What is the standard treatment approach for newly diagnosed multiple myeloma?

Standard Treatment Approach for Newly Diagnosed Multiple Myeloma

For newly diagnosed multiple myeloma patients, treatment should be stratified based on transplant eligibility, with high-dose therapy plus autologous stem cell transplantation for eligible patients and combination therapies including proteasome inhibitors, immunomodulatory drugs, and steroids for non-eligible patients. 1

Diagnosis and Staging

Before initiating treatment, proper diagnosis and staging are essential:

• Diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of multiple myeloma defining events (MDE) 1
• Diagnostic workup should include:
  • Detection of M-protein by serum and urine protein electrophoresis 2
  • Quantification of immunoglobulins and characterization of heavy/light chains 2
  • Bone marrow aspiration and biopsy 2
  • Skeletal imaging (X-ray survey or MRI) 2
• Risk stratification should be performed using:
  • Cytogenetics to identify high-risk features: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 1
  • International Staging System combining β2-microglobulin and serum albumin levels 2

Treatment Algorithm for Newly Diagnosed Multiple Myeloma

1. Transplant-Eligible Patients (typically age <65 years)

• First-line therapy: Anti-CD38 monoclonal antibody plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation 1
• For high-risk patients, daratumumab-VRd (Dara-VRd) is recommended 3
• Induction should consist of 3-4 cycles before proceeding to stem cell collection 3
• Peripheral blood progenitor cells are preferred over bone marrow as stem cell source 2
• High-dose melphalan 200 mg/m² is the preferred preparative regimen prior to transplantation 2
• Maintenance therapy:
  • Standard-risk patients: lenalidomide maintenance 1
  • High-risk patients: bortezomib plus lenalidomide maintenance 1

2. Transplant-Ineligible Patients (typically age >65 years)

• First-line therapy options:
  • VRd for 8-12 cycles followed by maintenance 1
  • Daratumumab, lenalidomide, dexamethasone (DRd) until progression 1
  • Melphalan, prednisone, and thalidomide for standard-risk patients 4
  • Melphalan, prednisone, and bortezomib (MPV) for high-risk patients 4
• Oral melphalan (9 mg/m²/day for 4 days) and prednisone (30 mg/m²/day for 4 days) remains a standard treatment option, with cycles repeated every 4-6 weeks until stable response 2
• Long-term administration of bisphosphonates (oral or intravenous) should be proposed to reduce skeletal events 2

3. Special Considerations

• Patients with indolent (smoldering) myeloma should not receive immediate treatment 2
• For patients with stable response to initial treatment (plateau phase), chemotherapy can be stopped safely 2
• Interferon-α (3 million units/m² three times weekly) can significantly prolong remission induced by conventional chemotherapy 2
• Daratumumab-based regimens have shown significant improvements in progression-free survival and overall survival in transplant-ineligible patients 5

Treatment of Relapsed/Refractory Disease

• For relapses after unmaintained remission, regimens similar to those used initially can induce a second remission 2
• Triplet regimens are usually needed at relapse, with the choice varying with each successive relapse 1
• Options include:
  • Thalidomide alone or in combination with high-dose dexamethasone 2
  • Bortezomib-based regimens 2
  • Newer agents such as carfilzomib, pomalidomide, panobinostat, ixazomib, elotuzumab, and daratumumab 6
  • CAR-T cell therapy and bispecific antibodies for later lines of therapy 1

Response Evaluation

• Assessment of response is based on serum and urine electrophoresis 2
• Complete response requires bone marrow aspiration (<5% plasma cells) and immunofixation 2
• Minimal residual disease (MRD) assessment is increasingly important for evaluating depth of response 5

Common Pitfalls and Caveats

• Multiagent chemotherapy has not proven superior and may be even inferior in elderly patients 2
• Proper risk stratification is essential as treatment approaches differ for standard vs. high-risk disease 3
• Spinal cord compression requires immediate intervention with high-dose dexamethasone, surgical decompression if due to bone fragments, and local radiotherapy 7
• When monitoring response with free light chain assays, it's crucial to use the same test for serial measurements to ensure accurate relative quantification 8