What is the recommended treatment approach for a patient with relapsed refractory multiple myeloma?

Treatment of Relapsed Refractory Multiple Myeloma

For first relapse, triplet therapy with daratumumab-lenalidomide-dexamethasone (DRd) is the preferred regimen, providing superior efficacy with 91.3% overall response rate and median progression-free survival of 45 months across all cytogenetic risk groups. 1, 2

Initial Assessment at Relapse

Before selecting therapy, perform comprehensive risk stratification including:

• Bone marrow biopsy with FISH to detect high-risk cytogenetics (del(17p), t(4;14), t(14;16), 1q abnormalities) and assess for disease evolution 3, 2
• Evaluate prior treatment exposure and refractoriness - specifically document lenalidomide, bortezomib, and anti-CD38 antibody exposure 3
• Assess relapse kinetics - biochemical versus clinical relapse, duration of prior response (responses <18 months indicate high-risk disease) 3
• Screen for extramedullary disease and plasma cell leukemia, which require more aggressive cytotoxic approaches 3, 2

First Relapse Treatment Algorithm

For Lenalidomide-Sensitive Patients (Not Progressing on Lenalidomide)

Primary recommendation: Daratumumab-lenalidomide-dexamethasone (DRd) 3, 1, 2

• Provides median PFS of 45.0 months versus 17.5 months with lenalidomide-dexamethasone alone 1
• Subcutaneous daratumumab formulation reduces infusion reactions and administration time 3

Alternative option: Carfilzomib-lenalidomide-dexamethasone (KRd) 3

• Use if daratumumab was part of initial therapy or is unavailable 3
• Network meta-analysis shows KRd among top three regimens for first relapse 3

For frail patients or indolent relapse: Ixazomib-lenalidomide-dexamethasone (IRd) 3

• All-oral regimen improves quality of life in frail patients 3
• Reasonable first choice when convenience and tolerability are priorities 3

For Lenalidomide-Refractory Patients (Progressing on Lenalidomide Maintenance)

Primary recommendation: Daratumumab-bortezomib-dexamethasone (DVd) 3, 1

• Demonstrated superior efficacy in lenalidomide-refractory population 3
• Median PFS 11.2 months versus 7.1 months with bortezomib-dexamethasone alone in OPTIMISMM trial 3

Alternative options for lenalidomide-refractory disease:

• Carfilzomib-pomalidomide-dexamethasone (KPd) - use if prior daratumumab exposure 3
• Pomalidomide-bortezomib-dexamethasone (PomVd) - effective in >70% lenalidomide-refractory patients 3
• Daratumumab-pomalidomide-dexamethasone (DPd) 3
• Isatuximab-pomalidomide-dexamethasone 3

Salvage Autologous Stem Cell Transplantation

Consider second ASCT if: 3, 2

• Patient never received prior transplant, OR
• Progression-free survival after first ASCT was ≥18 months 3
• Provides median time to progression of 19 months versus 11 months with cyclophosphamide 2

Do not offer second ASCT if PFS after first transplant was <18 months - median overall survival only 6 months in this population 3

Second or Later Relapse

Treatment principle: Use triplet regimens containing at least two drug classes the patient is not refractory to 3

For Proteasome Inhibitor-Refractory Disease

• Switch to immunomodulatory drug-based regimens with monoclonal antibody 3, 2
• DRd or daratumumab-pomalidomide-dexamethasone 2

For Immunomodulatory Drug-Refractory Disease

• Switch to proteasome inhibitor-based regimens with monoclonal antibody 3, 2
• DVd or daratumumab-carfilzomib-dexamethasone 2

For Triple-Class Refractory Disease (Refractory to IMiDs, PIs, and Anti-CD38)

Selinexor-based regimens: 4

• Selinexor-bortezomib-dexamethasone (XVd): 100 mg orally once weekly for patients with ≥1 prior therapy 4
• Selinexor-dexamethasone (Xd): 80 mg orally on days 1 and 3 weekly for patients refractory to ≥2 PIs, ≥2 IMiDs, and anti-CD38 antibody after ≥4 prior therapies 4

Additional options for heavily pretreated disease: 3

• Venetoclax for t(11;14) myeloma 3
• Panobinostat added to proteasome inhibitor regimen 3
• Bendamustine-based regimens 3

Treatment Duration

Continue therapy until disease progression for most patients 3, 2

• For indolent relapse, treat until plateau is reached 2
• For aggressive relapse or high-risk cytogenetics, continuous treatment is mandatory to suppress disease burden 2
• Insufficient data to support MRD-based treatment discontinuation 3

Essential Supportive Care

Thromboprophylaxis: 1, 5

• Full-dose aspirin or therapeutic anticoagulation for all patients on immunomodulatory drugs (lenalidomide, pomalidomide) 1, 5

Infection prophylaxis: 1, 5

• Herpes zoster prophylaxis with acyclovir or valacyclovir for all patients on proteasome inhibitors 1, 5
• Pneumocystis jiroveci prophylaxis for patients receiving high-dose glucocorticosteroids 1

Antiemetic prophylaxis: 4

• Mandatory for selinexor-based regimens due to high rates of nausea and vomiting 4

Critical Pitfalls to Avoid

Do not use lenalidomide-based regimens in patients progressing on lenalidomide maintenance - switch to proteasome inhibitor with monoclonal antibody instead 1, 2

Do not delay restaging at relapse - evaluation for plasma cell leukemia or extramedullary disease is critical as these require different treatment approaches 3, 1

Do not use single or doublet therapy when triplet combinations are tolerated - triplet regimens consistently demonstrate superior outcomes 3, 1

Do not overlook high-risk cytogenetics - these patients require intensified therapy with continuous treatment rather than treatment-free intervals 1, 2

Do not use subcutaneous bortezomib interchangeably with intravenous - subcutaneous administration is preferred for patients with pre-existing peripheral neuropathy 5

Do not repeat FISH for primary translocations at relapse - only test for progression-associated abnormalities (17p deletion, 1q amplification) 3