Infection Risk in Multiple Myeloma Patients Receiving New Generation Therapies

SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 34,920 new cases will be diagnosed in 2021 and 12,410 patients are expected to die of the disease. Multiple Myeloma (MM) in 2021 remains an incurable disease. The therapeutic goal therefore is to improve Progression Free Survival (PFS) and Overall Survival (OS). Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients will eventually relapse, requiring multiple lines of therapy for disease control. The availability of newer agents has transformed Multiple Myeloma into a chronic disease. Patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The median survival for patients with myeloma is over 10 years.

Infection is a leading cause of morbidity and mortality in patients with Multiple Myeloma. In a study of over 3000 newly diagnosed Multiple Myeloma patients, approximately 50% of early deaths (deaths occurring in less than 6 months following diagnosis) were associated with infections (J Clin Oncol. 2005;23:9219-9226). The increased susceptibility to infection in this patient group has been attributed to disease-related deficits in the innate or adaptive immune system, including hypogammaglobulinaemia, qualitative and quantitative abnormalities of dendritic cells, T cells, and Natural Killer cells, as well as renal function impairment, and therapies administered at different stages of the disease. Further, the introduction of new therapeutic agents such as Proteasome Inhibitors (PIs), Immunomodulatory drugs and monoclonal antibodies, with novel mechanisms of action, for first and later lines of therapy, for both Hematopoietic Stem Cell Transplantation eligible and ineligible patients, has significantly improved survival, but has also changed the spectrum of infections in patients with Multiple Myeloma. The epidemiology and risks for infection with the use of new therapeutic agents however remains unclear. The present study was conducted to determine patterns, risks and outcomes of infections in patients with Multiple Myeloma, managed with new therapeutic agents and monoclonal antibodies.

In this study, patients with Multiple Myeloma treated with second generation therapies and other monoclonal antibodies were identified from pharmacy and clinical databases, collected from 2 major tertiary referral centers for Multiple Myeloma management in Australia. Agents considered new generation therapies included Pomalidomide, Carfilzomib, Isatuximab, Daratumumab and Elotuzumab. Following commencement of new generation therapy, 60% of the patient’s had previously received Autologous Stem Cell Transplantation and 93% of the patient’s had Relapsed or Refractory Multiple Myeloma. Patients were then followed for episodes of infection, from the commencement of therapy with any newer agents, until completion of treatment, death or end of study, which ever occurred first. Prophylaxis with antibiotics for bacterial infections was not routinely used, but antiviral prophylaxis with Valaciclovir was used when patients received therapy with Proteasome Inhibitors. Patients received prophylaxis with Trimethoprim/Sulfamethoxazole for Pneumocystis jirovecii pneumonia when steroid doses exceeded 16-20 mg of Prednisone equivalent per day.

Each episode of infection was classified as Microbiologically Defined (MDI) when pathogens were isolated on microbiological testing, Clinically Defined (CDI) when sites of infection were identified but no pathogens were isolated on microbiological testing, and Fever of Unknown Focus (FUF) when patients had febrile episodes with no pathogen or site identified. Univariate and multivariate analyses were performed to determine risk factors for infection.

A total of 148 patients with Multiple Myeloma were followed for a median of 13.2 months, and 345 infection episodes were identified. Of these, 29% (100 out of 345) were defined as Microbiologically Defined Infections, 58% (200 out of 345) were defined as Clinically Defined Infections, and 13% (45 out of 345) were defined as Fever of Unknown Focus. Of those with Microbiologically Defined Infections, 50% of infections were attributed to viruses, whereas 45% were attributed to bacterial infection. Respiratory Syncytial Virus was the most frequently isolated virus accounting for 24% of episodes, followed by Rhinovirus at 16% and Influenza virus at 14%. E. coli was the most frequently isolated bacteria at 20%, followed by Haemophilus influenza at 11%. The most common infection site was the respiratory tract (56.8%), hospital admission occurred in 41.7% of infection episodes, and the 30-day all-cause mortality rate was 5.4%. Treatment with Proteasome Inhibitors resulted in 16.8 times increased risk for infections, combination of IMiD and PI was associated with 13.44 times higher risk, monoclonal antibody combination therapy was associated with 10.44 times higher risk, and more than 4 lines of therapy was associated with 7.72 times higher risk for infections (P<0.05).

It was concluded from this study that majority of infections are caused by viruses, in patients with Multiple Myeloma treated with newer therapeutic agents. Treatment with a Proteasome Inhibitor and more than 4 lines of therapy were associated with higher risk for infection.

Epidemiology and Risks of Infections in Patients With Multiple Myeloma Managed With New Generation Therapies. Lim C, Sinha P, Harrison SJ, et al. Clinical Lymphoma, Myeloma & Leukemia. 2021;21:444-450.