Multiple Myeloma

Last updated: January 2025 | Medical Reviewer: Oncol.net Editorial Board

Overview

Multiple myeloma accounts for about 2% of all cancers and 18% of blood cancers. Approximately 35,000 new cases are diagnosed annually in the United States. The disease typically affects older adults (median age 69 at diagnosis) and is twice as common in African Americans as in Caucasians.

Over the past two decades, treatment advances have dramatically improved outcomes. The median survival has more than doubled - from 3-4 years in the 1990s to 8-10+ years today. Novel therapies including proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and CAR-T cell therapy have transformed myeloma into a manageable chronic disease for many patients.

Disease Biology

Normal Plasma Cells vs. Myeloma Cells

• Normal plasma cells: Produce antibodies (immunoglobulins) to fight infections, represent <5% of bone marrow cells
• Myeloma cells: Cancerous plasma cells that:
  • Multiply uncontrollably
  • Crowd out normal blood cells (causing anemia, low platelets, low white blood cells)
  • Produce abnormal proteins (M-protein or monoclonal protein)
  • Secrete factors that damage bones (osteoclast-activating factors)
  • Accumulate in bone marrow and sometimes form tumors (plasmacytomas)

M-Protein (Monoclonal Protein)

• Abnormal antibody or antibody fragment produced by myeloma cells
• Types:
  • IgG: 50% of cases
  • IgA: 20%
  • Light chain only (kappa or lambda): 15-20% - called light chain myeloma
  • IgD, IgE, IgM: Rare
  • Non-secretory: 1-3% - no detectable M-protein
• Detected by:
  • Serum protein electrophoresis (SPEP)
  • Immunofixation
  • Free light chain assay
• Used to diagnose, monitor disease, and assess treatment response

Disease Spectrum

Progression from Precursor States

Multiple myeloma typically evolves through defined stages:

1. MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Precursor condition: M-protein present but no myeloma symptoms
• Prevalence: 3% of people >50 years, 5% >70 years
• Criteria:
  • M-protein <3 g/dL
  • Clonal plasma cells <10% in bone marrow
  • No myeloma-related organ damage (no CRAB criteria)
• Risk of progression: 1% per year to myeloma or related disorder
• Management: Observation with periodic monitoring (no treatment)

2. Smoldering Multiple Myeloma (SMM)

• Intermediate stage between MGUS and active myeloma
• Criteria:
  • M-protein ≥3 g/dL and/or clonal plasma cells 10-60% in bone marrow
  • No myeloma-related organ damage (no CRAB criteria)
• Risk of progression: 10% per year for first 5 years, then decreases
• Management: Close observation; clinical trials evaluating early treatment for high-risk SMM

3. Active (Symptomatic) Multiple Myeloma

• Requires treatment
• Meets diagnostic criteria (see below)

Signs and Symptoms (CRAB Criteria)

Active myeloma is diagnosed when CRAB criteria or myeloma-defining biomarkers are present:

CRAB Criteria

• C - Calcium elevation (hypercalcemia):
  • Serum calcium >11 mg/dL or >1 mg/dL above upper limit of normal
  • Symptoms: Confusion, constipation, excessive thirst/urination, nausea, fatigue
  • Caused by bone destruction releasing calcium
• R - Renal (kidney) insufficiency:
  • Creatinine >2 mg/dL or creatinine clearance <40 mL/min
  • Caused by light chain deposition in kidneys, hypercalcemia, dehydration
  • Can lead to kidney failure requiring dialysis
• A - Anemia:
  • Hemoglobin <10 g/dL or >2 g/dL below lower limit of normal
  • Symptoms: Fatigue, weakness, shortness of breath, pale skin
  • Caused by myeloma cells crowding out red blood cell production
• B - Bone disease:
  • Lytic lesions (punched-out holes in bones), osteoporosis, or pathologic fractures
  • Most common symptom: Bone pain (especially back, ribs, hips)
  • Complications: Fractures (especially spine - can cause nerve compression), spinal cord compression
  • 70-80% of patients have bone involvement at diagnosis

Myeloma-Defining Biomarkers (Alternative to CRAB)

Treatment indicated even without CRAB symptoms if:

• Clonal plasma cells ≥60% in bone marrow
• Free light chain ratio ≥100 or ≤0.01
• >1 focal lesion on MRI (≥5 mm)

Other Common Symptoms

• Frequent infections (due to low normal antibodies and white blood cells)
• Easy bruising or bleeding (low platelets)
• Neurological symptoms (from spinal cord compression, hypercalcemia, or nerve damage)
• Unexplained weight loss

Diagnosis

Laboratory Tests

• Complete blood count (CBC): Check for anemia, low platelets, low white blood cells
• Comprehensive metabolic panel: Kidney function, calcium, albumin
• Protein studies:
  • Serum protein electrophoresis (SPEP)
  • Urine protein electrophoresis (UPEP)
  • Immunofixation (serum and urine)
  • Serum free light chain assay
  • Quantitative immunoglobulins (IgG, IgA, IgM)
• Beta-2 microglobulin and albumin: Prognostic markers for staging
• LDH: Prognostic marker

Bone Marrow Tests

• Bone marrow aspirate and biopsy: Required for diagnosis
  • Assess percentage of plasma cells
  • Cytogenetics and FISH testing for chromosomal abnormalities
  • Flow cytometry to confirm clonal plasma cells
• Genetic/molecular testing: Identify high-risk features

Imaging

• Skeletal survey (X-rays): Traditional imaging for bone lesions (being replaced by advanced imaging)
• Whole-body low-dose CT: More sensitive than X-rays for detecting lytic lesions
• MRI: Preferred for evaluating spine, assessing spinal cord compression
• PET/CT: Increasingly used for staging and treatment response

Staging and Risk Stratification

Revised International Staging System (R-ISS)

ISS (International Staging System) based on:

• ISS I: Beta-2 microglobulin <3.5 mg/L and albumin ≥3.5 g/dL
• ISS II: Not I or III
• ISS III: Beta-2 microglobulin ≥5.5 mg/L

High-risk cytogenetics: del(17p), t(4;14), t(14;16)

Treatment

Treatment Approach Overview

• Multiple myeloma is generally incurable but highly treatable
• Pattern: Induction → Stem cell transplant (if eligible) → Maintenance → Relapse → Salvage therapy → Repeat
• Most patients go through multiple lines of therapy over years
• Goal: Achieve deepest possible response, prolong remission, maintain quality of life

First-Line Therapy (Transplant-Eligible Patients)

Induction Therapy (3-4 cycles):

• Triplet regimens:
  • VRd: Bortezomib (Velcade) + Lenalidomide (Revlimid) + Dexamethasone - most common
  • Dara-VRd: Adding daratumumab to VRd - newer, more effective
  • KRd: Carfilzomib + Lenalidomide + Dexamethasone
• Goal: Reduce myeloma burden before stem cell collection and transplant

Stem Cell Collection and Autologous Stem Cell Transplant (ASCT):

• Standard for fit patients <70-75 years
• Process:
  • Stem cells collected from blood after mobilization (G-CSF + plerixafor)
  • High-dose melphalan chemotherapy (destroys bone marrow)
  • Stem cell infusion (rescue bone marrow)
  • Recovery over 2-4 weeks
• Improves progression-free survival by 12-18 months vs chemotherapy alone
• Can be delayed and done at first relapse (similar overall survival)

Maintenance Therapy:

• Lenalidomide maintenance: Standard post-transplant, continued until progression
• Improves progression-free and overall survival

First-Line Therapy (Transplant-Ineligible Patients)

• Dara-VRd or Dara-Rd: Daratumumab + Revlimid + Dexamethasone (continuous until progression)
• VRd: Bortezomib + Lenalidomide + Dexamethasone
• VCd: Bortezomib + Cyclophosphamide + Dexamethasone (if lenalidomide not tolerated)
• Continued until progression or intolerance

Drug Classes

Proteasome Inhibitors

• Bortezomib (Velcade), carfilzomib (Kyprolis), ixazomib (Ninlaro)
• Block protein degradation machinery, causing myeloma cell death
• Side effects: Peripheral neuropathy (bortezomib), cardiac effects (carfilzomib)

Immunomodulatory Drugs (IMiDs)

• Lenalidomide (Revlimid), pomalidomide (Pomalyst), thalidomide
• Multiple mechanisms: immune stimulation, anti-angiogenesis, direct anti-myeloma
• Side effects: Blood clots (require prophylaxis), low blood counts, fatigue, neuropathy (thalidomide)

Monoclonal Antibodies

• Daratumumab (Darzalex): Anti-CD38, backbone of modern regimens
• Isatuximab (Sarclisa): Anti-CD38, alternative to daratumumab
• Elotuzumab (Empliciti): Anti-SLAMF7
• Side effects: Infusion reactions, increased infections

CAR-T Cell Therapy

• Idecabtagene vicleucel (Abecma): Anti-BCMA CAR-T
• Ciltacabtagene autoleucel (Carvykti): Anti-BCMA CAR-T
• Approved for relapsed/refractory myeloma (after 4+ prior lines)
• Very effective: 70-80% response rates in heavily pretreated patients

Bispecific Antibodies

• Teclistamab (Tecvayli): BCMA x CD3 bispecific
• Elranatamab (Elrexfio): BCMA x CD3 bispecific
• Newer class showing promising results in relapsed disease

Supportive Care

• Bisphosphonates: Zoledronic acid or pamidronate monthly - prevent bone complications
• Radiation therapy: For localized bone pain, impending fractures, spinal cord compression
• Orthopedic surgery: Stabilize fractures, decompress spinal cord
• Infection prophylaxis: IVIG for recurrent infections, antiviral prophylaxis
• VTE prophylaxis: Aspirin or anticoagulation (IMiD-containing regimens)
• Pain management: Multimodal approach

Prognosis

• Overall 5-year survival: ~60% (has improved dramatically)
• Median survival: 8-10 years overall, >10 years for standard-risk disease
• Varies by:
  • Age and fitness (younger, fitter patients do better)
  • Genetics (standard-risk vs high-risk)
  • Stage (R-ISS I vs III)
  • Response to treatment (achieving MRD-negativity improves outcomes)
• Most patients: Live through multiple lines of therapy, experiencing periods of remission and relapse
• Continuous improvement: New drugs approved regularly, outcomes continue to improve

Frequently Asked Questions

Is multiple myeloma curable?

Multiple myeloma is generally considered incurable with current therapies. However, it is highly treatable, and many patients live 10-15+ years with good quality of life. A small percentage of patients (<10%) achieve very deep, durable remissions that last many years and may represent functional cures. Research into curative approaches continues.

Should I get a stem cell transplant?

Autologous stem cell transplant improves progression-free survival and is standard for eligible patients (generally <70-75 years, good organ function). However, it can be done upfront after induction or delayed until first relapse with similar overall survival. The decision depends on response to induction, patient preference, and individual factors. Discuss with your myeloma specialist.

What is MRD and why does it matter?

MRD (minimal residual disease) testing detects very low levels of myeloma cells that standard tests miss (sensitivity 1 in 100,000-1,000,000 cells). MRD-negative status (no detectable myeloma cells by sensitive testing) is associated with longer remissions and better survival. It's becoming an important treatment goal and is used in clinical trials.

How long will I be on treatment?

Unlike many cancers, myeloma treatment is continuous. After initial induction and possibly transplant, maintenance therapy (usually lenalidomide) continues until progression or intolerance - often years. When myeloma relapses, another line of therapy begins. Most patients are on some form of treatment for the remainder of their lives.

Can I work during myeloma treatment?

Many patients continue working during treatment, though you may need flexibility or accommodations. Treatment schedules vary - some require weekly visits, others monthly. Side effects (fatigue, neuropathy, etc.) may affect work capacity. Transplant requires 2-3 months off. Discuss your individual situation with your employer and healthcare team.

Sources and References

• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines: Multiple Myeloma
• American Cancer Society: Multiple Myeloma Statistics
• International Myeloma Working Group (IMWG) Criteria
• National Cancer Institute SEER Database
• Kumar SK et al. Multiple Myeloma. Nature Reviews Disease Primers. 2017