Multiple Myeloma

Definition

Epidemiology

• Accounts for ~1% of all malignancies and >10% of hematologic malignancies
• ~30,000 new cases/year in the United States
• Median age at diagnosis: 65–70 years; only 2% of patients are <40
• More common in males and in people of African descent (Black Americans have nearly twice the incidence of White Americans)
• Almost all cases evolve from a premalignant MGUS (monoclonal gammopathy of undetermined significance) phase

Pathogenesis

Genetic Events

• Primary IgH translocations (chromosome 14q32) occur in ~40% of cases, fusing the IgH locus to oncogenes such as cyclin D1 and cyclin D3 — dysregulation of D-cyclins drives cell proliferation
• Hyperdiploid myeloma (trisomies) accounts for another ~40%
• Progression from MGUS → myeloma is driven by RAS mutations and MYC abnormalities; secondary events include deletion 17p, deletion 1p, and amplification 1q (all adverse prognostic markers)

Bone Marrow Microenvironment

• The cytokine IL-6 (produced by bone marrow fibroblasts and macrophages) is a major growth factor for myeloma plasma cells
• NF-κB signaling and other paracrine loops (SDF-α, MIP-1-α) sustain tumor growth

Bone Destruction Mechanism

1. Osteoclast activation: Myeloma cells upregulate RANKL and decrease OPG (osteoprotegerin) → increased RANKL/OPG ratio → osteoclast activation → bone resorption
2. Osteoblast suppression: Elevated IL-3, IL-7, and DKK1 simultaneously suppress bone formation

Clinical Manifestations ("CRAB" Criteria)

• Recurrent bacterial infections — myeloma suppresses normal B-cell function; despite elevated total immunoglobulin (from M protein), functional antibody production is severely depressed
• Hyperviscosity (less common) — from high levels of circulating M protein
• Peripheral neuropathy — especially with AL amyloid
• Many patients are initially asymptomatic, detected incidentally on blood tests

Bone Marrow Histology

• Marrow plasma cells usually >30% of cellularity at diagnosis
• Cells may resemble normal plasma cells or show abnormal features: prominent nucleoli, Russell bodies (cytoplasmic inclusions of condensed immunoglobulin)
• Skeletal lesions: "punched-out" lytic defects 1–4 cm, most common in vertebral column, ribs, skull, pelvis, femur

M Protein (Paraprotein) Types

Diagnosis

1. ≥10% clonal plasma cells on bone marrow biopsy OR biopsy-proven plasmacytoma
2. M protein in serum or urine (absent in non-secretory myeloma)
3. One or more myeloma-defining events:
   • Hypercalcemia (>11 mg/dL)
   • Renal insufficiency (creatinine >2 mg/dL or CrCl <40 mL/min)
   • Anemia (Hb <10 g/dL or >2 g/dL below normal)
   • Bone lesions (≥1 lytic lesion on skeletal survey, CT, or PET-CT)
   • Clonal BM plasma cells ≥60%
   • Serum free light chain ratio ≥100

   • 1 focal lesion on MRI

Staging (Revised ISS)

Treatment

Transplant-Eligible Patients (~50% of newly diagnosed)

1. Induction (~3–4 months): VRd (bortezomib + lenalidomide + dexamethasone) is the standard; daratumumab can be added (DaraVRd) for high-risk disease
2. Autologous stem cell transplantation (ASCT) with high-dose melphalan — prolongs event-free and overall survival (not curative)
3. Maintenance therapy with lenalidomide post-transplant

Transplant-Ineligible Patients

• DRd (daratumumab + lenalidomide + dexamethasone) or VRd at attenuated doses
• Bortezomib + melphalan + prednisone (VMP) is an alternative

Relapsed/Refractory Myeloma

• Multiple salvage regimens combining proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory agents (lenalidomide, pomalidomide), anti-CD38 monoclonals (daratumumab, isatuximab), anti-BCMA agents (belantamab, teclistamab, idecabtagene vicleucel CAR-T)
• Second ASCT may be considered if first remission lasted >1 year

Supportive Care

• Bisphosphonates (zoledronic acid, pamidronate) for bone disease
• G-CSF and antimicrobial prophylaxis for infections
• Radiation for painful or impending fracture lesions
• Treat hypercalcemia with hydration, bisphosphonates

Prognosis

Differentiation from Related Disorders

Multiple Myeloma: Symptoms, Treatment, Diet & Danger

1. Symptoms

🦀 C — Calcium (High blood calcium / Hypercalcemia)

• Confusion, memory problems
• Excessive thirst and urination
• Constipation
• Nausea and loss of appetite
• Extreme fatigue and weakness

🦀 R — Renal (Kidney problems)

• Swelling in the legs
• Reduced urine output
• Fatigue from waste build-up in the blood

🦀 A — Anemia (Low red blood cells)

• Fatigue and weakness
• Shortness of breath
• Dizziness
• Pale skin

🦀 B — Bone problems

• Bone pain — most common first symptom (back, ribs, sternum/breastbone, skull, hips)
• Pathologic fractures (broken bones from minor injury)
• Vertebral collapse → back pain or height loss

Other important symptoms

Important: Many people have no symptoms at all early on — the disease is discovered incidentally on routine blood tests.

2. Treatment

Step 1 — Induction Chemotherapy (All patients)

• V — Bortezomib (Velcade) — a proteasome inhibitor
• R — Lenalidomide (Revlimid) — an immunomodulatory drug
• d — Dexamethasone — a steroid

Step 2 — Stem Cell Transplant (Eligible patients ~50%)

• Autologous stem cell transplantation (ASCT): Patient's own stem cells are collected, then high-dose chemotherapy (melphalan) destroys the myeloma, and the stem cells are returned to rebuild the bone marrow
• Not a cure, but significantly extends survival
• Suitable for patients under ~65–70 with good overall health

Step 3 — Maintenance Therapy

• Lenalidomide taken long-term after transplant to keep myeloma in remission

For patients NOT eligible for transplant

• Daratumumab + Lenalidomide + Dexamethasone (DRd)
• Bortezomib + Melphalan + Prednisone (VMP)

Supportive treatments (equally important)

Newer/Advanced treatments (relapsed disease)

• CAR-T cell therapy (e.g., idecabtagene vicleucel) — reprograms immune cells to kill myeloma
• Bispecific antibodies (teclistamab, elranatamab) — newer immunotherapy
• Carfilzomib, pomalidomide, isatuximab — for resistant disease

3. Foods to Help (Dietary Guidance)

• Reducing inflammation (which drives myeloma progression)
• Supporting the immune system
• Maintaining weight and strength during treatment
• Potentially slowing progression in early/precursor stages

Foods to INCLUDE ✅

Foods to LIMIT or AVOID ❌

Special dietary concerns during treatment

• During chemotherapy: Eat small, frequent meals; prioritize protein (eggs, fish, poultry, legumes) to maintain muscle mass
• Kidney disease: Limit potassium and phosphorus if told by your doctor (bananas, dairy, nuts may need restriction)
• Hydration: Drink plenty of water (2–3 liters/day unless restricted) — critical for kidney protection

Always consult a registered dietitian who specializes in oncology, as dietary needs vary by individual and treatment phase.

4. Is It Dangerous?

Why it is dangerous

• It is not curable with current standard therapy (except in rare cases with allogeneic transplant)
• It progressively destroys bones, kidneys, and the immune system
• Renal failure, severe infections, and pathologic fractures are common causes of death
• It tends to relapse — even after treatment, the disease comes back

Survival has improved dramatically

Factors that affect outcome

Key message

• Achieve complete remission
• Live 10+ years with good quality of life
• Some younger patients with early detection may live 15–20 years

Can a 20-Year-Old Reduce the Risk of Multiple Myeloma?

First — the honest picture

What Actually Causes Myeloma (Risk Factors)

Protocols a 20-Year-Old Can Follow

🏋️ 1. Maintain a Healthy Body Weight

• Obesity increases myeloma risk by 1.5–3× relative risk through:
  • Hyperinsulinemia / insulin resistance — stimulates plasma cell growth factors including IGF-1
  • Chronic low-grade inflammation — promotes the MGUS → myeloma progression
  • Disrupted sex hormone levels
• Maintaining a BMI of 18.5–24.9 and avoiding abdominal fat accumulation is protective

A 2026 clinical trial (NUTRIVENTION) showed that reducing BMI and insulin resistance in people with myeloma precursor states slowed disease progression — these same mechanisms apply preventively in healthy young people. [PMID: 41342739]

🥗 2. Eat a High-Fiber, Anti-Inflammatory Diet

🏃 3. Exercise Regularly

• Physical activity reduces chronic inflammation, improves insulin sensitivity, and helps maintain healthy body weight — all directly relevant to myeloma risk
• Aim for: 150 minutes moderate aerobic activity/week + 2× strength training
• Resistance training specifically helps maintain muscle mass and metabolic health

🚭 4. Avoid Chemical Exposures

• Benzene — found in gasoline, cigarette smoke, certain industrial solvents; avoid prolonged exposure
• Organic solvents — in paint thinners, dry cleaning chemicals, degreasers
• Herbicides and pesticides — use protective equipment if working with these; wash produce thoroughly
• Ionizing radiation — avoid unnecessary X-rays; follow "as low as reasonably achievable" (ALARA) principles
• Smoking — cigarette smoke is a benzene delivery system; do not smoke

🍺 5. Limit or Avoid Alcohol

• Alcohol is associated with ~4% of cancers worldwide
• It promotes insulin resistance, increases inflammation, and disrupts immune surveillance
• If you do drink, keep it minimal

💤 6. Prioritize Sleep and Stress Management

• Chronic sleep deprivation and high cortisol (stress hormone) impair immune surveillance — the first line of defense against abnormal cell proliferation
• Aim for 7–9 hours of quality sleep per night
• Manage stress through exercise, mindfulness, social connection

🩺 7. Know Your Family History

• If you have first-degree relatives (parent, sibling) with myeloma or MGUS, your risk is modestly elevated
• In that case, ask your doctor about periodic blood tests (serum protein electrophoresis) starting in your 40s to catch MGUS early

Summary Table — Your 20s Prevention Protocol

Bottom Line

If a close family member has had myeloma, mention it to your doctor. Otherwise, no special screening is needed at your age — just live well.