What is the best management approach for an HIV-positive patient with multiple myeloma, currently on bortezomib (Velcade), daratumumab (Darzalex), dexamethasone, and cyclophosphamide therapy, who has never received Antiretroviral Therapy (ART)?

Immediate Initiation of Antiretroviral Therapy (ART) is Mandatory

This HIV-positive patient must start ART immediately, regardless of CD4 count or viral load, while continuing the current multiple myeloma regimen of bortezomib, daratumumab, dexamethasone, and cyclophosphamide. The patient's immunocompromised state from both untreated HIV and myeloma chemotherapy creates a critical situation requiring urgent intervention.

Critical Management Priorities

Start ART Without Delay

• Initiate ART immediately as untreated HIV significantly increases morbidity and mortality, particularly in patients receiving immunosuppressive chemotherapy for multiple myeloma 1
• The combination of untreated HIV with proteasome inhibitor and corticosteroid therapy dramatically increases infection risk, which is already elevated in myeloma patients 1
• Modern ART regimens are highly effective and well-tolerated, with minimal drug-drug interactions with myeloma therapies 1

Continue Current Myeloma Therapy

• The bortezomib, daratumumab, dexamethasone, and cyclophosphamide regimen should be continued as this is an effective combination for multiple myeloma 2, 3
• This quadruplet regimen (D-VCd) has demonstrated excellent efficacy with ≥VGPR rates of 44% after 4 cycles and 12-month progression-free survival of 87% in newly diagnosed patients 3
• The LYRA study showed this combination was well-tolerated with manageable toxicity profiles 2, 3

Essential Supportive Care Modifications

Mandatory Prophylaxis

• Herpes zoster prophylaxis is required for all patients on proteasome inhibitors like bortezomib 1
• Pneumocystis jirovecii prophylaxis (PCP) is critical given the combination of HIV, high-dose dexamethasone, and daratumumab-induced immunosuppression 4
• Antibacterial prophylaxis with levofloxacin should be considered during initial cycles given the dual immunosuppression 4

Thromboprophylaxis

• Full-dose aspirin is recommended as the regimen includes dexamethasone, though the patient is not on an immunomodulatory drug (lenalidomide/thalidomide) 1
• Consider therapeutic anticoagulation if additional high-risk features for thrombosis are present 1

Infection Monitoring and Management

Enhanced Surveillance

• The combination of daratumumab with bortezomib increases grade 3/4 infection rates (23.1% in the ALCYONE trial) compared to bortezomib alone (14.7%) 5
• Monitor closely for infections as the patient faces triple immunosuppression: untreated HIV, corticosteroids, and anti-CD38 therapy (daratumumab) 5, 6
• Daratumumab can cause false-positive indirect Coombs tests, which may complicate blood bank procedures 1

Infusion Reaction Management

• Daratumumab infusion-related reactions occur in approximately 45-54% of patients, primarily during the first infusion 3, 6
• Most reactions are grade 1-2, with only 2-8.6% being grade 3 3, 6
• The split-first dose approach used in the LYRA study (dividing the first daratumumab dose) may improve tolerability 3

Stem Cell Preservation Considerations

Limit Alkylator Exposure

• Minimize cyclophosphamide exposure to preserve stem cell reserve if the patient may be a future transplant candidate 1
• The current regimen uses cyclophosphamide 300 mg/m² weekly, which is relatively stem cell-sparing compared to higher-dose alkylator regimens 3
• Consider stem cell harvest after 4 cycles if the patient achieves adequate disease control and HIV viral suppression 1

Administration Preferences

Bortezomib Route

• Subcutaneous bortezomib is strongly preferred over intravenous administration to reduce peripheral neuropathy risk 1
• This is particularly important given the prolonged therapy anticipated and potential for HIV-related neuropathy 1

Daratumumab Formulation

• Either intravenous daratumumab or subcutaneous daratumumab with hyaluronidase-fihj can be used 1
• Subcutaneous formulation reduces infusion time and infusion-related reactions but may not be appropriate if significant thrombocytopenia develops 1

Common Pitfalls to Avoid

• Never delay ART initiation while waiting for myeloma treatment response—both conditions require simultaneous management 1
• Do not underestimate infection risk—the combination of untreated HIV, corticosteroids, and daratumumab creates profound immunosuppression requiring aggressive prophylaxis 4, 5
• Avoid excessive alkylator exposure that could compromise future transplant options 1
• Do not skip herpes zoster prophylaxis—this is mandatory with proteasome inhibitors and the risk is amplified by HIV 1