What is the initial treatment approach for patients with Revised International Staging System (R-ISS) multiple myeloma?

Initial Treatment Approach for R-ISS Multiple Myeloma

All patients with newly diagnosed multiple myeloma should receive risk stratification using the Revised International Staging System (R-ISS), which incorporates ISS stage, cytogenetic abnormalities by FISH, and LDH levels to guide treatment intensity. 1

R-ISS Classification

The R-ISS stratifies patients into three prognostic groups 1:

• R-ISS Stage I: ISS stage I AND standard-risk cytogenetics AND normal LDH
• R-ISS Stage II: Neither R-ISS stage I nor III
• R-ISS Stage III: ISS stage III AND (high-risk cytogenetics OR elevated LDH)

High-risk cytogenetics include del(17p), t(4;14), t(14;16), t(14;20), and 1q amplification/del(1p) 1

Treatment Selection Based on Transplant Eligibility

Transplant-Eligible Patients

For transplant-eligible patients, initiate VRd (bortezomib, lenalidomide, dexamethasone) induction for 3-4 cycles, followed by high-dose melphalan (200 mg/m²) with autologous stem cell transplantation, then lenalidomide maintenance until progression. 1, 2

• VRd achieves 87% overall response rate with 30% complete response rate 1
• The addition of daratumumab to VTd (DaraVTD) improves 18-month progression-free survival to 93% versus 85% with VTd alone (P<0.0001), representing the most recent high-quality evidence for transplant-eligible patients 1
• Autologous transplantation improves median progression-free survival from 36 months to 50 months compared to VRd alone (P<0.001) 1
• Bortezomib-based regimens partially overcome the adverse prognosis of high-risk cytogenetics including t(4;14) and del(17p) 1, 3

Alternative induction regimens include VTd (94% response rate, 33% complete response) or VCD (47% complete response with modified dosing), though these lack direct comparative data with VRd 1

Transplant-Ineligible Patients

For transplant-ineligible patients, triplet therapy is mandatory: either VRd continuous therapy until progression, or daratumumab plus bortezomib-melphalan-prednisone (Dara-VMP). 1

• VRd demonstrates superior progression-free survival and overall survival compared to Rd alone (median overall survival 75 months vs 64 months, HR 0.709, P=0.025) 4
• Isatuximab-VRd shows 60-month progression-free survival of 63.2% versus 45.2% with VRd alone (HR 0.60, P<0.001), representing the most recent high-quality evidence 5
• VMP achieves 24% complete response rate with median time to progression of 24 months versus 16.6 months with melphalan-prednisone alone (HR 0.48, P<0.001) 6
• Continuous therapy is superior to fixed-duration therapy for immunomodulatory drug or proteasome inhibitor-based regimens 1

Risk-Adapted Treatment Modifications

R-ISS Stage III or High-Risk Cytogenetics

For R-ISS Stage III or high-risk cytogenetics patients, prioritize bortezomib-containing regimens (VRd or VMP) over lenalidomide-dexamethasone alone. 7

• VMP reduces progression risk by 46% (HR 0.54) and death risk by 27% (HR 0.73) compared to Rd-R in high-risk patients 7
• High-risk patients should be treated immediately upon biochemical relapse, particularly those with early relapse post-transplant 1
• Consider double autologous transplantation in high-risk patients 3

R-ISS Stage I or Standard-Risk

For R-ISS Stage I or standard-risk patients ≤75 years, VRd or Rd-R are equally effective; for patients >75 years, Rd-R demonstrates superior outcomes. 7

• Standard-risk patients >75 years show worse overall survival with VMP compared to Rd-R (HR 1.81) 7
• Close observation is appropriate for slowly progressive, asymptomatic biochemical relapse in standard-risk patients 1

Response Monitoring and Goals

Assess depth of response with each treatment cycle using serum/urine electrophoresis and immunofixation; aim for MRD-negative status, though this should not guide treatment decisions outside clinical trials. 1

• MRD-negative status associates with improved outcomes but requires validation 1
• Once best response is attained, assess minimally every 3 months 1
• Whole-body low-dose CT is superior to skeletal survey for bone surveillance 1

Essential Supportive Care

Initiate these measures immediately at diagnosis 1, 3, 8:

• Bisphosphonates (zoledronic acid or pamidronate) for all patients requiring therapy, continued throughout active disease 1
• Thromboprophylaxis: aspirin for standard-risk patients; enoxaparin or therapeutic anticoagulation for high-risk patients (prior thrombosis, immobility, concurrent erythropoietin) 1, 8
• Infection prophylaxis: acyclovir for all patients on bortezomib-based regimens; consider levofloxacin during first two cycles 8

Critical Treatment Pitfalls

Avoid these common errors 1, 3:

• Do not administer prolonged induction (>4-6 cycles) in transplant candidates before stem cell collection 1
• Do not use melphalan in transplant-eligible patients as it impairs stem cell harvest 3
• Administer bortezomib subcutaneously rather than intravenously to reduce peripheral neuropathy risk 3
• For renal failure patients, start bortezomib-dexamethasone immediately without dose adjustment 1, 3
• Do not delay treatment for extensive workup; initiate therapy promptly while completing staging 3