The therapeutic landscape in multiple myeloma (MM) has significantly expanded since the development of immunomodulatory agents such as thalidomide. These include newer immunomodulatory agents such as lenalidomide and pomalidomide and proteasome inhibitors bortezomib, ixazomib and carfilzomib.1,2,3 Frequent adverse events encountered by patients receiving these agents include cytopenias (eg, neutropenia, anemia, thrombocytopenia), venous thromboembolism, peripheral neuropathy, gastrointestinal complaints (nausea, vomiting, diarrhea), skin reactions, and infections.

As these newer medications have been incorporated into the routine treatment modalities for MM, there have been improvements in patient outcomes, as well as increased reporting of adverse events.4 One sometimes under-recognized adverse event includes infections. A study conducted by Augustson and colleagues demonstrated that 45% of deaths within 60 days of entering a clinical trial for MM in the United Kingdom were attributable to infections.5

This retrospective study evaluated 3107 patients newly diagnosed with MM and found that 10% (299 patients) of these patients died within 60 days of trial entry. Of the 135 deaths related to infection, only 8% had neutropenia diagnosed at initial diagnosis. The most common infections that were diagnosed included pneumonia (66%), generalized sepsis (23%), and miscellaneous infections (11%, eg, osteomyelitis and peritonitis). Twenty-five percent of patients with pneumonia experienced thoracic pain, which may not be considered a “typical” symptom associated with pneumonia. Thirty-three percent of the patients who died due to infections had their infections develop at home; close to 50% of them had a delay in hospital presentation. In addition to infectious complications contributing to mortality, renal failure was also present in many patients who died (28%).

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Outside of neutropenia, there are undoubtedly additional factors that could contribute to infectious-related morbidity and mortality. A recent study conducted by Brioli and colleagues aimed to further evaluate these connections by conducting a retrospective analysis of 479 patients with MM between 2003 and 2015 at a single center in Germany.6 With these 479 patients, there were 1690 “cases” identified; a “case” could include an induction treatment, stem cell collection, stem cell transplantation, and medication courses.

There were 627 patients (37%) who had an infection recorded in their charts. A total of 313 patients (65%) experienced at least 1 infection at some point throughout the study. Of the 144 patients who died by the completion of the study, the 2 most common causes of death were progression of disease (44%) and infections (31%). Patients with infections were more likely to die at a younger age compared with those who did not develop an infection (patients aged 73 years vs 64 years, respectively, P <.001). The most significant risk factors associated with developing an infection included relapsed disease, anemia present prior to treatment initiation, plasma cell burden in the bone marrow of more than 70%, multiple bone lesions at diagnosis, and treatment with high-dose chemotherapy and stem cell transplantation.

The most common infections seen were pneumonia (24%), bacteremia (20%), urinary tract infection (UTI, 20%), central venous catheter infections (7%) and Clostridium difficile infection (3.4%). When isolated, the most common bacterias that were detected included coagulase-negative staphylococci, Escherichia coli, Staphylococcus aureus, Enterococci and Pseudomonas. When compared with patients who did not develop an infection, patients with infections were more likely to diagnosed with MM at an earlier age (61 years vs 67 years, P <.001) and have more bone lesions (20% vs 10%, P <.003). This increased rate of infection in younger patients is mostly based on those patients eventually receiving high-dose chemotherapy and undergoing stem cell transplantation.

There was no change in the rate of infections based on the time period that the patients were diagnosed with MM (2003–2008 vs 2009–2015). According to the study authors, these time intervals were chosen because after 2009, the use of immunomodulators and proteasome inhibitors significantly increased. Based on this, the authors concluded that there was no difference in the rates of infections based on the utilization of newer agents. With respect to treatment phases, infections were least likely to develop during induction therapy compared with other treatment phases such as mobilization chemotherapy, high-dose chemotherapy with stem cell transplantation, and long-term treatment.

This recent study highlights several key points. Infections are common in patients with MM both before and during treatment, are not always secondary to neutropenia, and continue to significantly contribute to morbidity and mortality within MM. Health care practitioners (HCPs) should routinely evaluate their patients with MM for infectious symptoms and manage true infections aggressively. Based on this most recent paper, it does not appear that newer agents increase the risk of infections, however it will be important to collect additional data with these agents in the future. If there are no absolute contraindications, patients with MM should be considered for the pneumonia and shingles vaccines.

References

  1. Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114(4):772–778.
  2. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008–5014.
  3. Richardson PG, Sonneveld P, Schuster MW, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487–2498.
  4. Brioli A, Mügge LO, Hochhaus A, Von Lilienfeld-Toal M. Safety issues and management of toxicities associated with new treatments for multiple myeloma. Expert Rev Hematol. 2017;10(3):193–205.
  5. Augustson BM, Begum G, Dunn JA, et al. Early mortality after diagnosis of multiple myeloma: analysis of patients entered onto the United Kingdom Medical Research Council trials between 1980 and 2002—Medical Research Council Adult Leukaemia Working Party. J Clin Oncol. 2005;23(36):9219–9226.
  6. Brioli A, Klaus M, Sayer H, et al. The risk of infections in multiple myeloma before and after the advent of novel agents: a 12-year survey. Ann Hematol. 2019;98(3):713–722.