LETTERS TO THE EDITOR

Table 1. Overall characteristics of patients with myeloma (2009 to

Invasive fungal infections in patients with multiple 2011).
myeloma: a multi-center study in the era of novel Patients’ Overall PMCC AH
myeloma therapies characteristics n=372 (%) n=251 (%) n=121 (%)
Age (median; IQR): years 65 64 67
Multiple myeloma (MM) is a hematologic malignancy (58-72) (56 -71) (59-75)
with increasing prevalence in older populations.1 Gender:
Infections, particularly pyogenic infections and reactivation Male 226 (61) 148 (59) 78 (64)
of latent viral infections,2 are a leading cause of morbidity Female 146 (39) 103 (41) 43 (36)
and mortality in patients with MM. Previously, invasive
aspergillosis (IA) had been found to be a significant oppor- Treatment received:
tunistic infection in patients with myeloma managed with Immunomodulatory drug 316 (85) 225 (90) 91(75)
intensive conventional combination chemotherapeutic reg- Bortezomib 93 (25) 63 (25) 30 (25)
imens with nearly 50% attributable mortality. IA tended to ASCT 135 (36) 101 (40) 34 (28)
occur early in the treatment course in patients with higher Anti-fungal prophylaxis:
disease stage.3 However, the treatment of myeloma has Fluconazole 118 (32) 103 (41) 15 (12)
undergone a paradigm shift with the use of immunomodu- Mold active agent# 6* (2) 6 (2) 0 (0)
latory drugs (IMiDs), proteasome inhibitors (PI) and autol- Invasive fungal infection: n = 9 (%) n = 7 (%) n = 2 (%)
ogous hematopoietic stem cell transplant (ASCT) as the Proven 3 (33) 3 (43) 0 (0)
new standard of care. Probable 2 (22) 2 (29) 0 (0)
The epidemiology and outcomes of invasive fungal infec- Possible 4 (44) 2 (29) 2 (100)
tions (IFI) are well defined in other hematology popula-
tions, and are supported by guidelines for antifungal pro-
PMCC: Peter MacCallum Cancer Centre; AH: Austin Hospital. #Mold active agents
phylaxis.4 However, the disease burden and characteristics include voriconazole, posaconazole and liposomal amphotericin. *Of the 6 patients
of IFI in patients with MM in the era of novel agents have who received mold active antifungal prophylaxis, 2 received posaconazole following
not been previously reported. In addition, the contribution allogeneic stem cell transplant and 4 received mold-active agent (voriconazole,
and impact of these novel agents and early use of ASCT on posaconazole) due to previous isolation of Aspergillus sp. in sputum and multiple
lines of previous therapy (median = 3).
risk of IFI is uncertain. Therefore, our study aimed to define
the role of antifungal prophylaxis, the epidemiology, risk
factors and outcomes of IFI in patients with MM receiving
novel agents. relapses.5 IFI was defined and classified according to the
The study was conducted at the Peter MacCallum European Organisation for Research and Treatment of
Cancer Centre (PMCC) and Austin Hospital (AH) which Cancer (EORTC)/Mycoses Study Group (MSG) criteria.6
are tertiary referral centers for MM in Victoria, Australia. We received approval from human research ethics commit-
All patients with MM and an IFI managed at both centers tees at both institutions.
from January 2009 to December 2011 were identified ret- Overall 372 patients received treatment for MM at both
rospectively from electronic medical management and dis- centers and were followed for a median of 24 months. Nine
charge records, antimicrobial restricted approval and phar- patients (2.4%) were diagnosed with 9 episodes of IFI: 3
macy dispensing systems and included in this study. were proven, 2 probable and 4 possible according to
Clinical, microbiology and radiology records of the identi- EORTC/MSG criteria. Rates of invasive mold infection and
fied patients were further reviewed using a standardized IA were 0.8% (3 of 372) and 0.3% (1 of 372), respectively.
tool to capture the following: patient demographics, The IFI rate was 2.2% (3 of 135) following ASCT and 2.5%
myeloma type, stage and treatment received (number of (6 of 237) for patients who had not received an ASCT. The
treatment cycles, lines of therapy), known predispositions rate of IFI in patients who received 3 lines or more of ther-
for IFI (neutropenia, receipt of corticosteroids or apy was 15.0%. Patients' characteristics are shown in Table
chemotherapy), use of antifungal prophylaxis, clinical fea- 1.
tures, type and site of IFI, antifungal treatment received and Patients with an IFI had a median age of 62 (IQR, 59-64)
outcomes (need for intensive care management and all- years and were predominantly male (6 of 9). A majority of
cause mortality at 30 days). patients (6 of 9) were International Staging System stage 1
During the study period, patients with MM received at myeloma diagnosis. Most IFI episodes (8 of 9) occurred
treatment consistent with prevailing international practices with myeloma progression (n=5) or after a second or third
including the use of IMiDs, (lenalidomide or thalidomide) autograft (n=3) at a median of 35 (26-60) months following
and/or PI (bortezomib) in combination with corticos- initial disease diagnosis after having received a median of 5
teroids. Fluconazole prophylaxis was routinely used for the lines of therapy. Predisposing factors for IFI were present in
period of ASCT (up to 3 months post transplant) for all the majority of instances: neutropenia less than 0.5x109/L
patients at PMCC and in patients with past and/or expect- for ten days or more temporally related to onset of an IFI (8
ed history of mucositis at AH during the period of neu- of 9 cases), corticosteroid therapy (≥0.5 mg/kg/day of pred-
tropenia. Patients suspected of having an IFI or with per- nisolone equivalent over 4 weeks in 3 of 9), and T-cell sup-
sistent febrile neutropenia with unclear source were inves- pressive chemotherapy prior to diagnosis of IFI (6 of 9).
tigated with high-resolution computer tomography (CT) of The sites of involvement were pulmonary (6 of 9) and
the chest and sinuses or position emission tomography-CT disseminated (3 of 9). Isolated fungal pathogens included
scan followed by directed tissue sampling for microscopy Candida albicans, Candida parapsilosis, Scedosporium prolifi-
and fungal culture. Molecular testing with Aspergillus poly- cans (proven), Aspergillus fumigatus, and Scopulariopsis sp.
merase chain reaction and galactomannan testing on serum (probable). All patients with an IFI received antifungal
and BAL were routinely used at PMCC. A line of therapy treatment. The majority of episodes 5 of 9 (55.6%) (2
as defined by the International Myeloma Workshop con- proven, one probable and 2 possible) required management
sensus panel recommendations was used to provide an in the intensive care unit and overall 30-day all-cause mor-
estimate of disease burden, treatment and number of tality was (4 of 9) 44.4%. Characteristics of IFI episodes and

haematologica 2015; 100:e28

 LETTERS TO THE EDITOR
outcomes are summarized in Table 2. Univariate and mul- lack of use of mold-active prophylaxis (2%), the rates of
tivariate regression analysis of risk factors was performed invasive mold infection and IA in this study (0.8% and
using IFI as the evaluable outcome. Univariate analysis 0.3%, respectively) are comparable to rates reported in
demonstrated that receipt of bortezomib (P=0.01) and 3 or other studies of MM patients during the last decade (0.5%-
more lines of therapy for MM (P<0.01) were associated 0.7%).7,8 The use of fluconazole prophylaxis in the study
with IFI (Table 3). Multivariate logistic regression analysis was consistent with Australian antifungal guidelines.4 In
demonstrated that receipt of 3 or more lines of therapy this context, our IFI rate of 2.2% following ASCT remains
within three years was independently associated with an within the anticipated range expected following ASCT for
increased risk of IFI (P=0.02) (Table 3). patients with other hematologic malignancies.9,10 The
In our study, we observed an overall low IFI rate of 2.4% uptake of a diagnostic driven approach to persistent neu-
with an invasive mold infection rate of 0.8%. Despite the tropenic fever following ASCT does not appear to have led

Table 2. Clinical features and outcomes of patients with myeloma and an invasive fungal infection.
Pt. Disease N. of Treatment AF EORTC/ Prolonged High- Clinical Site of Microbiology Treatment Outcome
n. status lines regimen prophylaxis MSG neutropenia dose presentation infection Results
of prior prior to IFI steroids
therapy to IFI
1 Progression 6 DTPACE Fluconazole Proven Yes Yes Febrile Sinus Blood culture: Liposomal Death
neutropenia Scedosporium amphotericin from
prolificans disseminated
infection
2 Progression 5 Melphalan Fluconazole Proven Yes No Febrile Not Blood culture: Caspofungin Survived
neutropenia applicable Candida followed by past
following parapsilosis voriconazole 30 days
second ASCT for
progressive disease
3 Progression 5 Bortez and None Proven No No Persistent Not Blood culture: Caspofungin Death
romi fevers applicable Candida from
Respiratory albicans respiratory
failure from concurrent failure
influenza A infection
4 Progression 3 DVPACE Fluconazole Probable Yes Yes Persistent Chest BAL: Caspofungin Death
fever Scopulariopsis and from
Respiratory sp. voriconazole respiratory
symptoms failure
5 Progression 6 Melphalan Fluconazole Probable Yes No Persistent fever Chest BAL: Voriconazole Survived
Respiratory symptoms Aspergillus followed by past 30
following third ASCT for fumigatus posaconazole days
progressive disease
6 Progression 5 Cyclop and None Possible Yes No Persistent HRCT: BAL: Culture Voriconazole Survived
bortez febrile nodules negative past 30
neutropenia in upper days
lobe
7 Induction 1 Len and None Possible Yes Yes Febrile HRCT: BAL: Culture Voriconazole Survived
dex neutropenia multiple negative; past 30
Respiratory cavitatory Aspergillus days
symptoms nodules PCR positive

8 Progression 4 Melphalan None Possible Yes No Febrile HRCT: BAL: Culture Posaconazole Survived
neutropenia Right negative past 30
following middle days
second ASCT lobe
for progressive nodules
disease
9 Progression 2 Len None Possible Yes No Febrile with HRCT: BAL: Culture Posaconazole Death
evolving skin multiple negative followed by from
lesions for scattered liposomal disseminated
investigation nodules amphotericin bacterial
infection

AF: antifungal; IFI: invasive fungal infection; EORTC: European Organization for Research and Ttreatment of Cancer; MSG: Mycology Study Group; ASCT: autologous hematopoietic stem
cell transplantation; HRCT: high-resolution computer tomography; BAL: broncho-alveolar lavage DTPACE: dexamethasone-thalidomide-cisplatin-doxorubicin-cyclophosphamide and
etoposide; DVPACE: dexamethasone-bortezomib-cisplatin-doxorubicin-cyclophosphamide and etoposide; Bortez and romi: bortezomib and romidepsin; cyclo: cyclophosphamide; len and
dex: lenalidomide and dexamethasone.

haematologica 2015; 100:e29

LETTERS TO THE EDITOR

Table 3. Impact of multiple myeloma treatment factors on risk of developing invasive fungal infection.
Univariate Multivariate*
Variable Number with an IFI Number of patients OR P OR P
(95% CI) (95% CI)
Age ≤ 65 years 7 188 3.48 0.12 2.60 0.25
Age > 65 years 2 184 (0.71-16.98) (0.50-13.48)
Receipt of AF prophylaxis 4 122 1.66 0.46
No AF prophylaxis 5 250 (0.44-6.30)
< 3 lines of therapy 3 332 19.35 <0.01 15.08 0.02
≥ 3 lines of therapy 6 40 (4.63-80.88) (1.64-138.30)
ASCT 3 135 1.13 0.87
No ASCT 6 237 (0.28-4.59)
Received bortezomib 6 93 6.34 0.01 0.93 0.95
No bortezomib 3 279 (1.55-25.90) (0.10-8.77)
< 10 cycles of treatment 3 235 3.54 0.08 1.88 0.42
≥ 10 cycles of treatment 6 137 (0.87-14.39) (0.41-8.68)
IFI: invasive fungal infection; OR: odds ratio; CI: confidence interval; AF: anti-fungal; ASCT: autologous hematopoietic stem cell transplant. *Covariates were included in the
model if univariate analysis demonstrated P<0.20. All analyses were performed using Stata (v.9.0, StataCorp Inc., Texas, USA) and P≤0.05 was considered statistically signifi-
cant.

to a higher IA rate through increased detection in our study and IA, including following ASCT, remain low. This is in
in comparison to other centers using a similar approach.11 the context of fluconazole prophylaxis during ASCT, over-
We observed that IFI occurred mostly during the period all low use of mold-active prophylaxis and diagnostic driv-
of disease progression (85.7%) with a median of 35 months en strategies for neutropenic fever. It appears cumulative
between initial myeloma diagnosis and an episode of IFI treatment exposure and disease burden (≥ 3 lines of therapy
and a median of 5 lines of treatment. This is in contrast to in 3 years) is a greater determinant of IFI risk than type of
older studies where a much earlier onset of IFI had been individual therapy. Therefore, a high-risk group has been
reported.3,8 This shift could be because IMiDs and PI are identified which could benefit from mold-active prophylax-
inherently less myelosuppressive compared with conven- is or enhanced surveillance for IFI.
tional chemotherapy which now tends to be used in com-
bination for patients with refractory or progressive dis- Benjamin W. Teh,1,2 Jasmine C. Teng,3 Karin Urbancic,4
ease.12 Cumulative deficits in various arms of the immune Andrew Grigg,5 Simon J. Harrison,2,6 Leon J. Worth,1,7
system, in particular of cell-mediated immunity due to pro- Monica A. Slavin,1,7,8 and Karin A. Thursky1,7,8
gressive disease, could also account for our findings.2
The impact of novel agents and use of ASCT on risk of 1
Department of Infectious Diseases, Peter MacCallum Cancer
IFI has not been previously evaluated. In our study, the type Centre, East Melbourne; 2Sir Peter MacCallum Department of
of treatment, including receipt of ASCT and bortezomib Oncology, University of Melbourne; 3Department of Infectious
did not appear to be independently associated with risk of Diseases, St Vincent’s Hospital Melbourne, Fitzroy; 4Department of
developing an IFI. However, the number of lines of therapy Pharmacy, Austin Hospital, Heidelberg; 5Department of Haematology,
was significantly associated with an increased risk of devel- Austin Hospital, Heidelberg; 6Department of Haematology, Peter
oping an IFI. With 3 or more lines of therapy, the IFI rate MacCallum Cancer Centre, East Melbourne; 7Department of
was 15.0%, which would warrant consideration of antifun- Medicine, University of Melbourne; and 8Victorian Infectious Diseases
gal prophylaxis or surveillance. This finding suggests cumu- Service, Peter Doherty Institute for Infection and Immunity, Parkville,
lative exposure to immunosuppressive treatment and dis- Australia
ease burden is a greater determinant of IFI risk than type of
individual therapy. Correspondence: ben.teh@petermac.org
Mortality rates of up to 60% were reported in the earlier doi:10.3324/haematol.2014.114025
era of conventional therapy.3 IFI in our patients was still Funding: Dr. Benjamin W. Teh is supported by a National Health
associated with significant morbidity and mortality with and Medical Research Council Postgraduate scholarship.
nearly 60% of episodes requiring ICU management and a Key words: fungal infection, myeloma, novel agents.
30-day all-cause mortality rate of 44%. These outcomes
Information on authorship, contributions, and financial & other disclo-
underscore the need for improvement in early diagnosis
sures was provided by the authors and is available with the online version
and treatment.
of this article at www.haematologica.org.
Our study has several limitations. Intensity of diagnostic
evaluation for IFI was determined by the treating physician,
which may have resulted in selection bias favoring diagno- References
sis of IFI in symptomatic and unwell patients. Although the
number of detected cases of IFI was limited, these were 1. Turesson I, Velez R, Kristinsson SY, Landgren O, editors. Patterns of
drawn from a large heterogeneously treated myeloma multiple myeloma during the past 5 decades: stable incidence rates
patient population and our data have allowed us to define for all age groups in the population but rapidly changing age distribu-
tion in the clinic. Mayo Clin Proc; 2010: Elsevier.
the relationship between antifungal prophylaxis, IFI and
2. Teh BW, Harrison SJ, Pellegrini M, Thursky KA, Worth LJ, Slavin
outcomes. MA. Changing treatment paradigms for patients with plasma cell
In our dedicated study of IFI in patients with MM, the myeloma: impact upon immune determinants of infection. Blood
first in the era of novel anti-myeloma agents, rates of IFI Rev. 2014;28(2):75-86.

haematologica 2015; 100:e30

 LETTERS TO THE EDITOR

3. Lortholary O, Ascioglu S, Moreau P, Herbrecht R, Marinus A, 2014;55(8):1844-8.

Casassus P, et al. Invasive aspergillosis as an opportunistic infection 8. Pagano L, Caira M, Candoni A, Offidani M, Fianchi L, Martino B, et
in nonallografted patients with multiple myeloma: a European al. The epidemiology of fungal infections in patients with hemato-
Organization for Research and Treatment of Cancer/ Invasive Fungal
logic malignancies: the SEIFEM-2004 study. Haematologica.
Infections Cooperative Group and the Intergroupe Francais du
Myelome. Clin Infect Dis. 2000;30(1):41-6. 2006;91(8):1068-75.
4. Slavin MA, Heath CH, Thursky KA, Morrissey CO, Szer J, Ling LM, 9. Cornet M, Fleury L, Maslo C, Bernard JF, Brucker G, Invasive
et al. Antifungal prophylaxis in adult stem cell transplantation and Aspergillosis Surveillance Network of the Assistance Publique-
haematological malignancy. Intern Med J. 2008;38(6b):468-76. Hopitaux de P. Epidemiology of invasive aspergillosis in France: a six-
5. Rajkumar SV, Harousseau JL, Durie B, Anderson KC, Dimopoulos M, year multicentric survey in the Greater Paris area. J Hosp Infect.
Kyle R, et al. Consensus recommendations for the uniform reporting 2002;51(4):288-96.
of clinical trials: report of the International Myeloma Workshop
Consensus Panel 1. Blood. 2011;117(18):4691-5. 10. Jantunen E, Salonen J, Juvonen E, Koivunen E, Siitonen T, Lehtinen T,
6. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, Edwards JE, et al. Invasive fungal infections in autologous stem cell transplant
Calandra T, et al. Revised definitions of invasive fungal disease from recipients: a nation-wide study of 1188 transplanted patients. Eur J
the European Organization for Research and Treatment of Haematol. 2004;73(3):174-8.
Cancer/Invasive Fungal Infections Cooperative Group and the 11. Gil L, Kozlowska-Skrzypczak M, Mol A, Poplawski D, Styczynski J,
National Institute of Allergy and Infectious Diseases Mycoses Study Komarnicki M. Increased risk for invasive aspergillosis in patients
Group (EORTC/MSG) Consensus Group. Clin Infect Dis.
with lymphoproliferative diseases after autologous hematopoietic
2008;46(12):1813-21.
7. Nosari AM, Pioltelli ML, Riva M, Marbello L, Nichelatti M, Greco A, SCT. Bone Marrow Transplant. 2009;43(2):121-6.
et al. Invasive fungal infections in lymphoproliferative disorders: a 12. Andhavarapu S, Roy V. Immunomodulatory drugs in multiple
monocentric retrospective experience. Leuk Lymphoma. myeloma. Expert Rev Hematol. 2013;6(1):69-82.

haematologica 2015; 100:e31