Is it safe to give Paxlovid (nirmatrelvir/ritonavir) to a patient with multiple myeloma on Velcade (bortezomib), Darzalex (daratumumab), and Revlimid (lenalidomide) who is COVID-19 positive?

Paxlovid Use in Multiple Myeloma Patients on VRd-Daratumumab with COVID-19

Yes, Paxlovid can be given to this patient, but requires careful management of drug-drug interactions, particularly with dexamethasone dose reduction and close monitoring for potential interactions with the myeloma regimen. 1

Critical Drug Interaction Considerations

Ritonavir in Paxlovid is a strong CYP3A inhibitor that can cause potentially severe, life-threatening drug interactions that must be addressed before prescribing 1. The FDA label explicitly warns that all medications must be reviewed prior to prescribing to assess potential interactions and determine if dose adjustments, interruptions, or additional monitoring are needed 1.

Specific Interactions with This Regimen:

Dexamethasone (component of VRd regimen):

• Dexamethasone is a CYP3A substrate, and ritonavir will significantly increase dexamethasone exposure 1
• Recommendation: Hold or significantly reduce dexamethasone during the 5-day Paxlovid course to avoid corticosteroid toxicity (Cushing's syndrome, adrenal suppression, hyperglycemia) 1
• This is particularly important as COVID-19 guidelines already recommend reducing dexamethasone to 20 mg weekly in myeloma patients during the pandemic 2

Bortezomib (Velcade):

• No significant CYP3A-mediated interaction expected; bortezomib can be continued 1

Lenalidomide (Revlimid):

• Primarily renally eliminated, not a CYP3A substrate; no dose adjustment needed for drug interaction purposes 1
• However, monitor renal function as both COVID-19 and lenalidomide can affect kidneys 2

Daratumumab (Darzalex):

• Monoclonal antibody with no CYP-mediated metabolism; no interaction with Paxlovid 1
• Can be continued, though some guidelines suggest extending daratumumab dosing intervals during COVID-19 to reduce healthcare exposure 2

Dosing Recommendations

Standard dose: 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) twice daily for 5 days 1

Renal adjustment required if:

• Moderate renal impairment (eGFR 30-60 mL/min): Reduce to 150 mg nirmatrelvir with 100 mg ritonavir twice daily 1
• Severe renal impairment (eGFR <30 mL/min): 300 mg nirmatrelvir with 100 mg ritonavir once on Day 1, then 150 mg nirmatrelvir with 100 mg ritonavir once daily Days 2-5 1
• This is particularly relevant as myeloma patients frequently have renal impairment 2

Timing and Administration

Initiate Paxlovid as soon as possible after COVID-19 diagnosis and within 5 days of symptom onset 1. The evidence shows that oral antivirals including ritonavir-nirmatrelvir are associated with low rates of severe COVID-19 in myeloma patients 3.

Complete the full 5-day course even if symptoms improve, as this maximizes viral clearance 1. A prospective study of 139 myeloma patients treated with ritonavir-nirmatrelvir showed 88.2% had mild infection with this approach 3.

Clinical Monitoring

Monitor for:

• Signs of corticosteroid excess if dexamethasone is continued (even at reduced doses) 1
• Hepatotoxicity, as ritonavir can cause transaminase elevations 1
• Renal function, particularly if patient has baseline renal impairment common in myeloma 2, 1
• COVID-19 symptom progression, as myeloma patients remain at higher risk for severe disease despite treatment 4, 3

Evidence Supporting Use

Multiple myeloma patients have increased hospitalization and mortality from COVID-19, especially those on active chemotherapy 4. However, prospective data demonstrates that ritonavir-nirmatrelvir prevents severe disease in MM patients, with comparable efficacy to molnupiravir 3. In a study of 169 myeloma patients, only 3% developed severe COVID-19 when treated with these antivirals 3.

Common Pitfalls to Avoid

• Do not continue full-dose dexamethasone during Paxlovid treatment without considering the interaction 1
• Do not prescribe without checking renal function and adjusting dose accordingly 1
• Do not assume all myeloma drugs are safe to continue - review each agent individually 1
• Do not delay treatment while sorting out interactions; the 5-day window from symptom onset is critical 1

The benefit of reducing hospitalization and death with Paxlovid outweighs the manageable drug interaction risks in this population when appropriately monitored 1, 3.