What is the recommended initial treatment for a treatment-naive older adult patient with myeloma presenting with encephalopathy?

Treatment-Naive Older Adult with Myeloma and Encephalopathy

For a treatment-naive older adult patient with myeloma presenting with encephalopathy, initiate bortezomib-based therapy immediately, specifically bortezomib plus dexamethasone (VD) doublet, avoiding lenalidomide initially due to the urgent need to address potential hypercalcemia or renal dysfunction causing encephalopathy. 1

Immediate Clinical Assessment

The encephalopathy in this patient requires urgent evaluation for reversible causes directly related to myeloma:

• Assess serum calcium immediately - hypercalcemia >11.5 mg/dL is a CRAB criterion and can cause altered mental status 2
• Check renal function - creatinine >2 mg/dL or estimated creatinine clearance <40 mL/min indicates myeloma kidney 2
• Evaluate for hyperviscosity syndrome - particularly if IgA or IgM paraprotein is present 2

Recommended Initial Regimen

Bortezomib 1.3 mg/m² subcutaneously on days 1,4,8,11 of a 21-day cycle plus dexamethasone 20 mg orally on days 1,2,4,5,8,9,11,12 is the optimal starting regimen for this clinical scenario. 1, 2

Rationale for This Approach:

• Bortezomib works rapidly in renal failure - it is not renally cleared and achieves quick responses in patients with renal impairment, which may be contributing to encephalopathy 2
• Dexamethasone addresses hypercalcemia - high-dose steroids rapidly lower calcium levels within 24-48 hours 2
• Avoid lenalidomide initially - lenalidomide requires dose adjustment for renal dysfunction and has slower onset of action 1

Critical Dosing Modifications for Frail/Encephalopathic Patients

Reduce dexamethasone to 20 mg once weekly (rather than the schedule above) if the patient is over 75 years or appears frail, as standard dexamethasone dosing significantly increases mortality in this population. 1, 2

The 2013 Mayo Clinic guidelines specifically warn that thalidomide-dexamethasone resulted in shorter overall survival (41.5 vs 49.4 months) in frail elderly patients, particularly those over 75 years with poor performance status. 2

Essential Supportive Care During Initial Treatment

• Mandatory herpes zoster prophylaxis with acyclovir 400 mg twice daily when using bortezomib 1
• Aggressive hydration with normal saline if hypercalcemia is present (target urine output 100-150 mL/hour) 2
• Consider bisphosphonates (zoledronic acid or pamidronate) once renal function is assessed and hydration initiated 3
• Hold thromboprophylaxis initially - aspirin is only needed when lenalidomide is added later 1

Transition Strategy After Encephalopathy Resolves

Once the patient's mental status normalizes and you've addressed the underlying metabolic derangements:

Transition to the triplet regimen VRd (bortezomib, lenalidomide, dexamethasone) for 8-12 cycles, which is the standard of care for transplant-ineligible elderly patients. 1, 2

• Lenalidomide 25 mg orally days 1-21 of each 28-day cycle (dose-adjust for creatinine clearance) 1
• Continue bortezomib 1.3 mg/m² subcutaneously on days 1,8,15 of each 28-day cycle 1
• Reduce dexamethasone to 20 mg once weekly for patients over 75 years 1

Common Pitfalls to Avoid

Never use melphalan-containing regimens (MPT, VMP) if there is any possibility the patient could become transplant-eligible after clinical improvement, as melphalan is stem cell toxic. 1 The older guidelines from 2009-2013 recommended MPT or VMP as standards 2, but current practice has shifted away from melphalan in North America. 2

Do not start with lenalidomide-dexamethasone alone in a patient with encephalopathy - while this is an acceptable regimen for standard-risk elderly patients 2, the slower onset of action and need for renal dose adjustment make it suboptimal when urgent disease control is needed. 1

Avoid high-dose dexamethasone (40 mg) in elderly patients - a randomized trial showed lenalidomide plus low-dose dexamethasone (40 mg weekly) had superior overall survival compared to high-dose dexamethasone (40 mg on days 1-4,9-12,17-20), with less thrombosis, infections, and fatigue. 2

Monitoring During Initial Cycles

• Assess response after every 2 cycles with serum protein electrophoresis, immunofixation, and free light chains 1, 3
• Monitor closely for peripheral neuropathy with bortezomib - if grade 2 or higher develops, reduce dose to 1.0 mg/m² or switch to weekly dosing 2
• Reassess mental status and metabolic parameters (calcium, creatinine) within 48-72 hours of starting treatment 2