How should I evaluate and treat a newly diagnosed multiple myeloma patient, including diagnostic workup, staging, transplant eligibility assessment, first‑line therapy for transplant‑eligible and transplant‑ineligible patients, supportive care, and relapse options?

Multiple Myeloma Management

Diagnostic Workup

All patients with suspected multiple myeloma require measurement of monoclonal protein, serum-free light chain assay, bone marrow aspiration/biopsy with demonstration of plasma cell clonality, and FISH cytogenetics evaluating del(17p), t(4;14), and t(14;16) as mandatory abnormalities. 1

Essential Laboratory Studies

• Complete blood count with differential to assess for anemia (present in 73% at diagnosis) 2
• Serum creatinine and estimated glomerular filtration rate (renal failure occurs in 19% at presentation) 2
• Serum calcium, beta-2 microglobulin, albumin, and lactate dehydrogenase 1
• Serum protein electrophoresis with immunofixation 1
• 24-hour urine protein electrophoresis 1
• Serum-free light chain assay (critical for light-chain only myeloma where no M-spike is visible) 1, 3

Imaging Requirements

• Whole-body low-dose CT scan is the preferred baseline imaging modality for bone surveillance. 1
• FDG-PET/CT or MRI may be used as alternatives at baseline and provide valuable diagnostic and prognostic information 1
• Traditional skeletal surveys are less sensitive and should be replaced by more advanced imaging 1

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy with ≥10% clonal plasma cells required for diagnosis 4, 2
• FISH cytogenetics must evaluate del(17p), t(4;14), t(14;16), t(14;20), and 1q amplification/del(1p) 1, 5, 4

Risk Stratification

All patients must undergo risk stratification using the Revised International Staging System (R-ISS) combining ISS stage, cytogenetic abnormalities, and LDH levels. 1, 6

High-Risk Features

• Cytogenetic abnormalities: del(17p), t(4;14), t(14;16), t(14;20), 1q amplification/del(1p) 1, 5, 4
• ISS stage III (beta-2 microglobulin ≥5.5 mg/L) 1
• Elevated LDH 1, 6
• Plasma cell labeling index >3% 5
• Extramedullary disease or plasma cell leukemia presentation 1, 5
• Double-hit (≥2 high-risk factors) or triple-hit (≥3 high-risk factors) myeloma 4

Standard-Risk Features

• Hyperdiploidy, t(11;14), t(6;14) 1, 5
• ISS stage I-II 1

Transplant Eligibility Assessment

Chronologic age and renal function alone should not determine transplant eligibility; instead, use comprehensive geriatric assessment including Karnofsky Performance Status, organ function, Freiburg Comorbidity Index, and instrumental activities of daily living. 1

Transplant-Eligible Criteria

• KPS >70% 1
• Normal or near-normal organ function (particularly cardiac, pulmonary, hepatic) 1
• eGFR >30 mL/min (though renal failure is not an absolute contraindication) 1
• Freiburg Comorbidity Index 0 or Charlson Comorbidity Index 0 1

Transplant-Ineligible Criteria

• KPS <70% 1
• Severe organ impairment 1
• Advanced frailty on geriatric assessment 1
• Age >75 years with significant comorbidities 5

First-Line Therapy: Transplant-Eligible Patients

For standard-risk transplant-eligible patients, administer VRd (bortezomib, lenalidomide, dexamethasone) for 3-4 cycles, followed by high-dose melphalan with autologous stem cell transplantation, then lenalidomide maintenance until progression. 1, 5, 4

Standard-Risk Disease

• VRd induction achieves 100% partial response rate, 74% very good partial response rate, and 52% complete response rate 1
• Avoid prolonged induction (>4-6 cycles) as this impairs stem cell collection 5
• Avoid agents with stem-cell toxicity (melphalan, prolonged immunomodulatory drug exposure >4 cycles) 1
• Collect ample stem cells (sufficient for >1 transplant) upfront 1
• High-dose melphalan (200 mg/m²) conditioning followed by autologous stem cell transplantation 1, 5
• Lenalidomide maintenance starting day 90-110 at 10-15 mg daily until progression increases progression-free survival and possibly overall survival 1, 5

High-Risk Disease

• Add daratumumab to VRd (Dara-VRd) for high-risk cytogenetics, as this improves 18-month progression-free survival to 93% versus 85% with VRd alone 5, 6, 4
• Consider proteasome inhibitor-based maintenance (bortezomib plus lenalidomide) rather than lenalidomide alone, as lenalidomide maintenance shows limited benefit in high-risk disease 5
• Bortezomib-based regimens partially overcome adverse prognosis of t(4;14) and del(17p) 1, 6

First-Line Therapy: Transplant-Ineligible Patients

For standard-risk transplant-ineligible patients, administer DRd (daratumumab, lenalidomide, dexamethasone) until progression. 5

Standard-Risk Disease

• DRd (daratumumab, lenalidomide, dexamethasone) until progression is the preferred option 5, 7
• Alternative regimens: VMP (bortezomib, melphalan, prednisone) or MPT (melphalan, prednisone, thalidomide) 1, 5
• Use weekly bortezomib schedules rather than twice-weekly dosing to reduce polyneuropathy, especially in elderly, unfit, or frail patients 1, 5

High-Risk Disease

• VRd for 8-12 cycles followed by bortezomib-based maintenance until progression 5, 4
• Bortezomib plus lenalidomide maintenance is needed for high-risk myeloma 4

Dose Modifications for Frail/Elderly Patients

• Reduce dexamethasone dose to 20 mg/week instead of 40 mg/week for patients >75 years or those with significant frailty 5
• Consider two-drug combinations rather than triplet therapy based on geriatric assessment findings 1, 5

Special Clinical Situations

Renal Failure

• Start bortezomib and dexamethasone-based regimens immediately without dose adjustment in patients with renal failure 1, 5
• Bortezomib has the advantage of rapid clearance of free light chains, accelerating kidney response 1
• Avoid nephrotoxic drugs and maintain euvolemia 1
• Bortezomib and thalidomide require no dose adjustment; lenalidomide and pomalidomide require starting dose reduction based on creatinine clearance 1
• VMP reversed renal impairment in 40% of patients 1

Pre-existing Neuropathy

• Use DRd (daratumumab, lenalidomide, dexamethasone) instead of VRd to avoid bortezomib-related neuropathy 5
• If bortezomib is necessary, use weekly subcutaneous administration rather than twice-weekly intravenous 1

Hypercalcemia

• Manage with intravenous fluids and bisphosphonates 1
• Start treatment promptly to prevent renal complications 1

Painful Bone Lesions

• Initiate analgesia and bisphosphonates immediately 1
• Consult orthopedic oncology for lesions at high risk of fracture 1
• Use local radiotherapy to promptly ameliorate localized bone pain 1

Essential Supportive Care

Bone Protection

• Administer intravenous bisphosphonates (zoledronic acid or pamidronate) for all patients requiring therapy, continued throughout active disease, as zoledronic acid improves overall survival by 5.5 months independent of skeletal-related events 1, 5, 6
• Continue bisphosphonates with active disease and resume after disease relapse 1
• Zoledronic acid has increased risk of renal toxicity; monitor renal function 1

Thromboprophylaxis

• Aspirin (100 mg/day) for standard-risk patients receiving immunomodulatory drug-based regimens 5, 6
• Enoxaparin (40 mg subcutaneously daily), therapeutic-dose warfarin, or direct thrombin inhibitors for high-risk patients 1, 5, 6
• High-risk features for thrombosis: combination with steroids or anthracyclines (20-40% VTE rate without prophylaxis) 1

Infection Prophylaxis

• Acyclovir for all patients on bortezomib-based regimens 6
• Consider levofloxacin during first two cycles 6
• Granulocyte colony-stimulating factor for patients at high risk for febrile neutropenia (common with immunomodulatory drugs and daratumumab) 1

Anemia Management

• Erythropoiesis-stimulating agents and optimal iron supplementation if myeloma-related anemia does not improve with chemotherapy 1
• Grade 3-4 anemia occurs in 3-19% with novel agents 1

Cytopenias

• Dose reduction for grade 3-4 thrombocytopenia (common with proteasome inhibitors and immunomodulatory drugs) 1
• Interrupt treatment for grade 4 thrombocytopenia 1

Relapsed/Refractory Disease

A triplet regimen is usually needed at relapse, with choice varying based on prior therapies, depth and duration of response, and time to progression. 4

Treatment Selection Principles

• Consider all prior therapies when selecting relapse regimen 1
• Patients who delayed initial transplant may use salvage or delayed transplant as consolidation at first relapse 1
• For patients who achieved only minimal response after autologous stem cell transplantation, bortezomib-based regimens are valuable 1

Common Pitfalls to Avoid

• Never use carfilzomib-lenalidomide-dexamethasone (KRd) as initial therapy due to higher risk of serious cardiac, renal, and pulmonary toxicity 5
• Avoid tandem autologous transplant as routine practice (should not be routinely recommended) 1
• Do not use chronologic age alone to determine transplant eligibility 1
• Avoid prolonged induction therapy (>4-6 cycles) in transplant-eligible patients 5

Monitoring and Response Assessment

Assess depth of response for all patients using International Myeloma Working Group criteria. 1

• Monitor response after induction, post-transplant, and during maintenance 1
• The level of minimal response required to proceed to transplant is not established; refer patients for transplant independent of depth of response 1
• Regular assessment for treatment toxicity, infection, renal complications, and thrombotic events 8