Background: Relapsed/refractory multiple myeloma (MM) patients are at an increased risk of infectiondue to the immunsuppressive nature of the disease and the host factors. Albeit their excellent efficacy outcomes, bispecific antibodies (BsAbs), especially those targeting BCMA, increase the risk of infection significantly. Specifically, atypical infections including viral infections are becoming a big problem. Seroprevalence of latent viruses and determinants for opportunistic infections differ per region, thus it is important to comprehensively understand the similarities and differences amongst patients undergoing the same treatment. More specifically, cytomegalovirus (CMV) is endemic across many Asian countries, South American and African countries. CMV is one of the most important complications in immunocompromised patients. It can cause multi-organ disease, including pneumonia, gastroenteritis, retinitis and encephalitis. For patients undergoing BCMA BsAbs treatment, the reported clinically significant CMV infection risk ranges from 13% to 39.4%, and the reactivation rate 66.7%. Putting this into context, the reported clinically significant CMV infection risk is 41.8% without prophylaxis for patients undergoing hematopoietic stem cell transplantation. This similar rate of CMV related events clearly calls for an action. Unfortunately, even in the most recent IMWG guideline there are varied views on CMV related items including prophylactic schema.

As BsAbs prolong survival of MM patients, supportive care is becoming increasingly important to ensure good quality of life and sustain treatment response. Infection control constitutes a major pillar of such supportive care. BsAbs are already very expensive, thus dealing with complications secondary to desultory use will ultimately tantamount to significant financial burden in any given healthcare system. Therefore, implementing prophylactic measures and establishing active monitoring know-hows is important. To close the gaps of current guidelines on infection risk mitigation and subsequently BsAb treatment optimization, we aim to investigate the efficacy and safety of letermovir for the prevention of clinically significant CMV infection in patients undergoing elranatamab therapy.

Study design & methods: This is an open-label, single arm, multicenter study conducted in Korea and registered on clinicaltrials.gov as NCT06920251.

Major inclusion / Exclusion criteria:

-Subjects have documented CMV IgG seropositvity at any point.

-Plasma CMV DNA titer unquantifiable (i.e. < lower limit of quantification) during screening

-Subject has received 3 or more prior lines of antimyeloma therapy

-Subject must have received at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody. Anti-BCMA ADC exposure is allowed. Prior treatment with non-BCMA BsAbs is allowed. (Prior anti-BCMA BsAbs exposure is NOT allowed)

Treatment:

Elranatamab will be given per label and until progression.

Letermovir prophylaxis will be given from W3-W16 (total of 98 days).

Objectives/ Endpoints:

Primary: To evaluate the efficacy of letermovir in the prevention of clinically significant CMV infection during the first 6 cycles of elranatamab

Secondary: To evaluate the efficacy of letermovir in the prevention of clinically significant CMV infection at the end of letermovir prophylaxis (end of W16) and during the first 12 cycles of elranatamab

To determine the incidence of CMV disease at the end of letermovir prophylaxis (end of W16), and, during the first 6 and 12 cycles of elranatamab

To determine the CMV viremia during the first 6 and 12 cycles of elranatamab

To evaluate the frequency of elranatamab treatment schedule modification due to CMV related events

Exploratory:

To determine the incidence of opportunistic infection other than CMV during the first 6 and 12 cycles of elranatamab

CMV specific immunity

Statistics: Letermovir prophylaxis results in 17.5% clinically significant CMV infection for allogeneic transplantation patients. Based on our experience (JKMS 2025), we expect that without prophylaxis, clinically significant CMV infection will occur in 39.4% of the patients undergoing elranatamab treatment. Based on one-sample multiple testing procedure for phase II clinical trial (one-sided α error rate 5%, power 90%, p0 39.4 versus p1 17.5), the optimal sample size is 35. Considering the drop-off rate of 10%, 40 patients will be enrolled

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2025
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