Reducing infection-related morbidity and mortality in patients with myeloma
Authors: Karthik Ramasamy
Journal: The Lancet Oncology (2019)

Myeloma survival has substantially improved in the past 10 years.1Thorsteinsdottir S Dickman PW Landgren O et al.Dramatically improved survival in multiple myeloma patients in the recent decade: results from a Swedish population-based study.Haematologica. 2018; 103: e412-e415Crossref PubMed Scopus (60) Google Scholar Although most myeloma deaths are accountable to progressive disease, a substantial proportion of early deaths and deaths in remission are due to infections.2Augustson 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: 9219-9226Crossref PubMed Scopus (345) Google Scholar Febrile infections induce considerable morbidity and frequently lead to drug interruption or drug discontinuation. Drug discontinuation can lead to inferior treatment responses, translating to poorer survival outcomes. Agents with new mechanisms of action and drug combinations dominate current clinical investigations in myeloma. We commend researchers for drawing our focus to an area of supportive care in myeloma. Myeloma is a disease of the elderly, with 40% of newly diagnosed patients in the UK older than 75 years. In their Article in The Lancet Oncology, Mark Drayson and colleagues3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar present findings that showed that 12 weeks of fixed-duration levofloxacin prophylaxis reduced the occurrence of febrile episodes and deaths (95 [19%] febrile episodes or deaths in 489 patients in the levofloxacin group vs 134 [27%] in 488 patients in the placebo group; hazard ratio [HR] 0·66, 95% CI 0·51–0·86; p=0·0018). Independent to levofloxacin, use of prophylactic low dose co-trimoxazole significantly reduced febrile infections and death. Additionally, use of levofloxacin for a fixed duration was not associated with an increase in adverse events; 597 serious adverse events were reported up to 16 weeks from the start of trial treatment—308 (52%) of which were in the levofloxacin group versus 289 (48%) in the placebo group). The results of this trial3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar provide a good basis for considering fixed-duration quinolone prophylaxis for newly diagnosed patients with myeloma starting therapy, but several questions remain. Although the primary endpoint of the study was met, there were no differences in overall survival at end of 1 year.3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar This result could be partly explained by the high number of patients who had poorly controlled myeloma in this trial. Therefore, further trials are required to confirm this finding. There has been a switch to a continuous anti-myeloma therapy approach in newly diagnosed patients.4Benboubker L Dimopoulos MA Dispenzieri A et al.Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma.N Engl J Med. 2014; 371: 906-917Crossref PubMed Scopus (601) Google Scholar The risk for infections remains higher during the overall treatment period compared with time not receiving chemotherapy. Therefore, the duration of antibiotic prophylaxis might need to be extended to cover the ongoing risk of infection. Patients in this trial were primarily treated with immunomodulatory imide drug-based or proteasome inhibitor-based drug combinations,3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar but clinicians are moving towards monoclonal antibody-based drug combinations based on the results from the ALCYONE and MAIA studies.5Mateos M-V Dimopoulos MA Cavo M et al.Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma.N Engl J Med. 2018; 378: 518-528Crossref PubMed Scopus (595) Google Scholar, 6Facon T Kumar SK Plesner T et al.Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA).Blood. 2018; 132 (LBA–2.)Google Scholar Grade 3 and grade 4 infections were higher in the daratumumab group than in the non-daratumumab group in both studies. Whether the results from Drayson and colleagues' study can be extrapolated to chemotherapy treatment combinations is unclear. Moreover, it remains to be confirmed whether these results for newly diagnosed patients with myeloma can be generalised to patients with relapsed myeloma. Finally, co-trimoxazole was shown to have an independent effect on both febrile infections and death. The question remains as to whether a combination of both levofloxacin and co-trimoxazole should be recommended for patients on anti-myeloma therapy. Data from the FIRST trial7Facon T Dimopoulos MA Meuleman N et al.A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial.Leukemia. 2019; (published online Aug 19.)DOI:10.1038/s41375-019-0539-0Crossref PubMed Scopus (74) Google Scholar provide criteria for identifying patients at high risk of grade 3 infection. These data have been validated in studies of patients with both relapsed and newly diagnosed myeloma. Therefore, patients who fit these criteria for high risk of grade 3 infection should be considered for antibiotic prophylaxis. Use of antibiotics could increase antibiotic resistance and induce gut dysbiosis. Drayson and colleagues3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar showed that fixed 12-week levofloxacin prophylaxis does not result in increased carriage of Clostridium difficile, extended-spectrum β-lactamase Gram-negative coliforms, or meticillin-resistant Staphylococcus aureus. Whether carriage would increase if prophylaxis was extended for a longer period is unclear. Emerging data suggest a strong link between gut microbiota and host anti-tumour immunity.8Li Y Tinoco R Elmén L et al.Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5−/− mice.Nat Commun. 2019; 101492Crossref PubMed Scopus (72) Google Scholar Immunotherapies show great promise in relapsed myeloma. Longer-term antibiotic prophylaxis-induced dysbiosis has the potential to modify endogenous anti-tumour immunity and efficacy of immunotherapy in patients with myeloma. Patients with myeloma have a high risk of viral infections. Therefore, other supportive measures to limit infections must be considered. Additional measures such as smoking cessation, infusion of intravenous immunoglobulins, pneumococcal vaccination, and seasonal influenza vaccination should also be contemplated. Data from a placebo-controlled, randomised study comparing two doses versus one dose of influenza vaccine showed higher antibody titres with two doses.9Branagan A Duffy E Foster C et al.Two dose series of high-dose influenza vaccine is associated with longer duration of serologic immunity in patients with plasma cell disorders.Blood. 2017; 130: 438Google Scholar We await further data from this study as to whether higher antibody titres translate to clinical benefit. Febrile infections lead to unplanned hospital admissions. Drayson and colleagues3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar report that health economic outcomes were collected in this study and we await these data.3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar A UK-wide study showed that emergency hospital admissions of patients with myeloma have higher health-care resource utilisation.10Kolovos S Nador G Kishore B et al.Unplanned admissions for patients with myeloma in the UK: low frequency but high costs.J Bone Oncol. 2019; 17100243Crossref PubMed Scopus (12) Google Scholar In conclusion, this study is timely in showing that fixed-duration levofloxacin prophylaxis reduces febrile infections and early deaths in patients with myeloma during induction chemotherap y.3Drayson MT Bowcock S Planche T et al.Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.Lancet Oncol. 2019; (published online Oct 23)https://doi.org/10.1016/S1470-2045(19)30506-6Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar However, further trials are required in this area. In particular, assessment of the therapeutic effects of a combination of co-trimoxazole and levofloxacin and investigation of various durations of antibiotic prophylaxis are crucial to optimise patient outcomes. I report research grants, advisory board, and speaker fees from Celgene, Takeda, Janssen, and Amgen, and speaker and advisory board fees from Sanofi, AbbVie, and Oncopeptides, outside the submitted work. Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trialAddition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy. Full-Text PDF Open Access