What is the definition, pathophysiology, diagnostic workup, and treatment options for multiple myeloma?

Multiple Myeloma: Definition, Pathophysiology, Diagnostics, and Treatment

Definition

Multiple myeloma is a malignant plasma cell neoplasm characterized by ≥10% clonal plasma cells in bone marrow (or biopsy-proven plasmacytoma) plus evidence of end-organ damage or specific myeloma-defining events. 1

• Accounts for 1% of all cancers and approximately 10% of hematological malignancies 1
• Incidence in Europe: 4.5-6.0 per 100,000 per year 1
• Median age at diagnosis: 65-70 years 1
• Almost all patients evolve from monoclonal gammopathy of undetermined significance (MGUS), which progresses to myeloma at 1% per year 1

Pathophysiology

Multiple myeloma develops through a stepwise progression from MGUS through smoldering myeloma (SMM) to symptomatic disease, driven by chromosomal instability and cytogenetic abnormalities. 1, 2

Disease Evolution Pathway:

• MGUS stage: Asymptomatic pre-malignant condition with 1% annual progression risk 1
• Smoldering myeloma: Intermediate stage with 10% annual progression in first 5 years, 3% in years 5-10, then 1.5% thereafter 1
• Symptomatic myeloma: Characterized by end-organ damage (CRAB criteria) 1

Cytogenetic Classification:

High-risk cytogenetics are defined by presence of t(4;14), t(14;16), t(14;20), gain 1q, del(17p), or p53 mutation. 1

• Four major subtypes account for >80% of cases: trisomic MM, t(11;14) MM, t(4;14) MM, and MAF MM [t(14;16) or t(14;20)] 1
• FISH is the standard technique for detecting cytogenetic abnormalities, as conventional karyotyping only reveals abnormalities in 20-30% of patients 1

Diagnostic Workup

Diagnosis requires a comprehensive laboratory, imaging, and bone marrow evaluation to establish clonal plasma cell burden and document end-organ damage. 1

Required Laboratory Tests:

• Monoclonal protein detection: Serum and 24-hour urine protein electrophoresis with immunofixation; serum-free light chain (FLC) measurement 1
• Immunoglobulin quantification: Nephelometric measurement of IgG, IgA, and IgM 1
• Complete blood count with differential 1
• Serum creatinine and calcium levels 1

Bone Marrow Evaluation:

• BM aspiration and/or biopsy to quantify plasma cell infiltration 1
• Cytogenetic/FISH studies are mandatory for risk stratification 1
• Immunophenotypic and molecular investigations should be performed 1

Imaging Studies:

• Skeletal bone survey (spine, pelvis, skull, humeri, femurs) is necessary 1
• MRI or CT scan for symptomatic sites even if skeletal survey is negative 1
• MRI provides greater detail and is recommended when spinal cord compression is suspected 1
• PET-CT is under evaluation but not systematically recommended 1

Diagnostic Criteria for Symptomatic Multiple Myeloma:

Both criteria must be met: 1

1. ≥10% clonal BM plasma cells OR biopsy-proven plasmacytoma
2. Evidence of end-organ damage (CRAB criteria):
   • Calcium: serum calcium >11.5 mg/dL 1
   • Renal insufficiency: creatinine >1.73 μmol/L (>2 mg/dL) or creatinine clearance <40 mL/min 1
   • Anemia: hemoglobin ≥2 g/dL below normal or <10 g/dL 1
   • Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures 1

OR any of these myeloma-defining events (even without CRAB): 1

• BM clonal plasma cells ≥60% 1
• Serum involved/uninvolved FLC ratio ≥100 (with involved FLC ≥100 mg/L) 1

• 1 focal lesion ≥5 mm on MRI 1

Differential Diagnosis:

MGUS criteria (all three required): 1

• Serum monoclonal protein <3 g/dL
• Clonal BM plasma cells <10%
• Absence of CRAB criteria

Smoldering myeloma criteria (both required): 1

• Serum monoclonal protein ≥3 g/dL and/or clonal BM plasma cells ≥10%
• Absence of CRAB criteria or myeloma-defining events

Treatment

Asymptomatic (Smoldering) Myeloma:

Immediate treatment is not recommended for patients with smoldering myeloma, except for high-risk patients who may be offered daratumumab therapy. 1, 3

Symptomatic Multiple Myeloma - Treatment Initiation:

Treatment should be initiated in all patients fulfilling CRAB criteria (calcium >11.0 mg/dL, creatinine >2.0 mg/dL, hemoglobin <10 g/dL, active bone lesions) or with myeloma-defining events. 1

Newly Diagnosed Transplant-Eligible Patients:

Quadruplet therapy with daratumumab or isatuximab combined with bortezomib, lenalidomide, and dexamethasone should be offered as initial therapy. 3

• This represents the current standard based on most recent evidence 3
• Followed by autologous stem cell transplantation (ASCT) for eligible patients 4
• Maintenance therapy with at least lenalidomide (with or without daratumumab, carfilzomib, and/or dexamethasone) should be offered post-transplant 1, 3
• Lenalidomide maintenance is Category 1 recommendation 1

Newly Diagnosed Transplant-Ineligible (Elderly) Patients:

Quadruplet therapy with daratumumab or isatuximab combined with bortezomib, lenalidomide, and dexamethasone should be offered. 3

Alternative regimens for elderly patients include: 1

• Melphalan/prednisone/thalidomide (MPT) 1
• Bortezomib/melphalan/prednisone (VMP) 1
• Bendamustine plus prednisone for patients with clinical neuropathy precluding thalidomide use 1

Relapsed/Refractory Disease - First Relapse:

Treatment selection depends on prior therapy exposure and duration of response. 1

For patients who received bortezomib-based therapy without lenalidomide or daratumumab upfront:

• Lenalidomide-based regimens should be used: KRd (carfilzomib/lenalidomide/dexamethasone), DaraRd (daratumumab/lenalidomide/dexamethasone), IRd (ixazomib/lenalidomide/dexamethasone), or EloRd (elotuzumab/lenalidomide/dexamethasone) 1
• DaraRd provides best progression-free survival 1

For lenalidomide-refractory patients:

• PomVd (pomalidomide/bortezomib/dexamethasone), DaraKd (daratumumab/carfilzomib/dexamethasone), IsaKd (isatuximab/carfilzomib/dexamethasone), or DaraVd (daratumumab/bortezomib/dexamethasone) 1
• PomVd shows best results as second-line therapy in lenalidomide-refractory patients 1

For patients with t(11;14) who failed lenalidomide and are PI-sensitive:

• VenVd (venetoclax/bortezomib/dexamethasone) is suitable 1

Relapsed/Refractory Disease - Third Line and Beyond:

For patients exposed or refractory to both bortezomib and lenalidomide:

• DaraKd, IsaPd (isatuximab/pomalidomide/dexamethasone), IsaKd, or EloPd (elotuzumab/pomalidomide/dexamethasone) are recommended 1

For triple-class refractory patients:

• Selinexor/dexamethasone (Sd) or belantamab mafodotin monotherapy 1
• T-cell redirecting therapies should be offered according to recommended principles 3

Repeat Transplantation:

Repeat ASCT may be considered in relapsed myeloma if progression-free survival after first transplant was ≥18 months. 1

• If ASCT not received after primary induction, it should be offered to transplant-eligible patients with relapsed disease 1

Key Treatment Principles:

• Triplet regimens are preferred over doublets based on tolerability and comorbidities 1
• Monoclonal antibody-based regimens in combination with immunomodulatory drugs and/or proteasome inhibitors should be considered at first relapse 1
• Prior therapies must be considered when selecting treatment at relapse 1
• Patients relapsing >1 year after treatment may respond to repeat course of previous therapy 1
• Patients relapsing during or within 1 year of therapy are considered less sensitive and require alternative agents 1

High-Risk Cytogenetics Management:

Combined therapy with second-generation proteasome inhibitors, monoclonal antibodies, and immunomodulatory drugs are associated with improved outcomes in patients with del(17p) and other high-risk features. 1

• High-risk patients require more aggressive upfront therapy 1
• Continuous treatment should be favored in high-risk disease 1

Supportive Care Considerations:

• Bisphosphonates (zoledronic acid or pamidronate) for two years, with extended dosing intervals if disease stable 5
• Denosumab is non-inferior to zoledronic acid and may be used, especially with renal impairment 5