suspect MM if high total protein/albumin ratio
- Avoid nephrotoxins (contrast, NSAIDs, dehydration)
- Patients are immunocompromised