Multiple Myeloma — Diagnosis, CRAB Criteria, and Smoldering Myeloma

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells in the bone marrow, leading to overproduction of monoclonal immunoglobulins (M protein). It represents the second most common hematologic cancer, accounting for approximately 1% of all cancers and 10% of hematologic malignancies.

[KEY_CONCEPT] The disease spectrum includes:

• Monoclonal gammopathy of undetermined significance (MGUS): Asymptomatic precursor condition
• Smoldering multiple myeloma (SMM): Intermediate stage with higher tumor burden but no end-organ damage
• Symptomatic multiple myeloma: Active disease requiring treatment

Epidemiology:

• Median age at diagnosis: 70 years
• Male-to-female ratio: 1.4:1
• African Americans have 2-fold higher incidence than Caucasians
• Annual incidence: 4-5 per 100,000 people

Pathophysiology: Myeloma develops through sequential genetic events including:

• Primary translocations involving immunoglobulin heavy chain (14q32)
• Secondary events: RAS mutations, MYC dysregulation, p53 loss
• Bone marrow microenvironment interactions promoting survival and drug resistance

[CLINICAL_PEARL] The "multiple" in multiple myeloma refers to the multiple bone lesions typically seen, not multiple types of plasma cells.

Risk Factors:

• Age (>65 years)
• Male gender
• African American race
• Previous MGUS or SMM
• Radiation exposure
• Obesity

Multiple myeloma presents with diverse clinical manifestations related to plasma cell infiltration and M protein effects. The classic presentation follows the CRAB criteria for end-organ damage.

Constitutional Symptoms:

• Fatigue and weakness (most common, >70% patients)
• Unintentional weight loss
• Recurrent infections due to hypogammaglobulinemia
• Easy bruising and bleeding

Bone-Related Manifestations:

• Bone pain (68% of patients): Often back pain, may be severe
• Pathologic fractures (vertebral compression most common)
• Hypercalcemia symptoms: confusion, constipation, polyuria, kidney stones

Renal Manifestations:

• Acute kidney injury (20-25% at presentation)
• Chronic kidney disease
• Proteinuria (often Bence Jones proteins)

Hematologic Findings:

• Anemia (85% of patients): Normocytic, normochromic
• Thrombocytopenia (bleeding manifestations)
• Rouleaux formation on blood smear

[HIGH_YIELD] Hyperviscosity syndrome (rare, <5%):

• Visual disturbances, headaches
• Bleeding (especially mucosal)
• Neurologic symptoms
• More common with IgM (Waldenström's) than IgG/IgA myeloma

Extramedullary Disease (advanced cases):

• Soft tissue plasmacytomas
• Central nervous system involvement
• Liver/spleen infiltration

Multiple myeloma diagnosis requires demonstration of clonal plasma cells and evidence of end-organ damage. The International Myeloma Working Group (IMWG) criteria define active myeloma requiring treatment.

Diagnostic Requirements (ALL must be present):

1. Clonal bone marrow plasma cells ≥10% OR biopsy-proven plasmacytoma
2. Serum and/or urine M protein (except in nonsecretory myeloma)
3. Evidence of end-organ damage (CRAB criteria) OR biomarkers of malignancy

[KEY_CONCEPT] CRAB Criteria for End-Organ Damage:

C - Calcium elevation:

• Serum calcium >11.5 mg/dL (2.9 mmol/L)
• OR >1 mg/dL (0.25 mmol/L) above upper limit of normal

R - Renal dysfunction:

• Serum creatinine >2 mg/dL (177 μmol/L)
• OR creatinine clearance <40 mL/min

A - Anemia:

• Hemoglobin <10 g/dL (100 g/L)
• OR >2 g/dL below lower limit of normal

B - Bone lesions:

• One or more osteolytic lesions on skeletal survey, CT, or PET-CT

[HIGH_YIELD] Biomarkers of Malignancy (SLiM criteria):

• S: Clonal bone marrow plasma cells ≥60%
• Li: Involved:uninvolved serum free light chain ratio ≥100
• M: >1 focal lesion on MRI (≥5 mm)

Diagnostic Workup:

Diagnostic Algorithm:

1. Initial Laboratory Studies ├── Complete blood count with differential ├── Comprehensive metabolic panel (including creatinine, calcium) ├── Serum protein electrophoresis (SPEP) ├── Serum immunofixation electrophoresis (SIFE) ├── Serum free light chains (κ and λ) ├── 24-hour urine protein electrophoresis (UPEP) ├── Urine immunofixation electrophoresis (UIFE) ├── β2-microglobulin and LDH └── Albumin

2. Bone Marrow Studies ├── Bone marrow aspirate and biopsy ├── Flow cytometry ├── Cytogenetics (conventional and FISH) └── Plasma cell percentage assessment

3. Imaging Studies ├── Skeletal survey (X-rays) OR ├── Low-dose whole-body CT OR └── PET-CT (preferred if available)

4. Additional Studies (if indicated) ├── MRI spine and pelvis (if normal imaging but symptomatic) ├── Echocardiogram (if amyloidosis suspected) └── Fat pad biopsy (if amyloidosis suspected)

[CLINICAL_PEARL] Smoldering Multiple Myeloma (SMM) criteria:

• Clonal bone marrow plasma cells 10-60% OR
• Serum M protein ≥3 g/dL
• NO CRAB features or biomarkers of malignancy
• No symptoms requiring treatment

Accurate staging and risk assessment guide treatment decisions and prognosis in multiple myeloma. The International Staging System (ISS) and Revised ISS (R-ISS) are standard prognostic tools.

International Staging System (ISS):

Revised International Staging System (R-ISS): Incorporates cytogenetics and LDH levels with ISS:

• R-ISS I: ISS I + standard-risk cytogenetics + normal LDH
• R-ISS II: Not R-ISS I or III
• R-ISS III: ISS III + high-risk cytogenetics OR elevated LDH

[HIGH_YIELD] Cytogenetic Risk Stratification:

High-Risk Cytogenetics:

• t(4;14) - FGFR3/MMSET
• t(14;16) - MAF
• t(14;20) - MAFB
• del(17p) - p53 deletion
• Gain 1q21

Standard-Risk Cytogenetics:

• t(11;14) - Cyclin D1
• Hyperdiploidy
• t(6;14) - Cyclin D3

Transplant Eligibility Assessment:

Transplant Candidacy Evaluation:

1. Age and Performance Status ├── Age <70 years (relative) ├── ECOG performance status 0-2 └── Adequate organ function

2. Cardiac Assessment ├── LVEF ≥40% ├── No recent MI or unstable angina └── Pulmonary function tests if indicated

3. Renal Function ├── Creatinine clearance >40 mL/min (relative) └── No dialysis dependence (relative)

4. Hepatic Function ├── Bilirubin <2x ULN └── ALT/AST <3x ULN

5. Infectious Disease Screening ├── HIV, HBV, HCV testing ├── CMV serology └── Active infection exclusion

[CLINICAL_PEARL] Minimal Residual Disease (MRD) testing:

• Flow cytometry: 10⁻⁴ sensitivity
• Next-generation sequencing: 10⁻⁵ sensitivity
• Increasingly important for treatment decisions and clinical trials

Special Considerations:

• Plasma cell leukemia: >2,000 plasma cells/μL or >20% plasma cells in peripheral blood
• Extramedullary disease: Indicates aggressive disease requiring intensified therapy
• Light chain-only disease: 15-20% of cases, often associated with renal dysfunction

Multiple myeloma treatment is individualized based on transplant eligibility, cytogenetic risk, and patient factors. Modern therapy combines novel agents with autologous stem cell transplant (ASCT) in eligible patients.

Treatment Algorithm by Transplant Eligibility:

Treatment Decision Tree:

Newly Diagnosed Multiple Myeloma │ ├── Transplant Eligible (Age <70, Good PS) │ ├── Induction Therapy (3-4 cycles) │ │ ├── VRd (Bortezomib-Lenalidomide-Dex) OR │ │ ├── CyBorD (Cyclophosphamide-Bortezomib-Dex) OR │ │ └── VTd (Bortezomib-Thalidomide-Dex) │ ├── Stem Cell Collection │ ├── High-Dose Melphalan + ASCT │ └── Maintenance: Lenalidomide until progression │ └── Transplant Ineligible (Age ≥70, Poor PS, Comorbidities) ├── Continuous Therapy │ ├── VRd OR │ ├── VMP (Bortezomib-Melphalan-Prednisone) OR │ └── DRd (Daratumumab-Lenalidomide-Dex) └── Treatment until progression or intolerance

[HIGH_YIELD] Standard Induction Regimens:

VRd (Bortezomib-Lenalidomide-Dexamethasone):

• Cycles 1-8: 21-day cycles
• Bortezomib 1.3 mg/m² SC days 1, 4, 8, 11
• Lenalidomide 25 mg PO days 1-14
• Dexamethasone 20 mg PO days 1-2, 4-5, 8-9, 11-12

DaraVRd (Daratumumab + VRd):

• Adding daratumumab 16 mg/kg IV weekly × 8 weeks, then every 2 weeks
• Improved response rates vs. VRd alone

Relapsed/Refractory Disease:

[CLINICAL_PEARL] Supportive Care Measures:

Infection Prevention:

• Antibiotic prophylaxis during induction (levofloxacin)
• PCP prophylaxis if prolonged steroid use
• IVIG for recurrent infections with hypogammaglobulinemia

Thrombosis Prevention:

• Aspirin 81 mg daily (low risk)
• LMWH or warfarin (high risk: obesity, immobilization, steroids, thalidomide/lenalidomide)

Bone Disease Management:

• Bisphosphonates: Zoledronic acid 4 mg IV monthly OR pamidronate
• Denosumab alternative if contraindication to bisphosphonates
• Calcium and vitamin D supplementation
• Dental evaluation before bisphosphonate therapy

Renal Protection:

• Hydration and avoid nephrotoxic drugs
• Light chain reduction with plasma exchange in severe cases
• Dose adjustments for renally cleared drugs

Novel Therapies:

• CAR-T cell therapy: Idecabtagene vicleucel (ide-cel) for relapsed/refractory
• Bispecific antibodies: Teclistamab (BCMA-targeted)
• Antibody-drug conjugates: Belantamab mafodotin
• Proteasome inhibitors: Carfilzomib, ixazomib
• Immunomodulatory drugs: Pomalidomide
• Monoclonal antibodies: Daratumumab, isatuximab

Multiple myeloma complications can be disease-related or treatment-related, requiring vigilant monitoring and proactive management.

Disease-Related Complications:

Renal Complications:

• Myeloma kidney: Most common cause of renal dysfunction
• Light chain cast nephropathy
• AL amyloidosis (5-10% of MM patients)
• Hypercalcemia-induced nephrotoxicity
• [HIGH_YIELD] Acute kidney injury requires urgent light chain reduction

Bone Disease:

• Osteolytic lesions in 80% of patients
• Pathologic fractures: Vertebral compression most common
• Osteonecrosis of jaw (2-10% with bisphosphonates)
• Hypercalcemia of malignancy

Hematologic Complications:

• Secondary malignancies: 3-4 fold increased risk
• Acute leukemia (therapy-related)
• Solid tumors
• Hyperviscosity syndrome (rare with MM)

Infectious Complications:

• Hypogammaglobulinemia: Deficient normal immunoglobulin production
• Increased bacterial, viral, and fungal infections
• Herpes zoster reactivation (especially with bortezomib)

Treatment-Related Complications:

Prognostic Factors:

Favorable Prognosis:

• ISS stage I
• Standard-risk cytogenetics
• Good performance status
• Transplant eligibility
• Achievement of minimal residual disease negativity

Poor Prognosis:

• ISS stage III
• High-risk cytogenetics [t(4;14), t(14;16), del(17p)]
• Elevated LDH
• Plasma cell leukemia
• Extramedullary disease
• Renal dysfunction

[KEY_CONCEPT] Survival Outcomes:

• Overall median survival: 6-7 years (significant improvement from 2-3 years historically)
• 10-year survival: 30-40% in transplant-eligible patients
• R-ISS I: Median OS >10 years
• R-ISS III: Median OS ~40 months

Smoldering Myeloma Management:

• Observation with serial monitoring every 3-6 months
• High-risk SMM (>80% progression risk at 2 years) may benefit from early treatment
• Clinical trials investigating early intervention strategies

Quality of Life Considerations:

• Fatigue management: Exercise, nutrition counseling
• Pain control: Multimodal approach, avoid NSAIDs
• Psychological support: Cancer-related distress common
• Fertility preservation: Important in younger patients

[CLINICAL_PEARL] End-of-Life Considerations:

• Disease progression with multi-drug resistance
• Goals of care discussions early in advanced disease
• Palliative care integration for symptom management
• Hospice care when appropriate for comfort-focused care