Table 4 Overview of management, treatment, and prophylaxis recommendations for patients with MM receiving BsAbs.

• Pay particular attention to Ig levels in this patient population (level IIC)

• IgG and IgM serology tests for diagnosis of viral infections may be used routinely, but interpreted with caution (level IIC)

• Monitor Ig levels monthly during Ig treatment (level IIC)

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• The expert panel discussed Ig replacement therapy for the following patients:

 ◦ Patients whose IgG levels <400 mg/dl (level IIC)

 ◦ Patients who have ≥2 severe recurrent infections by encapsulated bacteria, regardless of IgG level (level IIC)

 ◦ Patients with a life-threatening infection (level III)

 ◦ Patients with documented bacterial infection with no or insufficient response to antibiotic therapy (level IIC)

• Monthly IVIG treatment recommended for the duration of immunoparesis, and in absence of life-threatening infectious manifestations, until Ig levels are ≥400 mg/dl (level IIC)

• Maintain dosing during Ig treatment (level IIC)

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• Anti-bacterial or anti-fungal prophylaxis should be considered if neutropenia is prolonged or chronic despite G-CSF treatment (level IIC)

• Colony-stimulating factors recommended in patients with documented ≥Grade 3 neutropenia (level III)

• Avoid G-CSF during periods when a patient is at risk of CRS (level IIB)

• Withhold dosing in neutropenia cases where absolute neutrophil count <0.5 × 10⁹/L, or in febrile neutropenia cases, until neutrophil count has returned to normal levels (level IIB)

Viral infection

General

• Based on patient symptoms and clinical presentation (level IIC)

• PCR-based viral panels to diagnose viral infections and reactivations (level III)

• Acyclovir or valacyclovir against HSV and VZV in all RRMM patients (level III)

• Monitoring is not recommended while using these prophylactic treatments (IIB)

• Prophylaxis should be maintained whilst the patient is still receiving treatment for MM, and thereafter at the discretion of the individual physician (level III)

• Dependent on infectious agent

• Maintain dosing during prophylaxis

• Temporary discontinuation during anti-viral treatment until clinical resolution of infectious symptoms, or until the viral load is not clinically significant (level IIC)

CMV

• If infection risk is suspected, monitor using CMV DNA copies (level IIC)

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• Oral valganciclovir for CMV reactivation (level IIC)

• Alternatives: IV ganciclovir of foscarnet (level IIC)

• Follow standard guidelines for CMV reactivation

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EBV

• Not routinely recommended, but should be considered (level IIC)

• In cases of persistent fever and fatigue, monitor EBV DNA copies in order to exclude EBV DNA reactivation (level IIB)

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• Rituximab in post-allogenic HSCT patients (level IIA)

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VZV

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• Acyclovir or valacyclovir (level III)

• Vaccination against VZV recommended in RRMM patients (level IIB)

• Valacyclovir or IV acyclovir for VZV reactivation (as per standard treatment guidelines), different agents may be used if following local guidelines (level III)

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HBV

• Screen for core antibodies (level III) and surface antigens prior to starting MM treatment (level III)

• Monitor HBV DNA copies in core antigen positive patients (level III)

• If core antibody positive, administer prophylaxis, or monitor for HBV DNA copies, with pre-emptive anti-viral treatment for those with positive DNA tests/viremia (level III)

• If surface antigen positive, administer anti-viral prophylaxis: entecavir, tenofovir, lamivudine under the control of specialists, as per standard treatment guidelines (level III)

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• Maintain dosing during prophylaxis (level III)

• Discontinue if patient experiences reactivation (level IIC)

Influenza

• Direct testing of nasopharyngeal or respiratory secretions by PCR if influenza is suspected (level III)

• Influenza vaccination of patients receiving BsAbs and close contacts recommended (level III)

• Two-dose series, at least one month apart, of high-dose influenza vaccine may increase likelihood of seroprotection (level IIC)

• Oseltamivir or baloxivir, if influenza is confirmed, as per standard guidelines (level IIC)

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SARS-COV-2

• Follow center protocols (level III)

• If COVID-19 is suspected, PCR test on nasal, nasopharyngeal or respiratory secretions (level III)

• Follow CDC guidelines or local health authority guidelines for vaccination (level III)

• Treat with mAbs with proven efficacy against the prevalent variant (if effective prophylactic antibodies are available) (level IIC)

• Treat with available therapies, with consideration of concurrent medications; treatment is based on symptoms and physician assessment (level III)

• Temporary discontinuation in patients with COVID-19 until clinical resolution, together with RT-PCR clearance (level III)

• Blood, urine, sputum and fecal cultures. Test choice depends on infection site (level III)

• Imaging to provide greater insight and confirm extent of infection (level III)

• For further confirmation: imaging such as CT or PET-CT scans for pneumonia evaluation, suspected colitis, diverticulitis or abdominal abscesses, or procedural biopsy based on the infection site (level III)

• Recommended in patients with:

 ◦ Prolonged neutropenia (level IIC)

 ◦ High risk of infections (level IIC)

 ◦ History of recurrent bacterial infections (level IIC)

• In these circumstances, treat with levofloxacin, stopping treatment once patient no longer has neutropenia (level IIC)

• Risk of developing resistant pathogens should be considered with use of anti-bacterial prophylaxis (level IIC)

• Combining anti-bacterial prophylactic treatments is not recommended (level IIC)

• Dependent on infectious agent, targeted therapy recommended if agent can be identified (level III)

 ◦ Broad-spectrum antibiotics for patients with concomitant neutropenia (level III)

 ◦ Levofloxacin or equivalent, based on site of infection, for patients who do not have concomitant neutropenia (level IIC)

 ◦ For older patients who those with QT prolongation: third generation cephalosporins (level IIC)

• Treat until symptoms resolve (level III)

• Treating microbial colonizations is not recommended (level IIC), however treatment may be used in very immunocompromised patients (level IIB)

• Maintain dosing during prophylaxis (level III)

• Temporary discontinuation, until infection resolution, during anti-bacterial treatment (level III)

Fungal infection

General

• Routine monitoring is not recommended (level IIC)

• Serum galactomannan testing if aspergillosis is suspected (level IIC)

• Cultures, imaging, and diagnostic tests help identify the fungal infection, if suspected (level III)

• Biopsy to confirm mold in patient with sinusitis (level III)

• Not recommended (level IIC), unless patient has previous history of fungal infections (level IIC), prolonged neutropenia (level IIC), or history of prolonged high-dose corticosteroid use (<2 weeks) (IIC)

• Administer prophylaxis following consultation with an infectious disease specialist, if available (level III)

• If using prophylaxis: fluconazole is recommended (level IIC)

• Itraconazole and voriconazole can be considered (level IIC)

• Monitoring during anti-fungal prophylaxis is not recommended, unless for suspected aspergillosis, and depending on patient risk (level IIC)

• Dependent on infectious agent and investigations

• Treat as per infectious disease guidelines, and consult with an infectious disease provider (level III)

• Maintain dosing during prophylaxis, when needed (level III)

• Temporarily discontinue during anti-fungal treatment, until symptom resolution (level III)

P. jirovecii infection

• Routine monitoring is not recommended (level III)

• Review each case individually (level III)

• Recommended prophylaxis for all patients (level III)

• Trimethoprim-sulfamethoxazole (level IIC), dapsone or atovaquone if allergic to sulfonamide (level IIC)

• Inhaled or intravenous pentamidine for patients with neutropenia (level IIB)

• Treat as per standard anti-microbial regimens for PJP:

 ◦ Trimethoprim-sulfamethoxazole for 21 days (level III)

 ◦ Atovaquone 750 mg po BID for 21 days (for mild cases, sulfonamide allergy) (level III)

 ◦ Clindamycin and primaquine for 21 days (for moderate/severe cases, sulfonamide allergy) (level IIC)

• Maintain dosing during prophylaxis (level IIC)

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• Follow general guidelines on use of live attenuated vaccines, however it should be noted that live vaccines are contraindicated in MM patients (level IIC)

• Ensure post-stem cell transplant vaccinations have been carried out (level III)

• COVID-19 vaccination recommended as per CDC guidelines, in patients without history of transplant (level III)

• Yearly influenza vaccination, pneumococcal vaccination and varicella zoster vaccination recommended in patients without history of transplant (level III)

• Close contacts should receive seasonal vaccines (level III)

• Health-care providers caring for MM patients should be fully immunized and should receive seasonal vaccines (level III)

• Prior to traveling to endemic areas of infection, patients should receive travel vaccinations and undergo consultation with a disease specialist (level III)

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