Multiple Myeloma
Malignant plasma cell neoplasm producing monoclonal immunoglobulin. CRAB criteria define end-organ damage. Intern role: recognize, manage complications, support through chemo.
🔍 Overview
Overview
Multiple myeloma (MM) is a clonal plasma cell neoplasm in the bone marrow producing a monoclonal immunoglobulin (M-protein). Median age at diagnosis: 69 years, more common in African Americans (2×). The disease spectrum: MGUS → smoldering myeloma → active myeloma. Active myeloma requires CRAB criteria (end-organ damage): C alcium elevated (> 11) · R enal insufficiency (Cr > 2) · A nemia (Hgb < 10) · B one lesions (lytic on skeletal survey or PET/CT). SLiM criteria added in 2014: S ixty percent bone marrow plasma cells · Li ght chain ratio ≥ 100 · M RI with > 1 focal lesion ≥ 5mm -these define myeloma even without CRAB. IMWG, 2014
🧪 Workup
Workup
- SPEP + UPEP with immunofixation -detects M-protein. SPEP identifies the spike; immunofixation types it (IgG most common, then IgA). UPEP detects Bence Jones proteinuria (free light chains).
- Serum free light chains (sFLC) -kappa:lambda ratio. Abnormal ratio with elevated involved chain supports monoclonal process. Essential for light-chain-only myeloma (15%).
- CBC -anemia (normocytic, rouleaux on smear), may have leukopenia/thrombocytopenia with advanced marrow infiltration
- BMP -hypercalcemia, renal insufficiency (light chain cast nephropathy -"myeloma kidney")
- Albumin + β2-microglobulin -ISS staging: Stage I (β2M < 3.5, alb ≥ 3.5), Stage III (β2M ≥ 5.5). R-ISS, 2015
- LDH -elevated = high tumor burden/aggressive biology
- Bone marrow biopsy + aspirate -≥ 10% clonal plasma cells = myeloma. Send cytogenetics/FISH: high-risk features: del(17p), t(4;14), t(14;16), gain(1q), del(1p).
- Skeletal survey (whole-body low-dose CT or PET/CT) -lytic lesions (punched-out). Do NOT use DEXA or conventional XR for screening. PET/CT preferred (more sensitive).
- Quantitative immunoglobulins -immune paresis (suppression of uninvolved Ig classes → infection risk)
- Viscosity -if IgM or very high M-protein (hyperviscosity rare in IgG myeloma, more common in Waldenström)
🚨 Management
Management
- Transplant-eligible (< 70, good performance): Induction → stem cell collection → autologous stem cell transplant (ASCT) → maintenance. Standard induction: VRd (bortezomib/lenalidomide/dexamethasone) × 3-4 cycles. [SWOG S0777, 2017]. Post-ASCT maintenance: lenalidomide until progression. DETERMINATION, 2022
- Transplant-ineligible: VRd (dose-adjusted) or DRd (daratumumab/lenalidomide/dex) until progression. MAIA, 2019
- Supportive care (intern-critical):
- Bone disease: Zoledronic acid 4 mg IV q4 weeks (or denosumab if CrCl < 30). Reduces skeletal events. Check dental clearance first (ONJ risk).
- Infection prophylaxis: Acyclovir (VZV on bortezomib), TMP-SMX or levofloxacin first 3 months, IVIG if recurrent infections with hypogammaglobulinemia
- VTE prophylaxis: Lenalidomide + dex → aspirin (low risk) or LMWH/DOAC (high risk: prior VTE, obesity, immobility)
- Renal protection: Aggressive hydration, avoid NSAIDs and contrast if possible, treat hypercalcemia
- Pain: Radiation for focal bone pain, vertebroplasty/kyphoplasty for compression fractures
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Bortezomib | 1.3 mg/m² SQ weekly | SQ | Proteasome inhibitor. Peripheral neuropathy (dose-limiting). VZV reactivation → acyclovir prophylaxis. SWOG S0777, 2017 |
| Lenalidomide | 25 mg PO days 1-21/28 | PO | IMiD. VTE risk → thromboprophylaxis. Teratogenic. Dose-reduce for CrCl < 30. Maintenance post-ASCT: 10-15 mg. |
| Daratumumab | 16 mg/kg IV weekly → q2w → q4w | IV/SQ | Anti-CD38 mAb. Infusion reactions (pre-medicate). Interferes with blood bank crossmatch (anti-CD38 on reagent RBCs). MAIA, 2019 |
| Dexamethasone | 40 mg weekly (20 mg if > 75y) | PO | Backbone of all myeloma regimens. Hyperglycemia, insomnia, mood changes, infection risk. |
| Zoledronic acid | 4 mg IV over 15 min q4w | IV | Bone-modifying agent. Reduces SREs. Dental exam before starting (ONJ risk). Dose-adjust for CrCl. MRC Myeloma IX, 2012 |
| Carfilzomib | 20-56 mg/m² IV | IV | 2nd-gen proteasome inhibitor for relapsed MM. Cardiac toxicity (HF, HTN) -check echo baseline. Less neuropathy than bortezomib. |
💊 Medications
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Bortezomib | 1.3 mg/m² SQ weekly | SQ | Proteasome inhibitor. Peripheral neuropathy (dose-limiting). VZV reactivation → acyclovir prophylaxis. SWOG S0777, 2017 |
| Lenalidomide | 25 mg PO days 1-21/28 | PO | IMiD. VTE risk → thromboprophylaxis. Teratogenic. Dose-reduce for CrCl < 30. Maintenance post-ASCT: 10-15 mg. |
| Daratumumab | 16 mg/kg IV weekly → q2w → q4w | IV/SQ | Anti-CD38 mAb. Infusion reactions (pre-medicate). Interferes with blood bank crossmatch (anti-CD38 on reagent RBCs). MAIA, 2019 |
| Dexamethasone | 40 mg weekly (20 mg if > 75y) | PO | Backbone of all myeloma regimens. Hyperglycemia, insomnia, mood changes, infection risk. |
| Zoledronic acid | 4 mg IV over 15 min q4w | IV | Bone-modifying agent. Reduces SREs. Dental exam before starting (ONJ risk). Dose-adjust for CrCl. MRC Myeloma IX, 2012 |
| Carfilzomib | 20-56 mg/m² IV | IV | 2nd-gen proteasome inhibitor for relapsed MM. Cardiac toxicity (HF, HTN) -check echo baseline. Less neuropathy than bortezomib. |
🏥 Rounds
Pimp Questions
❓ What are the CRAB criteria?
C alcium > 11 mg/dL · R enal insufficiency (Cr > 2 or CrCl < 40) · A nemia (Hgb < 10 or 2 g below normal) · B one disease (lytic lesions, pathologic fractures, osteoporosis with compression fracture). Any one of these in the setting of a clonal plasma cell disorder = active myeloma requiring treatment. IMWG, 2014
❓ Why does daratumumab interfere with blood bank crossmatching?
Daratumumab (anti-CD38) binds to CD38 expressed on reagent red blood cells used in the blood bank, causing a panreactive indirect Coombs test. This makes antibody identification impossible. Solutions: (1) notify blood bank before starting daratumumab, (2) use DTT-treated RBCs (denatures CD38), (3) phenotype/genotype patient RBCs before first dose. Critical for transfusion safety.
❓ What is the mechanism of myeloma kidney (cast nephropathy)?
Free light chains (especially lambda) are filtered by glomeruli and form obstructive casts in distal tubules by binding with Tamm-Horsfall protein. This causes tubular obstruction, inflammation, and fibrosis → AKI/CKD. Aggravated by: dehydration, NSAIDs, IV contrast, loop diuretics (increase Tamm-Horsfall), hypercalcemia. Treatment: aggressive hydration, treat myeloma (reduce light chain production), consider plasmapheresis if very high FLC.
❓ What is the difference between MGUS, smoldering myeloma, and active myeloma?
MGUS: M-protein < 3 g/dL + < 10% marrow plasma cells + no CRAB. Risk of progression: ~1%/year. No treatment -observe. Smoldering myeloma: M-protein ≥ 3 OR 10-59% marrow plasma cells + no CRAB/SLiM. Higher risk (~10%/year first 5 years). Observation vs early treatment (emerging data). Active myeloma: CRAB or SLiM criteria met → treat. IMWG, 2014
❓ Why do myeloma patients need VZV prophylaxis on bortezomib?
Bortezomib (proteasome inhibitor) causes profound T-cell immunosuppression by inhibiting NF-κB signaling in T lymphocytes. This predisposes to VZV reactivation (shingles) in up to 13% without prophylaxis. Acyclovir 400 mg BID (or valacyclovir 500 mg daily) reduces risk to < 2%. Continue throughout bortezomib therapy + 3 months after.
❓ What high-risk cytogenetic features change myeloma prognosis?
High-risk FISH: del(17p) (loss of TP53 -worst prognosis), t(4;14) (FGFR3/MMSET), t(14;16) (MAF), t(14;20), gain(1q21), del(1p). Standard risk: t(11;14) (cyclin D1), t(6;14), hyperdiploidy. High-risk patients have median OS ~3-4 years vs > 7 years for standard risk. Treatment intensification (quadruplet induction, tandem ASCT) for high-risk.
Clinical Examples
📋 Case 1, Newly Diagnosed Myeloma with Renal Failure
Patient: 68M with fatigue, bone pain, and foamy urine × 2 months. Hgb 8.2, Ca 13.4, Cr 3.8 (baseline 1.0), total protein 10.8. SPEP: IgG kappa M-spike 5.1 g/dL. sFLC kappa 1240, ratio 98. BMBx: 72% clonal plasma cells.
Key findings: Active myeloma: CRAB criteria met (Ca 13.4, Renal Cr 3.8, Anemia Hgb 8.2) + SLiM (72% plasma cells). Myeloma kidney (cast nephropathy), light chains forming obstructive casts in distal tubules.
Management:
- Aggressive IVF (NS 200 mL/hr), dehydration worsens cast formation. Avoid IV contrast and NSAIDs
- Zoledronic acid 4 mg IV for hypercalcemia (hold if Cr > 4.5, use denosumab instead)
- Start VRd induction: bortezomib + lenalidomide (renal dose) + dexamethasone SWOG S0777, 2017
- Bortezomib is preferred in renal failure (not renally cleared, rapid light chain reduction)
- Transplant eligibility assessment, age alone does not exclude; assess fitness
Teaching point: Myeloma kidney is driven by free light chains, not M-protein. Rapid light chain reduction with bortezomib-based therapy is key to renal recovery. ~50% of patients with myeloma kidney recover renal function if treated promptly.
📋 Case 2, Transplant-Eligible Myeloma
Patient: 58F with back pain and pathologic L2 compression fracture. Hgb 9.8, Ca 10.8, Cr 1.1. SPEP: IgA lambda M-spike 3.2 g/dL. BMBx: 45% plasma cells. PET/CT: multiple lytic lesions. FISH: standard risk [t(11;14)].
Key findings: Standard-risk myeloma. Fit, age < 65, transplant-eligible. Bone disease with pathologic fracture. Standard risk t(11;14) has favorable prognosis.
Management:
- VRd induction × 3-4 cycles → stem cell collection → high-dose melphalan + autologous SCT (ASCT)
- ASCT deepens response and extends PFS by ~12 months IFM 2009, 2017
- Lenalidomide maintenance post-ASCT until progression (doubles PFS)
- Zoledronic acid monthly × 2 years for bone protection
- Radiation to L2 fracture for pain + kyphoplasty consult for structural support
Teaching point: Lenalidomide maintenance after ASCT is standard of care, it roughly doubles PFS. For t(11;14) specifically, venetoclax-based combinations are emerging as highly effective (BCL-2 overexpression).
📋 Case 3, Smoldering Myeloma: To Treat or Not?
Patient: 62M found to have M-spike 2.8 g/dL on routine labs. Asymptomatic. Hgb 13.2, Ca 9.8, Cr 0.9. sFLC ratio 18. BMBx: 22% plasma cells. No lytic lesions on PET/CT. No SLiM criteria.
Key findings: Smoldering myeloma: ≥ 10% plasma cells + M-protein ≥ 3 g/dL, but NO CRAB or SLiM criteria. Risk of progression ~10%/year for first 5 years. High-risk features: sFLC ratio > 20, M-spike > 2, BMBx > 20%.
Management:
- Standard approach: observation with monitoring q3-6 months (SPEP, CBC, Ca, Cr, sFLC)
- No treatment unless CRAB or SLiM criteria develop
- 20/2/20 risk model: 2+ risk factors (plasma cells > 20%, M-spike > 2 g/dL, sFLC ratio > 20) = high-risk smoldering
- Clinical trial enrollment for high-risk smoldering (early intervention trials ongoing)
- Annual skeletal imaging (low-dose CT or PET/CT) to detect new bone lesions
Teaching point: Treating smoldering myeloma is NOT standard of care outside clinical trials. The CRAB and SLiM criteria define the line between observation and treatment. However, high-risk smoldering patients may benefit from early intervention, encourage trial enrollment.
Sample Presentation
Mr. Wallace is a 71-year-old man presenting with progressive low back pain × 3 months, fatigue, and 15 lb weight loss. Found to have: Hgb 8.4, Ca 12.8, Cr 2.6, total protein 11.2. SPEP: IgG kappa M-spike 4.2 g/dL. sFLC: kappa 890, lambda 12, ratio 74. Skeletal survey: multiple lytic lesions in spine, pelvis, skull. BMBx: 65% clonal plasma cells, FISH: standard risk.
Key Points: Active myeloma with full CRAB: Ca 12.8, Cr 2.6, Anemia (Hgb 8.4), Bone lesions. Also meets SLiM (60% plasma cells). ISS Stage III (β2M likely elevated with that Cr). Immediate: IV hydration + zoledronic acid for hypercalcemia, transfuse for Hgb < 7, renal protection. Start VRd induction. Transplant-ineligible at 71 → consider DRd.
- SPEP + sFLC q1-2 cycles -track M-protein decline (response criteria: CR, VGPR, PR per IMWG)
- CBC + BMP before each cycle -cytopenias, renal function
- Ca²⁺ -trending (hypercalcemia is a myeloma emergency)
- Peripheral neuropathy assessment -on bortezomib. Grade ≥ 2 → dose-reduce or switch to carfilzomib.
- Echo -baseline + periodic on carfilzomib (cardiotoxicity)
- Dental exam q6 months on bisphosphonates (ONJ monitoring)
- Cr + urine protein -myeloma kidney monitoring. Improving Cr on treatment = good prognostic sign.
- Quantitative Ig -immune paresis monitoring. IVIG if recurrent serious infections.
📋 Summary
Summary
CRAB Defines the Disease
Calcium elevated, Renal insufficiency, Anemia, Bone lesions. These are what separate myeloma from smoldering myeloma and MGUS, which are the same clone without end-organ damage. Add the myeloma-defining events: clonal plasma cells 60% or more, a serum free light chain ratio of 100 or more, or more than one focal lesion on MRI, each of which mandates treatment before CRAB features appear.
Work It Up in Three Layers
Serum and urine protein electrophoresis with immunofixation, plus serum free light chains. Bone marrow biopsy with cytogenetics and FISH, which drive risk stratification. Whole-body low-dose CT, PET-CT or whole-body MRI for the bones. Do not order a skeletal survey: plain films need about 30% bone loss before a lesion is visible and they miss disease that modern imaging finds.
The Lesions Are Lytic and Cold
Bone scan is falsely negative in myeloma, because it detects osteoblastic activity and myeloma is purely osteolytic with suppressed osteoblasts. Ordering a bone scan for myeloma bone pain is a classic error and delays the diagnosis.
Protect the Kidney Early
Cast nephropathy from free light chains is the main renal lesion, worsened by dehydration, NSAIDs, contrast, hypercalcemia and infection. Aggressive hydration, avoid nephrotoxins, treat the hypercalcemia, and start anti-myeloma therapy quickly, since lowering the light chain burden is what actually rescues renal function. Bortezomib-based regimens are preferred in renal impairment because they do not need renal dose adjustment.
Standard Therapy Is a Triplet or Quadruplet
Proteasome inhibitor plus immunomodulatory drug plus dexamethasone, increasingly with daratumumab added. Autologous stem cell transplant for eligible patients, so avoid prolonged lenalidomide before stem cell collection, which impairs the harvest. Then maintenance, typically lenalidomide.
Know the Toxicity of Each Component
Bortezomib: peripheral neuropathy is dose-limiting, and it reactivates varicella zoster, so give acyclovir prophylaxis. Lenalidomide: VTE risk requires thromboprophylaxis, it is teratogenic, and it needs renal dose reduction. Daratumumab: infusion reactions requiring premedication, and it interferes with blood typing, so type and screen before the first dose or later crossmatching becomes difficult. Dexamethasone: hyperglycemia, insomnia, mood change and infection risk.
Manage the Bones and the Calcium
Bisphosphonates or denosumab for all patients with bone disease, which reduce skeletal-related events. Watch for osteonecrosis of the jaw, so arrange a dental review before starting. Denosumab where renal function precludes zoledronic acid. Radiation for painful focal lesions and for cord compression, and orthopedic input for an impending pathological fracture of a long bone.
Anticipate Infection and the Emergencies
Infection is the leading cause of death, driven by functional hypogammaglobulinemia plus treatment-related immunosuppression: vaccinate, give acyclovir with a proteasome inhibitor, and consider PJP prophylaxis and IVIG for recurrent infection. Recognize hypercalcemia, spinal cord compression, hyperviscosity and renal failure as the emergencies, each of which can be the presenting event.
📄 One Pager
Text version
One-Pager
Multiple Myeloma
CRAB + SLiM
Workup
SPEP/UPEP + immunofixation + sFLC + BMBx (cytogenetics/FISH) + skeletal survey (PET/CT preferred) + β2M/albumin (ISS staging) + quantitative Ig.
Treatment
Eligible: VRd × 3-4 → ASCT → lenalidomide maintenance. Ineligible: DRd or VRd continuous. Supportive: zoledronic acid, acyclovir, VTE prophylaxis, hydration.
Trials
SWOG S0777 (VRd) · MAIA 2019 (DRd) · DETERMINATION 2022 (ASCT role) · IMWG 2014 (diagnostic criteria)
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