Secondary immunodeficiency in multiple myeloma can be caused by the underlying disease and/or its treatment

Multiple myeloma (MM) is a largely incurable haematological malignancy that is frequently associated with secondary immunodeficiency (SID).1,2 Patients with MM show many abnormalities of immune function that develop due to the disease itself and/or its treatment, leading to significant morbidity and mortality from infections.3,4

Characteristics of MM include the dysfunctional replication of plasma cells,1,2 production of M-protein1 (an abnormal immunoglobulin*), and disrupted production of normal immunoglobulins.3


SID in MM can result from disease-related changes in humoral and cellular immunity:1-4

Humoral immunity

  • Impaired quantities and functions of B cells2,4
  • Reduced synthesis of normal immunoglobulins3
  • Accelerated catabolism of normal IgG in MM3
  • Hypogammaglobulinaemia3

Cellular immunity

  • Impaired quantities and functions of T cells, dendritic cells and natural killer cells1,2,4
  • Increased number of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs)1

MM treatments can lead to SID and increase the risk and severity of infections.2,4,5


Therapeutic causes of SID in MM: corticosteroids, chemotherapy, immunosuppressive therapies

Class of therapy  Immune dysfunction Infections
Corticosteroids Cellular immunity7
Hypogammaglobulinaemia – decreased naïve and transitional B cells, with no effect on memory B cells7
Increased incidence of infections7
Alkylating agents
e.g. bendamustine
Hypogammaglobulinaemia7 Increased incidence of infections7
Immunomodulatory drugs (IMiDs)
e.g. lenalidomide
Mechanisms unclear5 Incidence of high-grade infections increased two-fold with lenalidomide5
Proteasome inhibitors (PIs)
e.g. bortezomib
Decreased IgG, IgA, and IgM (but not hypogammaglobulinaemia)7 Increased incidence of HZ infection and VZV reactivation7
Anti-CD38 antibody
e.g. daratumumab
Risk of neutropaenia8, with no effect on B cells7 Increased incidence of infections (including VZV)7,8
Anti-SLAMF7/CD319 antibody
e.g. elotuzumab
Lymphopaenia8 Increased risk of infections (particularly VZV)8

Other MM treatments/modes of treatment delivery can also increase the risk of infections:

  • HSCT (neutropaenia, gastrointestinal mucositis)6
  • Central venous catheters6
  • *Also known as paraproteins
  • HSCT: haematopoietic stem cell transplantation; HZ: herpes zoster; IgA: immunoglobulin A; IgG: immunoglobulin G; IgM: immunoglobulin M; VZV: varicella zoster virus.
  • 1. Tamura, H., Int J Hematol. 2018; 107:278-85, 2. Li, L. and Wang, L., J Cancer. 2019; 10:1675-84, 3. Kyrtsonis, M.C. et al., Med Oncol. 1999; 16:73-7, 4. Pratt, G. et al., Br J Haematol. 2007; 138:563-79, 5. Ying, L. et al., Oncotarget. 2017; 8:46593-600, 6. Nucci, M. and Anaissie, E., Clin Infect Dis. 2009; 49:1211-25, 7. Patel, S.Y. et al., Front Immunol. 2019; 10:33, 8. Drgona, L. et al., Clin Microbiol Infect. 2018; 24:S83-94.

Focus on hypogammaglobulinaemia in multiple myeloma

Several MM-associated mechanisms can impact normal immunoglobulin production1, leading to hypogammaglobulinaemia and increasing the susceptibility of MM patients to infection.2

Decreased number and function of B cells1

  • Suppression of B cell progenitors, possibly due to attrition of the normal plasma cell and B cell progenitor compartments
  • Increased apoptosis of B cell progenitors due to interaction of myeloma cells with stromal cells
  • Abnormal B cell maturation due to a number of factors, e.g. an increased number of immunosuppressive CD5+ B cells

Immunosuppressive cytokines1

  • IL-4, a cytokine important for the induction of normal B cell responses, is decreased in MM

Altered T cell numbers, phenotype and function1

  • Disrupted T cell cytokine production may affect the proliferation and differentiation of B cells

Increased catabolism of IgG1

  • of both normal and clonal IgGThe catabolism of IgG is directly proportional to its concentration, leading to a 2-fold increase in the catabolic rate
  • The catabolic rate of other Ig classes is not affected
  • IL: interleukin; TGF: transforming growth factor.
  • 1. Kyrtsonis, M.C. et al., Med Oncol. 1999; 16:73-7, 2. Pratt, G. et al., Br J Haematol. 2007; 138:563-79.

Epidemiology and clinical predictors of infection in multiple myeloma patients

Changes in patterns of and risk factors for infection have been observed in patients with MM with the shift to routine usage of treatments that impact the immune system, such as IMiDs and PIs. In an Australian single-centre study, patients with MM receiving standard of care were investigated to better understand the epidemiology (types, severity, and timing of infections) and clinical predictors of infection.

A total of 199 MM patients diagnosed in 2008–2012 were followed for a median of 33 months. During this period, a total of 771 episodes of infection were recorded, with 32% of patients having ≥ 5 infections. The overall incidence of infection was 1.33 per patient-year. Incidences of bacterial and viral infections had bimodal distributions, with bacterial infections peaking at 4–6 and 70–72 months, and viral infections peaking at 7–9 and 52–54 months after MM diagnosis.


Frequency of infections in patients with MM (N = 199)

Frequency of infections in patients with MM (N = 199)

Baseline treatment characteristics of 199 MM patients

As initial induction regimen, 38.7% were thalidomide-based, 26.1% lenalidomide-based,18.6% bortezomib-based, 15.1% chemotherapy-based, and 2.0% were classified as "other"

For stem cell transplantation, 78.9% of the patients received an ASCT*, 2.5% an alloHCT† and 18.6% did not receive any stem cell transplant

Of a total of 771 episodes of infection:

  • 43.7% were clinically defined
  • 36.4% were microbiologically defined (54.1% bacterial, 40.2% viral and 5.7% fungal)
  • 19.8% were fever of unknown origin

Most infections during ASCT were high severity (93.3%). During induction and disease progression, high severity infections comprised 57.5% and 62.2% of all infections, respectively. The majority of infections during the plateau period were low severity (80.4%).

Nature of infections

Nature of infections

Severity of infections

Severity of infections

The nature and severity of 771 infections were assessed across different disease periods in 199 MM patients

Disease periods were defined as following:

  • Induction: from initial diagnosis to receipt of 4–6 cycles of induction chemotherapy
  • ASCT: from receipt of chemotherapy for stem cell mobilisation to day 30 following re-infusion of stem cells
  • Plateau: stable paraprotein levels with or without maintenance treatment
  • Progression: any period of increasing myeloma burden despite active anti-myeloma treatment and necessitating a change of therapy

Severity of infections was graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

Using conditional risk set modelling, specific therapies independently associated with increased risk of infection in MM patients were identified:

  • High-dose melphalan
  • Intravenous cyclophosphamide
  • Intensive combination systemic chemotherapy
  • Cumulative doses of corticosteroid over 2 months
  • *23 (11.6%) patients had 2 ASCTs, 2 (1.0%) patients had 3 ASCTs; †5 (2.5%) patients had ASCT prior to alloHCT.
  • ‡Regimens include vincristine-doxorubicin-dexamethasone and dexamethasone-doxorubicin-cyclophosphamide-etoposide ± thalidomide or lenalidomide. alloHCT: allogeneic haematopoietic stem cell transplant; ASCT: autologous haematopoietic stem cell transplant; CDI: clinically defined infections; FUF: fever of unknown focus; MDI: microbiologically defined infections.
  • Teh, B.W. et al., Br J Haematol. 2015; 171:100-8.

Early mortality after diagnosis of multiple myeloma

While introduction of new treatment approaches has improved the survival time of MM patients,1

many deaths still occur soon after diagnosis, before patients have time to reach the maximal benefit of these treatments.

A retrospective assessment of 3,107 newly diagnosed patients who were registered in five UK Medical Research Council MM trials (1980–2002) was performed to identify the direct and contributing causes of early deaths in MM.2
Early death (defined as within 60 days of trial entry) occurred in 299 (10%) patients.2


Cause of early death in MM2

Cause of early death in MM2

Bacterial infection was the direct cause of early mortality in 45% of deaths, with pneumonia being the most common.2

Types of fatal bacterial infections (n = 135)2

Types of fatal bacterial infections (n = 135)2
  • 1. Tamura, H., Int J Hematol. 2018; 107:278-85, 2. Augustson, B.M. et al., J Clin Oncol. 2005; 23:9219-26.

Infections are a substantial cause of death in multiple myeloma

To estimate the risk of infection and infection-related deaths in MM patients, a study of the nationwide Swedish Cancer Registry evaluated 9,253 patients diagnosed with MM from 1988 to 2004 with follow-up until 2007.

MM patients had a significant 7-fold increased risk of developing any infection vs matched controls* in the overall follow-up period (HR: 7.1; 95%CI: 6.8–7.4), with an even higher relative risk (11-fold) during the first year following diagnosis (HR: 11.5; 95%CI: 10.4–12.7). Infection risk in MM patients increased significantly with more recent calendar period of diagnosis†, potentially due to modern therapies.


Relative risk for bacterial and viral infection in MM patients compared with matched controls

Relative risk for bacterial and viral infection in MM patients compared with matched controls

Risks of infections in MM patients vs matched controls were determined for the first year following diagnosis and for overall follow-up.

Individual HRs for the following bacterial infections were: meningitis (HR 16.6), septicaemia (HR 15.6), pneumonia (HR 7.7), endocarditis (HR 5.3), osteomyelitis (HR 3.5), cellulitis (HR 3.0) and pyelonephritis (HR 2.9); for viral infections: herpes zoster (HR 14.8) and influenza (HR 6.1).

Of 2474 deaths that occurred within 1 year of MM diagnosis, 555 (22.4%) were due to infections. The 3-year risk of death due to infection was 12.2% in MM patients vs 2.2% in matched controls. The risk of infection-related death did not differ between age groups (> 65 and ≤ 65 years) over the three calendar periods of diagnosis.


Deaths within 1 year of MM diagnosis (N = 2474)

Deaths within 1 year of MM diagnosis (N = 2474)
  • *Matched controls (N=34,931) were of the same sex, age and county of residence, and were alive and without previous haematologic malignancy at the diagnosis date of the corresponding MM patient.
  • † Patients were stratified by three periods reflecting different treatment strategies (1988–1993, 1994–1999 and 2000–2004)
  • CI: confidence interval; HR: hazard ratio.
  • Blimark, C. et al., Haematologica. 2015; 100:107-13.

Impaired response to immunisation in multiple myeloma is associated with increased risk of a major infection

Response to immunisation in plateau-phase MM patients may identify those at risk of infection.1

A prospective study in the UK followed 102 patients with MM for a mean duration of 10 months.1 Patients in plateau phase were immunised with Pneumovax II (n = 40)1,a pneumococcal polysaccharide vaccine.#2 Patients were classified by their immune response.*1

MM patients with a poor/intermediate immunisation response to Pneumovax II had a higher frequency of septicaemia.1

Incidence of septicaemia in MM patients in plateau phase (n = 40)1

Incidence of septicaemia in MM patients in plateau phase (n = 40)1

Of the 18 patients who showed a good response to immunisation, none had a septicaemic episode recorded since diagnosis of MM.

Of the 22 patients with a poor/intermediate immunisation response, 22.7% of patients had a septicaemic episode recorded since diagnosis of MM

  • # Pneumovax II is a pneumococcal polysaccharide vaccine recommended for immunisation against disease caused by pneumococcal serotypes contained in the vaccine. *Immunisation responses, based on differences between pre- and post-immunisation IgG titres, were classified as: Good: ≥ 2-fold increase of specific IgG titres as well as the post-immunisation titre reaching the minimum of the normal range for age (calculated from the baseline results obtained in the control population); Poor: no difference between pre- and post-immunisation titres; Intermediate: inadequate response for inclusion in the good response group.
  • 1. Hargreaves, R. M., et al., J Clin Pathol. 1995; 48:260-6, 2. UK Medicines and Healthcare products Regulatory Agency, 2014, available at:

Management of infectious complications in multiple myeloma: Summary of expert recommendations

With the advent of new treatment approaches for MM and their impact on the immune system, there remains a need to determine the appropriate approaches to prophylaxis and treatment for infections. While data are lacking on certain topics, an expert panel published consensus recommendations based on their experience and available data on how to manage infectious complications in MM patients.

Summary of recommendations for assessment of infection risk:

  • Careful evaluation of performance status and past medical history (especially infections that can reactivate) before initiating first-line therapy
  • Quantitative evaluation of serum polyclonal immunoglobulins, absolute lymphocyte count, and absolute neutrophil count to help define the individual risk of infections
  • Information on recent vaccination history to define the pre-treatment vaccination schedule
  • HBV and HCV screening in all patients requiring active treatment
  • Colonisation screening (rectal swab culture to detect colonisation by MDR Gram negative bacteria) in hospitalised candidates for ASCT and in those undergoing intensive salvage therapy
  • Severe active infections (i.e. pneumonia, herpes zoster, HBV- or HCV-related hepatitis, CMV disease, tuberculosis) or uncontrolled HIV-disease contraindicate active therapies in MM until their complete resolution or control
  • CMV: cytomegalovirus; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; MDR: multidrug-resistant
  • Girmenia, C. et al., Blood Rev. 2019; 34:84-94.

Recommendations for intravenous immunoglobulin replacement therapy

  • IVIG is not recommended routinely for patients with MM
  • The use of IVIG may be reserved for patients with very low IgG levels (< 0.4 g/L) and recurrent life-threatening infections
  • ASCT: autologous haematopoietic stem cell transplant; CMV: cytomegalovirus; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; IVIG: intravenous immunoglobulin; MDR: multidrug-resistant.
  • Girmenia, C. et al., Blood Rev. 2019; 34:84-94.

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