Cytomegalovirus reactivation in patients with multiple myeloma administered daratumumab-combination regimens

Tabata, Rikako; Sato, Nobue; Yamauchi, Nobuhiko; Guo, Yong-Mei; Nakamura, H.; Nagata, Akihito; Song-Gi, Chi; Minami, Yosuke; Yuda, Junichiro

doi:10.1007/s00277-021-04525-9

Cited by 8 publications

(8 citation statements)

References 14 publications

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“… 42 Atypical infections are uncommon, however, reactivation of herpes zoster and Epstein–Barr virus/cytomegalovirus, pneumocystis jirovecii pneumonia (PJP), progressive multifocal leukoencephalopathy, bronchopulmonary aspergillosis, fungal meningitis, listeriosis, and disseminated cryptococcosis are reported. 43 – 50 As expected, infections occur at a higher rate in those patients with higher grade neutropenia and lymphopenia, notably heavily pretreated patients treated with combination regimens within the initial 6 months of treatment. In this population treated with daratumumab, the median time to severe infection was ~50 days in patients with severe lymphopenia versus ~90 days in those without severe lymphopenia.…”

Section: Fda-approved Next-generation Therapeuticssupporting

confidence: 59%

“…42 disseminated cryptococcosis are reported. [43][44][45][46][47][48][49][50] As expected, infections occur at a higher rate in those patients with higher grade neutropenia and lymphopenia, notably heavily pretreated patients treated with combination regimens within the initial 6 months of treatment. In this population treated with daratumumab, the median time to severe infection was ~50 days in patients with severe lymphopenia versus ~90 days in those without severe lymphopenia.…”

Section: Fda-approved Next-generation Therapeuticssupporting

confidence: 58%

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Toxicity management strategies for next-generation novel therapeutics in multiple myeloma

Steinbach

Julian

McClune

et al. 2022

Therapeutic Advances in Hematology

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The therapeutic options available for patients with multiple myeloma have greatly expanded over the past decade and incorporating these novel agents into routine clinical practice has significantly improved outcomes. The next generation of therapeutics is available for relapsed and refractory patients either as standard of care or in clinical trial, and these drugs represent a generational paradigm shift. Patients now have access to a multitude of novel immunotherapeutics, including monoclonal antibodies, an antibody–drug conjugate, chimeric antigen receptor T-cells (CAR-T), and bispecific T-cell redirecting antibodies, and novel oral therapies including selinexor (selective inhibitor of nuclear export) and venetoclax (bcl-2 inhibitor). While these drugs have the potential to be highly efficacious in certain subsets of patients when used as single agents or in combination regimens, they are each associated with unique toxicity profiles. It is imperative to understand these potential adverse events to ensure patient safety. Appropriate supportive care management is paramount to maximize drug exposure and therapeutic efficacy. The following review focuses its discussion on drugs and combination regimens that are currently FDA-approved and those that continue to be investigated in clinical trials, highlights the clinically relevant toxicity profiles for each of the different agents, and provides practical considerations for the treatment team.

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Section: Fda-approved Next-generation Therapeuticssupporting

confidence: 59%

Section: Fda-approved Next-generation Therapeuticssupporting

confidence: 58%

Toxicity management strategies for next-generation novel therapeutics in multiple myeloma

Steinbach

Julian

McClune

et al. 2022

Therapeutic Advances in Hematology

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“…Patients with MM who receive treatment based on anti‐CD38 monoclonal antibodies have a high risk of infections including severe and potentially lethal events, mainly in the respiratory tract 67,68 . In patients under daratumumab‐based therapy, there have been also reports of atypical, opportunistic infections including cytomegalovirus, leishmania and listeria infections 69–73 . Preventive measures are essential to reduce the infection burden and include antiviral and antibiotic prophylaxis, administration of intravenous/subcutaneous immunoglobulin depending on the tailored risk of infection, behavioral adaptations during outbreaks of communicable diseases and vaccination including booster shots 74–78 …”

Section: Discussionmentioning

confidence: 99%

“…67,68 In patients under daratumumab-based therapy, there have been also reports of atypical, opportunistic infections including cytomegalovirus, leishmania and listeria infections. [69][70][71][72][73] Preventive measures are essential to reduce the infection burden and include antiviral and antibiotic prophylaxis, administration of intravenous/subcutaneous immunoglobulin depending on the tailored risk of infection, behavioral adaptations during outbreaks of communicable diseases and vaccination including booster shots. [74][75][76][77][78] In conclusion, second-line treatment with Dara-Ixa-dex in patients with RRMM pre-treated with a lenalidomide-based regimen resulted in rapid and sustained responses along with a favorable effect on bone metabolism with no new safety concerns.…”

mentioning

confidence: 99%

Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide‐exposed patients after one prior line of therapy: Final results of the phase 2 study DARIA

Terpos,

Ntanasis‐Stathopoulos,

Gavriatopoulou

et al. 2024

American J Hematol

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The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara‐Ixa‐dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide‐based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% (n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow‐up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia (n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia (n = 2, each). Four patients died due to infections. In conclusion, second‐line treatment with Dara‐Ixa‐dex in patients with RRMM pre‐treated with a lenalidomide‐based regimen resulted in rapid responses along with a favorable effect on bone metabolism.

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“…However, few studies have evaluated CMV viremia in a systematic fashion in this population and the clinical relevance of asymptomatic reactivation remains unknown. In general, routine CMV monitoring is not recommended, but testing should be considered as clinically appropriate or in potentially high‐risk patients, such as those receiving >3 days of corticosteroids for management of CRS and/or ICANS, 84,87,117 while specific treatments such as daratumumab‐combination regimens for multiple myeloma prior to BCMA CAR‐T cell have also been associated with CMV risk 118,119 . Prospective studies are needed to determine whether and in whom to perform CMV monitoring, which may further inform the potential utility of prophylactic therapies such as letermovir in some patient subgroups.…”

Section: Special Considerationsmentioning

confidence: 99%

Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies

Kampouri,

Little,

Rejeski

et al. 2023

Transplant Infectious Dis

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BackgroundChimeric antigen receptor (CAR)‐T‐cell therapies have revolutionized the management of acute lymphoblastic leukemia, non‐Hodgkin lymphoma, and multiple myeloma but come at the price of unique toxicities, including cytokine release syndrome, immune effector cell‐associated neurotoxicity syndrome, and long‐term “on‐target off‐tumor” effects.MethodsAll of these factors increase infection risk in an already highly immunocompromised patient population. Indeed, infectious complications represent the key determinant of non‐relapse mortality after CAR‐T cells. The temporal distribution of these risk factors shapes different infection patterns early versus late post‐CAR‐T‐cell infusion. Furthermore, due to the expression of their targets on B lineage cells at different stages of differentiation, CD19, and B‐cell maturation antigen (BCMA) CAR‐T cells induce distinct immune deficits that could require different prevention strategies. Infection incidence is the highest during the first month post‐infusion and subsequently decreases thereafter. However, infections remain relatively common even a year after infusion.ResultsBacterial infections predominate early after CD19, while a more equal distribution between bacterial and viral causes is seen after BCMA CAR‐T‐cell therapy, and fungal infections are universally rare. Cytomegalovirus (CMV) and other herpesviruses are increasingly breported, but whether routine monitoring is warranted for all, or a subgroup of patients, remains to be determined. Clinical practices vary substantially between centers, and many areas of uncertainty remain, including CMV monitoring, antibacterial and antifungal prophylaxis and duration, use of immunoglobulin replacement therapy, and timing of vaccination.ConclusionRisk stratification tools are available and may help distinguish between infectious and non‐infectious causes of fever post‐infusion and predict severe infections. These tools need prospective validation, and their integration in clinical practice needs to be systematically studied. image

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Cytomegalovirus reactivation in patients with multiple myeloma administered daratumumab-combination regimens

Cited by 8 publications

References 14 publications

Toxicity management strategies for next-generation novel therapeutics in multiple myeloma

Toxicity management strategies for next-generation novel therapeutics in multiple myeloma

Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide‐exposed patients after one prior line of therapy: Final results of the phase 2 study DARIA

Infections after chimeric antigen receptor (CAR)‐T‐cell therapy for hematologic malignancies

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