What are the guideline‑recommended diagnostic work‑up and management strategies for multiple myeloma, including initial evaluation, risk‑adapted therapy, maintenance, supportive care, and relapse treatment?

Guideline Work-up and Management of Multiple Myeloma

Diagnostic Work-up

The diagnosis of multiple myeloma requires ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma PLUS at least one myeloma-defining event (MDE) 1.

Myeloma-Defining Events (CRAB + biomarkers):

• CRAB features: Hypercalcemia (corrected calcium >11 mg/dL), Renal failure (creatinine >2 mg/dL), Anemia (hemoglobin <10 g/dL), or lytic Bone lesions
• Biomarkers of malignancy:
  • Bone marrow clonal plasma cells ≥60%
  • Serum involved/uninvolved free light chain ratio ≥100 (with involved FLC ≥100 mg/L)

  • 1 focal lesion on MRI (≥5 mm)

  • Urine monoclonal protein ≥200 mg/24h 1, 2

Risk Stratification

High-risk disease is defined by specific cytogenetic abnormalities that fundamentally alter treatment approach 1:

High-risk criteria:

• Del(17p), p53 mutation, or bi-allelic del(1p)
• t(4;14), t(14;16), t(14;20) combined with gain(1q) or del(1p)
• Gain(1q) plus del(1p)
• Double-hit: Any two high-risk factors
• Triple-hit: Three or more high-risk factors 1, 2

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Initial Management: Transplant-Eligible Patients (<70 years, no significant comorbidities)

Induction Therapy

For transplant-eligible patients, quadruplet induction with daratumumab or isatuximab plus VRd (bortezomib/lenalidomide/dexamethasone) represents the new standard of care 3.

Preferred regimens (in order):

1. DaraVRd (daratumumab + VRd) - best risk-benefit profile 3
2. IsaVRd (isatuximab + VRd) - equivalent efficacy 3
3. DaraVTd (daratumumab + bortezomib/thalidomide/dexamethasone) - valid alternative 3
4. VRd alone - if quadruplets unavailable 3, 4

Duration: 4-6 cycles of induction 3

Stem Cell Collection and Transplantation

• Collect hematopoietic stem cells after 3-4 induction cycles 3
• High-dose melphalan 200 mg/m² is the standard conditioning regimen 3, 4
• Autologous stem cell transplantation (ASCT) is recommended for all eligible patients 3

Tandem ASCT considerations:

• Genetically defined high-risk disease 3
• Patients who received bortezomib/dexamethasone/cyclophosphamide induction 3

Consolidation

Consolidation is not standard practice except: If only 4 cycles of DaraVRd induction were given, consider 2 cycles of DaraVRd consolidation 3.

Maintenance Therapy

Daratumumab plus lenalidomide is the new standard of care for post-ASCT maintenance based on PERSEUS trial PFS results 3.

• Standard-risk patients: Lenalidomide can be discontinued after 2 years 1
• High-risk patients: Continue lenalidomide indefinitely, or consider bortezomib plus lenalidomide 1, 2

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Initial Management: Transplant-Ineligible Patients

Patient Selection Criteria

• Age ≥70 years with comorbidities
• IMWG Frailty Score assessment guides intensity

Treatment Regimens by Frailty Status

For fit transplant-ineligible patients (IMWG FS <2, age <80):

Preferred regimens:

1. IsaVRd (isatuximab + VRd) 3
2. DaraVRd (pending EMA approval at time of guideline) 3
3. DaraRd (daratumumab + lenalidomide/dexamethasone) - especially for IMWG FS ≥1 3, 4

Alternative regimens if above unavailable:

• DaraVMP (daratumumab + bortezomib/melphalan/prednisone) 3, 4
• VRd 3, 4

For frail patients (IMWG FS ≥2):

• DaraR (daratumumab + lenalidomide without dexamethasone) - dexamethasone-sparing strategy 3

Treatment duration: Continue until disease progression or unacceptable toxicity 4

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Relapsed/Refractory Disease Management

After First Line of Therapy

Belantamab mafodotin-based regimens represent a paradigm shift for early relapse 3.

BelaVd (belantamab mafodotin + bortezomib/dexamethasone) is the new standard of care for patients with 1-3 prior lines:

• DREAMM-7 trial: median PFS 36.6 vs 13.4 months compared to DaraVd (HR 0.41, P<0.001)
• 36-month OS: 74% vs 60% (HR 0.58, P<0.001)
• Caveat: Ocular toxicities occur in 79% but are manageable with dose modifications; 87% of visual acuity changes resolve 3

Alternative approaches:

• Selection based on prior therapy exposure and refractoriness
• Lenalidomide-sensitive patients should receive lenalidomide-containing regimens
• Triplet regimens generally required 2

Later Lines of Therapy

Emerging options (based on general knowledge and evidence context):

• CAR-T cell therapy (BCMA-directed)
• Bispecific antibodies (BCMA or GPRC5D-directed)
• Various triplet combinations based on prior exposures 1, 2

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Key Clinical Pitfalls and Caveats

Risk Stratification Errors

• Always perform cytogenetic testing at diagnosis - treatment intensity depends on risk classification
• High-risk patients require more aggressive maintenance strategies

Transplant Timing

• Selected standard-risk patients can delay ASCT until first relapse without compromising outcomes 1, 2
• This approach requires careful patient selection and shared decision-making

Frailty Assessment

• One-third of patients are >75 years; 30% are frail 4
• IMWG Frailty Score should guide treatment intensity, not just chronological age
• Dexamethasone dose reduction critical in frail patients

Maintenance Duration

• Do not stop maintenance prematurely in high-risk patients - indefinite lenalidomide or bortezomib/lenalidomide combinations needed 1
• Standard-risk patients can discontinue after 2 years 1

Ocular Monitoring with Belantamab

• Requires ophthalmologic monitoring due to corneal toxicity
• Most visual changes are reversible with dose modifications 3