Multiple Myeloma

See Also

Epidemiology

Elderly (median age 70 years old)
1. Those <65 years old with Multiple Myeloma represent only 15% of cases
Incidence: 36,000 new cases per year in United States (2025)
1. Represents 1.8% of all new cancers in U.S.
Deaths: 11,000 to 12,000 per year

Risk Factors

Demographics
1. Non-Hispanic black (RR 2, and associated highest mortality)
2. Male gender
3. Family History confers 2-4 fold increased risk (Autosomal Dominant trait)
Associated conditions
Associated exposures
1. Methylene chloride
2. Dioxin (agent orange)
Associated with certain occupational exposures
1. Farming Pesticides
2. Petroleum workers
3. Woodworkers
4. Leather workers
5. Ionizing radiation
6. Hairdresser
7. Firefighter

Pathophysiology

Malignant proliferation of Plasma Cells
1. Overproduce monoclonal Protein
2. Results from various genetic alterations (e.g. translocations, somatic mutations)
3. Plasmacytoma may also form solitary Plasma Cell Tumor
4. Abnormal Immunoglobulin (IgG, IgM, IgA are most common)
  1. May also involve light chains (either kappa or lambda)
On spectrum of plasma cell malignancy
1. Spontaneous (de novo) onset in 80% of cases
  1. Less than a third of Multiple Myeloma patients have a preceding known history of MGUS or SMM
2. Monoclonal Gammopathy of Undetermined Significance (MGUS) in 20% of cases
  1. Progression to Multiple Myeloma at rate of 1% per year (see MGUS for progression risks)
3. Smoldering Multiple Myeloma (SMM)
  1. Progression to Multiple Myeloma at rate of 10% per year for first five years (then decreases)
4. Clinical Multiple Myeloma
5. Plasma Cell Leukemia (Plasmacytic Leukemia)
Risk Factors for progression from MGUS or SMM to Multiple Myeloma (see below)
1. Non-IgG subtype
2. High levels of monoclonal Protein
3. Abnormal free light chain ratio
4. Gene alterations

Symptoms

Asymptomatic in 34% of cases (present with abnormal labs: Anemia, Proteinuria, Hypercalcemia)
Back pain or bone pain (58%)
Fatigue (32%)
Pathologic Fracture (up to 34-40% of cases)
Anorexia and weight loss (24%)
Paresthesias (5%)
1. Wrist Pain (Carpal Tunnel related Neuropathy)
Other presenting symptoms
1. Nausea or Vomiting
2. Spinal Cord Compression (5%)
3. Hyperviscosity Syndrome related symptoms

Signs
Bone Findings

Osteolytic lesions
Pathologic Fractures
Palpable swellings on accessible bones
Location
1. Sternum
2. Skull
3. Ribs
4. Vertebrae (May result in Spinal Cord Compression)

Differential Diagnosis
General

Primary or metastatic cancer
Benign bone lesions
Infections (Osteomyelitis, Vertebral Osteomyelitis)
Hyperparathyroidism
Vertebral Compression Fracture (Osteoporosis)

Differential Diagnosis
Plasma Cell Peripheral Disorder

See Plasma Cell Peripheral Disorder
Common
1. Monoclonal Gammopathy of Undetermined Significance (MGUS)
Uncommon
1. Waldenstrom Macroglobulinemia
2. Amyloidosis
3. B-Cell Non-Hodgkin Lymphoma
Rare
1. Plasmacytoma
2. Plasma Cell Leukemia

Labs
Initial

Comprehensive Metabolic Panel (including Serum Calcium, Serum Albumin and Protein, Renal Function tests, Electrolytes)
1. Hypercalcemia
  1. Serum Calcium >10.1 mg/dl (present in 28%, Serum Calcium >11 mg/dl in 13% of patients)
2. Renal Insufficiency
  1. Serum Creatinine >1.3 mg/dl (present in 48%, Creatinine >2 mg/dl in 23% of patients)
Complete Blood Count with Platelets
1. Normochromic Normocytic Anemia
  1. Hemoglobin <12 grams/dl (present in 65-73% of patients)
  2. Anemia is nearly always present at one point for every patient
Other initial tests to consider
1. Thyroid Stimulating Hormone (TSH)
2. Acute phase reactants (ESR, C-RP)
3. Serum Vitamin B12
4. Urinalysis
  1. Proteinuria (bence jones Proteins)
5. Peripheral Smear
  1. Myeloma Cells
  2. Rouleaux of Red Blood Cells

Labs
Confirmatory

Serum Protein Electrophoresis and Urine Protein electrophoresis for Monoclonal Peak
1. M Protein in either serum or urine: 97% of patients
2. Serum M Protein by electophoresis (82%) or immunofixation (93%)
3. Urine M Protein by electrophoresis: 75%
Immunofixation electrophoresis of serum and urine
Serum free light chain assay
Serum quantitative Immunoglobulins
24 Hour Urine Protein
Beta-2 microglobulin
Lactate Dehydrogenase (LDH)

Labs
Diagnosis - typically done in oncology

Bone Marrow Biopsy and aspirate (with cytogenetics, FISH, immunohistochemistry)
1. Typically performed by oncology

Imaging

Skeletal Survey (including Skull XRay)
1. Recommended imaging for primary providers
2. Classic "punched out" lytic lesions (66% of patients)
3. Pathologic Fractures (26% of patients)
PET/CT or whole body MRI
1. Typically obtained in oncology
Bone Densitometry or DEXA (consider)
1. Osteoporosis (23% of patients)

Diagnosis
Smoldering Multiple Myeloma

Absence of Myeloma defining events (CRAB factors) AND
No Amyloidosis AND
Serum monoclonal Protein (IgG or IgA) >= 3 g/dl
1. OR urinary monoclonal Protein >500 mg/24 hours
2. OR Clonal Bone Marrow plasma cells 10 to 60%

Diagnosis
Multiple Myeloma

Clonal Bone Marrow plasma cells >10% or biopsy proven bony or extramedullary Plasmacytoma AND
Myeloma defining event (>=1 CRAB factors, absence suggests Smoldering Multiple Myeloma)
1. Hypercalcemia
  1. Serum Calcium >11 mg/dl (or >1 mg/dl above upper range of normal)
2. Renal Insufficiency
  1. Serum Creatinine >2 mg/dl (or GFR <40 ml/min)
3. Anemia
  1. Hemoglobin <10 g/dl (or more than 2 g/dl below the lower limit of normal)
4. Osteolytic Bone lesions
  1. Osteolytic lesions (one or more) on XRay, CT or PET/CT
5. Other additional qualifying factors
  1. More than 1 MRI focal lesion >5 mm OR
  2. Clonal Bone Marrow plasma cells >60% OR
  3. Ratio involved to uninvolved serum free light chain >=100
    1. AND Involved free light chain >100 mg/L

Diagnosis
Plasma Cell Leukemia

All multiple meyloma criteria met AND
Plasma cells >5% on conventional Peripheral Blood Smear white cell differential count

Staging

Systems
1. International Staging (ISS)
  1. Standard staging system was used most commonly (as of 2017)
2. Revised International Staging (R-ISS)
  1. Better predictor of progression and survival than ISS (which it will likely replace)
3. Durie-Salmon Staging
Stage I
1. International Staging (ISS)
  1. Serum B2 Microglobulin <3.5 mg/L AND
  2. Serum Albumin >= 3.5 g/dl
2. Revised International Staging (R-ISS)
  1. ISS Stage I AND
  2. Normal serum Lactate Dehydrogenase (LDH)
  3. No high risk Chromosomes on cytogenetic studies (e.g. del(17p), t(4;14), t(14:16))
3. Durie-Salmon Staging
  1. Hemoglobin >10 g/dl
  2. Serum Calcium <12 mg/dl
  3. No bone disease or Plasmacytoma
  4. Serum paraprotein <5g/dl (IgG) or <3 g/dl (IgA)
  5. Urinary light chain excretion <4 g per 24 hours
Stage 2
1. International Staging
  1. Serum B2 Microglobulin 3.5 to 5.5 mg/L
2. Revised International Staging (R-ISS)
  1. Not R-ISS stage I or III
3. Durie-Salmon Staging
  1. Not DSS stage I or III
Stage 3
1. International Staging
  1. Serum B2 Microglobulin >=5.5 mg/L
2. Revised International Staging (R-ISS)
  1. ISS Stage III AND
  2. Increased Lactate Dehydrogenase (LDH) OR
  3. High risk Chromosomes (e.g. del(17p), t(4;14), t(14:16))
3. Durie-Salmon Staging
  1. Hemoglobin <8.5 g/dl
  2. Serum Calcium >12 mg/dl
  3. Skeletal Survey with >2 lytic lesions
  4. Serum paraprotein >7 g/dl (IgG) or >5 g/dl (IgA)
  5. Urinary light chain excretion >12 g per 24 hours

Evaluation
IMWG Mayo 2/20/20 Rule for Smoldering Multiple Myeloma (SMM) Progression

See Monoclonal Gammopathy of Undetermined Significance for MGUS related progression risk factors
Criteria (score 1 point for each positive criteria)
1. Serum monoclonal Protein >2 g/dl
2. Ratio involved to uninvolved free light chain >20
3. Marrow Plasma Cell Infiltration >20%
Three Factor Interpretation: SMM Progression Risk in 2 years
1. Score 0: Low Risk (6% risk of progression in 2 years)
2. Score 1: Intermediate Risk (17% risk of progression in 2 years)
3. Score 2-3: High Risk (44% risk of progression in 2 years)
Four Factor Interpretation: SMM Progression Risk in 2 years
1. Uses above three factor criteria and one additional point for any of the following chromosomal risks
  1. t(4;14)
  2. t(14:16)
  3. +1q
  4. Del13Q/Monosomy 13
2. Score 0: Low Risk (6% risk of progression in 2 years)
3. Score 1: Low-Intermediate Risk (23% risk of progression in 2 years)
4. Score 2: Intermediate Risk (46% risk of progression in 2 years)
5. Score 3-4: High Risk (63% risk of progression in 2 years)
References
1. Mateos (2020) Blood Cancer J 10(10):102 +PMID: 33067414 [PubMed]

Management
Combination Therapy

See oncology references for current management protocols
Indication
1. Symptomatic Multiple Myeloma
Preparation
1. Screen for HIV, Hepatitis B and Hepatitis C before initiating treatment
2. Consider Antiviral and Antibiotic prophylaxis during treatment
Protocol 1: Otherwise physically healthy patients (previously limited to age <65 years)
1. First: High dose myeloablative Chemotherapy
  1. Four drug regimens (preferred in 2025 NCCN guidelines)
    1. Daratumumab (Darzalex, DRd) or Isatuximab (Sarclisa) AND
    2. Lenalidomide AND
    3. Bortezomib (VRd) AND
    4. Dexamethasone
  2. Older three drug regimen options
    1. CDT: Cyclophosphamide AND Thalidomide AND Dexamethasone OR
    2. VCd: Bortezomib AND Cyclophosphamide AND Dexamethasone
2. Next: Stem Cell Transplant (follows initial myeloablative Chemotherapy for 3 to 6 months)
  1. Autologous Stem Cell Transplant (ASCT) with high dose Melphalan
3. Next: Maintenance Therapy
  1. One to 2 drug protocols taken for months to years (or indefinately) following Stem Cell Transplant
Protocol 2: Serious comorbidity (unable to tolerate marrow ablation and ASCT)
1. Thalidomide AND Alkylating Agent (Melphalan, Cyclophosphamide or Chlorambucil) AND Prednisolone OR
2. Bortezomib AND Doxorubicin AND Dexamethasone OR
3. Bortezomib AND Thalidomide AND Dexamethasone (VTd)
Medications used in first treatment of Multiple Myeloma
1. Immunomodulating Agents
2. Proteasome Inhibitors
  1. Bortezomib (Velcade)
  2. Carfilzomib (Kyprolis)
  3. Ixazomib (Ninlaro)
3. Monoclonal Antibodies
  1. Daratumumab (Darzalex, DRd)
  2. Elotuzumab (Empliciti)
  3. Isatuximab (Sarclisa)
4. Alkylating Agents
  1. Cyclophosphamide
  2. Melphalan (Alkeran)
5. Corticosteroids (Dexamethasone)
  1. Administered concurrently with Chemotherapy to reduce light chain renal load (Kidney injury risk)
Medications used to treat relapse
1. Chimeric Antigen receptor T Cells
  1. Ciltacabtagene autoleucel (Carvykti)
  2. Idecabtagene vicleucel (Abecma)
2. Antibody Drug Conjugates
  1. Belantamab mafodotin (Blenrep)
3. Nuclear Export Selective Inhibitors
  1. Selinexor (Xpovio)
Efficacy
1. Stem Cell Transplant (ASCT) has increased median overall survival rate >10 years
2. Palliative (Not curative)
3. Relapse is common

Management
Adjunctive

Radiotherapy
1. Localized conditions (e.g. severe bone pain, pathologic Fractures, local tumors)
Pain management
1. Analgesics
2. Neuropathy medications
3. Physical Activity
4. Radiotherapy (localized severe bone pain)
Bisphosphonates
1. Indicated in all treated patients (regardless of bony lesions)
  1. Prevents Vertebral Fractures and other bony complications (pathologic Fractures, osteolytic lesions, pain)
2. Treat for at least 2 years
  1. Preferred: IV Zoledronic acid or Pamidronate
  2. Alternative: Denosumab
3. Additional
  1. Vitamin D Supplementation should also be given, and consider Calcium Supplementation with caution
4. References
  1. Terpos (2013) J Clin Oncol 31(18): 2347-57 [PubMed]
Venous Thromboembolism prophylaxis
1. Reduces VTE Risk from 12-26% to 5-8% in Multiple Myeloma
2. Indications
  1. Active treatment of Multiple Myeloma (esp. immunomodulatory agents)
  2. Continue for first 4-6 months after diagnosis (or until disease controlled)
3. High risk patient prophylaxis
  1. Low Molecular Weight Heparin (e.g. Lovenox) 40 mg SQ daily
  2. Warfarin (Coumadin) and target INR 2-3
  3. Apixaban (Eliquis) 2.5 mg twice daily
  4. Rivaroxaban (Xarelto) 10 mg once daily
  5. Fondaparinux 2.5 mg once daily
4. Low risk patient prophylaxis
  1. Aspirin 81 to 324 mg once daily
5. Resources
  1. Impede-VTE score predicts VTE Risk specific to Multiple Myeloma
    1. https://www.mdcalc.com/calc/10498/impede-vte
6. References
  1. Falanga (2012) Curr Opin Oncol 24:702-10 [PubMed]
Prophylactic Antibiotics
1. First 3 months of treatment (some cases)
  1. Trimethoprim-sulfamethoxazole (Septra, Bactrim) OR
  2. Fluoroquinolone
2. Recurrent pneumococcal infections
  1. Penicillin
3. Proteasome Inhibitor therapy
  1. Antivirals (prevent Varicella Zoster Virus reactivation)
4. Absolute Neutrophil Count <500/uL
  1. Fluconazole
5. Other antimicrobial prophylaxis indications
  1. Viral seropositivity
  2. Multiple Myeloma new diagnosis
  3. Bispecific Antibody therapy (BsAbs)
  4. Chimeric Antigen Receptor T-Cell Therapy (CAR T-Cell Therapy)
  5. Autologous Stem Cell Transplant (ASCT)
Immunizations
1. Before Treatment (at least 2 weeks)
  1. Also update Immunizations for close contacts of the patient
  2. Pneumococcal Vaccine
  3. COVID Vaccine
  4. Influenza Vaccine
  5. Recombinant Zoster Vaccine
  6. Respiratory Syncytial Virus Vaccine (if >=60 years old)
2. After Autologous Stem Cell Transplant (ASCT)
  1. Give 50-70 days after
    1. Recombinant Zoster Vaccine
  2. Give 3 to 6 months after
    1. Pneumococcal Vaccine
      1. Also give after CAR T-Cell Therapy, BsAbs
  3. Give 6 months after
    1. Influenza Vaccine
    2. COVID Vaccine
  4. Give 6-12 months after
    1. Tetanus Diptheria Acellular Pertussis Vaccine (Tdap)
    2. Haemophilus influenzae B Vaccine
    3. Hepatitis A Vaccine
    4. Hepatitis B Vaccine
    5. Meningococcal Vaccine
    6. Polio Vaccine
    7. HPV Vaccine (up to age 45 years)

Management
Monitoring

Symptomatic improvement
Complication monitoring (see below)
1. Weight loss
2. Fatigue
3. Bone pain
4. Peripheral Neuropathy
5. Venous Thromboembolism
6. Infection
7. Chemotherapy adverse effects and toxicity (e.g. Pancytopenia)
Multiple Myeloma
1. Decrease in M Component
MGUS and SMM monitoring
1. Scheduled monitoring of paraproteins and serum light chains
2. MGUS follow-up every 6 months (indefinitely)
3. Smoldering Multiple Myeloma (SMM) follow-up every 3-6 months
Monitoring for relapse or progression
1. New or growing bone lesions (or Plasmacytoma)
2. Hypercalcemia
3. Hemoglobin decrease > 2 g/dl from baseline
4. Serum Creatinine increase >2 mg/dl
5. Hyperviscosity Syndrome
High risk patient monitoring
1. Labs every 3 months
  1. Complete Blood Count
  2. Serum Creatinine
  3. Serum Calcium
  4. Serum free light chain assay
  5. Urine and Serum Protein Electrophoresis (SPEP, UPEP)
2. Imaging every year
  1. Whole body MRI, Low dose CT or PET-CT

Complications

Peripheral Neuropathy
1. Nerve infiltration by amyloid
Immune Suppression
1. Infection presenting complaint in 25% of patients
2. Infection is the leading cause of morbidity and mortality in Multiple Myeloma
3. Start empiric Antibiotics for febrile illness
4. See above for prophylactic Antimicrobial Agents during treatment
5. See prevention below for Immunizations
Hypercalcemia
1. Initial Management
  1. Ensure euvolemia (consider crystalloid infusion)
  2. Corticosteroids
2. Additional management in Refractory Cases
  1. Bisphosphonates (esp. zoledronic acid, preferred) or Denosumab
  2. Furosemide
3. Other measures
  1. Calcitonin
Renal Failure
1. Renal Impairment is present in >30% of patients at time of Multiple Myeloma diagnosis
2. Dexamethasone is often given prophylactically with Chemotherapy to reduce light chain renal load
3. General measures
  1. Correct Electrolyte abnormalities
  2. Ensure euvolemia
  3. Avoid Nephrotoxins
  4. Consult nephrology as needed
4. Acute Kidney Injury
  1. Multifactorial (free light chains at proximal tubules, Hypercalcemia, Dehydration, nephrotoxicity)
  2. Treat Acute Kidney Injury with crystalloid (e.g. NS, at least 3 L/day)
5. Severe renal disease
  1. Hemodialysis may be required in up to 2% of patients
Venous Thromboembolism
1. Relative Risk is 9 fold higher than general population (esp. in first 6 months of diagnosis)
2. Consider other VTE Risk factors (e.g. Obesity, prior VTE, indwelling venous catheter, medical comorbidity)
3. Impede-VTE score predicts VTE Risk specific to Multiple Myeloma
  1. https://www.mdcalc.com/calc/10498/impede-vte
  2. Consider VTE Prophylaxis for patients at high risk (see above)
Anemia
1. Results from Bone Marrow invasion
2. Consider differential diagnosis for Anemia
3. Often improves with Multiple Myeloma treatment
4. Anemia management
  1. Red Blood Cell Transfusion for Hemoglobin <7 g/dl
  2. Erythropoiesis-stimulating agents may be considered (risk of thrombosis)
Invasive bone lesions (80-90%)
1. Pathologic Fractures
2. Bone pain
3. Osteoporosis
4. Hypercalcemia
Vertebral Fractures
1. See Vertebral Fracture
2. Intravenous Bisphosphonates (Pamidronate, Zoledronic acid)
  1. Continue indefinately
  2. Reduces fracture Incidence and pain
3. Surgical Intervention: Percutaneous Vertebroplasty or Kyphoplasty
  1. Indicated in refractory cases
4. Radiation Therapy
  1. Indicated for Spinal Cord Compression
Hyperviscosity Syndrome (uncommon to rare)
1. Findings: Fatigue, Headache, Visual disturbance, Retinopathy
2. Treat with Plasma Exchange, antimyeloma Chemotherapy

Prognosis

Invariably fatal but relates to staging
1. Stage I: 62 Month median survival
2. Stage 3: 29 Month median survival
Treated patients live asymptomatically for years
1. Five year survival is 61% as of 2020 (previously was 45% in 2007, and 30% in 1990)
2. Stem Cell Transplant (ASCT) has increased median overall survival rate >10 years
3. Median overall survival approaches 8 years with other modern management (including monoclonal antibodies)
Mortality from cause unrelated to Myeloma: 25%

Resources

Multiple Myeloma Research Web Server
1. https://www.myelomacenter.org/

References