What is the typical treatment plan for an adult patient with a diagnosis of multiple myeloma, considering their overall health and medical history?

Multiple Myeloma: Diagnosis and Treatment Overview

Diagnostic Criteria

Multiple myeloma requires ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma plus at least one myeloma-defining event (MDE). 1

The myeloma-defining events include:

• CRAB criteria: Hypercalcemia (serum calcium >11.0 mg/dL), Renal insufficiency (creatinine >2.0 mg/dL), Anemia (hemoglobin <10 g/dL or 2 g/dL below normal), and Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 2
• Bone marrow clonal plasmacytosis ≥60% 1
• Serum involved/uninvolved free light chain ratio ≥100 (provided involved FLC ≥100 mg/L and urine monoclonal protein ≥200 mg/24 hours) 1
• >1 focal lesion on MRI 1

Essential Diagnostic Workup

• Serum protein electrophoresis (SPEP) with immunofixation to detect monoclonal protein 2
• 24-hour urine protein electrophoresis (UPEP) - random samples are insufficient 3
• Quantification of IgG, IgA, and IgM immunoglobulins 2
• Complete blood count, serum creatinine, calcium, LDH, and β2-microglobulin 2
• Bone marrow aspiration and biopsy to quantify plasma cell infiltration 2
• Cytogenetic analysis by FISH to detect high-risk features including t(4;14), del(17p), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 1
• Whole-body imaging with CT, PET-CT, or MRI to assess bone disease and extramedullary involvement 4, 2

Risk Stratification

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

• Double-hit myeloma: Any two high-risk factors 1
• Triple-hit myeloma: Three or more high-risk factors 1
• Revised International Staging System (R-ISS) combines β2-microglobulin, albumin, LDH, and high-risk cytogenetics to predict survival 5

Treatment Algorithm for Newly Diagnosed Multiple Myeloma

Transplant-Eligible Patients

For transplant-eligible patients, induction therapy consists of anti-CD38 monoclonal antibody (daratumumab) plus bortezomib, lenalidomide, and dexamethasone (Dara-VRd) for 3-4 cycles, followed by autologous stem cell transplantation (ASCT). 1

• Standard-risk patients can receive VRd (without daratumumab) as an alternative 6
• Selected standard-risk patients may collect stem cells, receive additional induction cycles, and delay transplant until first relapse 6
• High-dose melphalan 200 mg/m² is the preferred preparative regimen prior to ASCT 7
• Peripheral blood progenitor cells are the preferred stem cell source 7

Post-Transplant Maintenance

• Standard-risk patients: Lenalidomide maintenance 6, 1
• High-risk patients: Bortezomib plus lenalidomide maintenance 6, 1

Transplant-Ineligible Patients

For transplant-ineligible patients, treatment consists of VRd for 8-12 cycles followed by maintenance, or alternatively daratumumab, lenalidomide, and dexamethasone (DRd) until progression. 6, 1

Alternative regimens for transplant-ineligible patients include:

• Bortezomib/melphalan/prednisone (VMP): Bortezomib 1.3 mg/m² subcutaneously days 1,8,15,22; melphalan 9 mg/m² orally days 1-4; prednisone 60 mg/m² orally days 1-4; repeated every 35 days 4
• Lenalidomide/low-dose dexamethasone (Rd): Lenalidomide 25 mg orally days 1-21; dexamethasone 40 mg orally days 1,8,15,22; repeated every 28 days 4
• Daratumumab is FDA-approved in combination with lenalidomide and dexamethasone for newly diagnosed patients ineligible for ASCT 8

Smoldering (Asymptomatic) Myeloma

Patients with smoldering myeloma should not receive immediate treatment. 7, 2

• Observation with monitoring at 3-6 month intervals with laboratory tests 2
• Annual bone survey or as clinically indicated 3
• Multiparameter flow cytometry may predict progression risk (>95% abnormal plasma cells indicates higher risk) 3

Treatment of Relapsed/Refractory Disease

At first relapse, triplet therapy is preferred over doublet therapy, with regimens containing two novel agents (proteasome inhibitor, immunomodulatory drug, or monoclonal antibody) plus steroids. 2

FDA-Approved Regimens for Relapsed/Refractory Disease

• Carfilzomib/lenalidomide/dexamethasone (KRd): Carfilzomib 20 mg/m² (cycle 1) and 27 mg/m² (subsequent cycles) IV days 1,2,8,9,15,16; lenalidomide 25 mg orally days 1-21; dexamethasone 40 mg days 1,8,15,22; 28-day cycles 4
• Carfilzomib once weekly 20/70 mg/m² in combination with dexamethasone (Kd) or daratumumab plus dexamethasone (DKd): Starting dose 20 mg/m² on Cycle 1 Day 1, escalate to 70 mg/m² on Cycle 1 Day 8 if tolerated; administered as 30-minute infusion on days 1,8,15 of each 28-day cycle 9
• Daratumumab combinations: FDA-approved with lenalidomide/dexamethasone, bortezomib/dexamethasone, carfilzomib/dexamethasone, or pomalidomide/dexamethasone for relapsed/refractory disease 8
• Pomalidomide/dexamethasone: Pomalidomide 4 mg orally days 1-21 of each 28-day cycle for patients who received ≥2 prior therapies including lenalidomide and a proteasome inhibitor 10

Triple-Class Refractory Disease

For triple-class refractory patients (refractory to proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody), selinexor/dexamethasone or belantamab mafodotin monotherapy is recommended. 4

• CAR-T cell therapy and bispecific antibodies are additional options for heavily pretreated patients 1

Special Populations

For patients with t(11;14) who are refractory to lenalidomide and proteasome inhibitor-sensitive, venetoclax plus bortezomib and dexamethasone (VenVd) is recommended. 4

Supportive Care

Bone Disease Management

Long-term bisphosphonates should be administered to reduce skeletal events. 7, 2

Tumor Lysis Syndrome Prophylaxis

For patients with high tumor burden, renal insufficiency, or elevated LDH, aggressive IV hydration with normal saline (150-200 mL/hour to achieve urine output >100 mL/hour) and rasburicase (0.2 mg/kg IV single dose or 3-6 mg fixed dose) is recommended before initiating chemotherapy. 2

• Do not delay chemotherapy for extended periods while attempting conservative measures alone, as this worsens outcomes 2

Thromboprophylaxis

Thromboprophylaxis is mandatory for patients receiving immunomodulatory drugs (lenalidomide, pomalidomide, thalidomide) in combination with other therapies. 9, 10

• The choice of regimen should be based on individual thrombotic risk factors 10

Infection Prophylaxis

Consider antiviral prophylaxis to decrease the risk of herpes zoster reactivation. 9

Premedication Requirements

Dexamethasone premedication (administered 30 minutes to 4 hours before treatment) is required for all doses during Cycle 1 to reduce infusion-related reactions. 9

• Reinstate dexamethasone premedication if infusion reactions occur in subsequent cycles 9

Common Pitfalls and Caveats

• Hydration must be carefully monitored in patients at risk for cardiac failure; adjust based on volume status 9
• Monitor serum potassium levels regularly during carfilzomib treatment 9
• For patients with BSA >2.2 m², calculate drug doses using a BSA of 2.2 m² 9
• Dose adjustments are not needed for weight changes ≤20% 9
• Multiagent chemotherapy has not proven superior and may be inferior in elderly patients 7
• Spinal cord compression requires immediate intervention with high-dose dexamethasone, surgical decompression if due to bone fragments, and local radiotherapy 7
• When monitoring with free light chain assays, use the same test for serial measurements to ensure accurate quantification 7

Follow-Up Monitoring

For patients in remission, follow-up every 3-6 months includes CBC, serum chemistry (creatinine, albumin, calcium, LDH, β2-microglobulin), quantitative immunoglobulins, SPEP with immunofixation, and serum free light chain assay. 3

• Annual bone survey or as clinically indicated 3
• MRI, CT, or PET-CT as clinically indicated for suspected progression or extramedullary disease 3
• Bone marrow assessment when disease progression is suspected 3