What is the recommended treatment for a patient with multiple myeloma (MM) with M-Protein noted and a pelvic lesion seen on Positron Emission Tomography (PET) scans?

Treatment Recommendation for Multiple Myeloma with M-Protein and Pelvic Lesion on PET

For a patient with newly diagnosed multiple myeloma presenting with M-protein and a pelvic bone lesion on PET scan, treatment should be initiated immediately with a bortezomib-based triplet regimen, with the specific choice depending on transplant eligibility and risk stratification.

Initial Assessment and Risk Stratification

Before selecting treatment, complete the following workup 1:

• Cytogenetic testing by FISH to identify high-risk abnormalities: del(17p), t(4;14), and t(14;16) 1
• ISS staging using serum β2-microglobulin and albumin levels 1
• Revised ISS (R-ISS) incorporating ISS stage, cytogenetics, and LDH 1
• Bone marrow aspirate to quantify plasma cell percentage 1
• Renal function assessment (creatinine clearance) 1
• Performance status evaluation (ECOG or Karnofsky) 1

The presence of an osteolytic pelvic lesion on PET-CT confirms this is active multiple myeloma requiring treatment, not smoldering disease 1.

Treatment Selection Algorithm

For Transplant-Eligible Patients (Age ≤65-70 years, fit)

Primary recommendation: Daratumumab + VRd (D-VRd) as induction therapy 2

• This four-drug combination (daratumumab-bortezomib-lenalidomide-dexamethasone) demonstrated superior progression-free survival compared to VRd alone, with 84.3% vs 67.7% PFS at 48 months (HR 0.42, p<0.001) 2
• Complete response rates were significantly higher: 87.9% with D-VRd vs 70.1% with VRd 2
• MRD-negative status achieved in 75.2% vs 47.5% 2

Alternative if D-VRd unavailable: VRd alone 3

• Bortezomib (subcutaneous) 1.3 mg/m² on days 1,4,8,11 for cycles 1-8 4
• Lenalidomide 25 mg days 1-14 4
• Dexamethasone 20 mg on dosing days 4
• Continue for 4-6 cycles before stem cell collection 1

For high-risk cytogenetics (del(17p), t(4;14), t(14;16)):

• Bortezomib-based regimens partially overcome the adverse prognosis of these abnormalities 1
• Consider double autologous transplant in high-risk patients 1

For Transplant-Ineligible Patients (Elderly, comorbid, frail)

Primary recommendation: VRd or Daratumumab-VMP (D-VMP) 1, 5

For VRd in non-transplant setting 4:

• Carfilzomib-based regimens (KRd) showed no superiority over VRd and had more toxicity in the ENDURANCE trial 4
• VRd remains standard of care for standard-risk and intermediate-risk disease 4

For D-VMP 5:

• Daratumumab 16 mg/kg IV combined with bortezomib-melphalan-prednisone
• Demonstrated improved outcomes in elderly patients 5

Alternative regimens 1:

• Lenalidomide plus low-dose dexamethasone (Rd) continued until progression 1
• VMP with weekly bortezomib schedule preferred in frail/elderly patients to reduce peripheral neuropathy 1

Supportive Care Mandates

Bone Disease Management

Initiate intravenous bisphosphonates immediately 1:

• Zoledronic acid or pamidronate reduces skeletal-related events 1
• Continue throughout active disease and resume at relapse 1
• Zoledronic acid showed 5.5-month OS improvement independent of skeletal events, suggesting anti-myeloma properties 1

Additional Supportive Measures

• Thromboprophylaxis: Enoxaparin 40 mg subcutaneous daily for high-risk patients on IMiD-based regimens; aspirin 100 mg daily for standard-risk 1
• Infection prophylaxis: Acyclovir for varicella zoster prevention with bortezomib 1
• Pain management: Analgesics and consider radiation therapy for symptomatic pelvic lesion 1
• Orthopedic consultation if pelvic lesion at high risk for pathologic fracture 1

Treatment Duration and Consolidation

Transplant-Eligible Pathway 5, 2:

1. Induction: 4-6 cycles D-VRd or VRd
2. Stem cell collection
3. High-dose melphalan 200 mg/m² with autologous stem cell transplant 1
4. Consolidation: 2 cycles of same induction regimen 5
5. Maintenance: Lenalidomide until progression 1

Non-Transplant Pathway 1, 4:

• Continue VRd or D-VMP for 9-12 cycles
• Transition to lenalidomide maintenance until progression 1

Critical Pitfalls to Avoid

• Do not delay treatment for extensive workup; initiate therapy promptly while completing staging 1
• Avoid prolonged melphalan exposure in transplant candidates as it impairs stem cell collection 1
• Use subcutaneous bortezomib rather than IV to reduce peripheral neuropathy risk 1
• Do not use carfilzomib-based regimens as first-line in standard-risk disease given equivalent efficacy but higher toxicity versus VRd 4
• Monitor for renal function closely; if renal failure present, start bortezomib-dexamethasone immediately 1

High-Risk Disease Considerations

For patients with del(17p), t(4;14), or t(14;16) 1:

• Bortezomib-containing regimens are mandatory 1
• Consider allogeneic transplant or tandem auto-allo transplant in clinical trial setting for young patients with poor-risk features who achieve good response 1
• Isatuximab-VRd showed benefit across risk groups including high-risk cytogenetics 6