Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia: a randomized trial

Accepted Manuscript Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia

Angelo Vacca, Carolina Marasco, Assunta Melaccio, Azzurra Sportelli, Ilaria Saltarella, Antonio Solimando, Franco Dammacco, Roberto Ria PII: DOI: Reference:

S1521-6616(17)30633-2 doi:10.1016/j.clim.2017.11.014 YCLIM 7975

To appear in:

Clinical Immunology

Received date: Revised date: Accepted date:

26 August 2017 13 October 2017 27 November 2017

Please cite this article as: Angelo Vacca, Carolina Marasco, Assunta Melaccio, Azzurra Sportelli, Ilaria Saltarella, Antonio Solimando, Franco Dammacco, Roberto Ria , Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yclim(2017), doi:10.1016/ j.clim.2017.11.014

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ACCEPTED MANUSCRIPT SUBCUTANEOUS IMMUNOGLOBULINS IN PATIENTS WITH MULTIPLE MYELOMA AND SECONDARY HYPOGAMMAGLOBULINEMIA Angelo Vacca, Carolina Marasco, Assunta Melaccio, Azzurra Sportelli, Ilaria Saltarella, Antonio Solimando, Franco Dammacco, Roberto Ria Department of Biomedical Sciences and Human Oncology, Section of In ternal Medicine and Clinical On cology,

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Correspondence: Prof. Roberto Ria, M.D., Department of Internal Medicine and Clinical Oncology, University of Bari “Aldo Moro” Medical School, Policlinico – Piazza Giulio Cesare, 11 I-70124 BARI (Italy) Phone: +39-080-559.31.06 Fax: +39-080-559.31.06 e-mail: [email protected]

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University of Bari “Aldo Moro” Medical School, Bari, Italy

ACCEPTED MANUSCRIPT ABSTRACT Multiple myeloma is commonly associated with a reduction of non-paraprotein immunoglobulins, resulting in a higher risk of infections that represent the leading cause of the patients’ death. Therefor e, immunoglobulin replacement therapy appears a logical approach. A total number of 46 myeloma patients were enrolled: 24 of them were assigned to r eceive subcutaneous immunoglobulins, and 22 were controls. The primary endpoint was the evaluation of the annual rate of severe

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infections in immunoglobulins-receiving patients as compared with those untreated. Subcutaneous immunoglobulins-

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treated patients showed a significantly lower number of sever e infections per year. Adverse events were limited to the site of infusion and were easily manageable. Health-related quality of life was significantly better in subcutaneous immunoglobulins-receiving patients.

By decreasing the rate of infections, the prophylactic administration of SCIg improves both adherence to

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chemotherapy and health-related quality of life, and is cost-effective by reducing the need of hospitalization and the

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use of antibiotics.

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Keywords: hypogammaglobulinemia; infections; multiple myeloma; quality of life; subcutaneous immunoglobulin.

Highlights

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Immune dysfunction is an important feature of multiple myeloma. Immune dysfunction leads to infections that are the major cause of mortality. Subcutaneous immunoglobulins are safe also during active phase of disease. Less infections in subcutaneous immunoglobulins-treating patients are evidenced.

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1. Introduction Multiple myeloma (MM) is a malignant plasma cell tumor that, in spite of the r emarkable improvement of its prognosis following the introduction of effective anti-angiogenic and immunomodulatory drugs, still remains incurable [1]. Immune dysfunction is an important feature of the disease and frequently leads to infectious complications that

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are the major cause of morbidity and mortality [2].

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A number of immune defects have been described in MM patients, due to production of a wide range of soluble factors in the bone marrow microenvironment, that make the same environment immunosuppressive [3]. In particular, dendritic cell dysfunction, impaired co-stimulatory pathways, and quantitative, phenotypic and functional abnormalities in T cells, B cells and NK cells have been reported in these patients [3]. The major immune defects

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associated with infections are a reduction in the serum levels of polyclonal immunoglobulins (Ig) and the failure to synthesize a suitable antibody response following immunization [4]. The impairment of the antibody-synthesizing

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property is related neither to the presence or absence of a serum M-component, nor to the extent of disease, and the rate of infections has been found to be consistently elevated (compared to controls) throughout the course of the disease, the highest prevalence occurring during the first year following diagnosis. Moreover, the risk of infections has

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increased in recent years; this observation can possibly be explained by the fact that the novel agents, through their

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effect on the patients’ immune system, increase their susceptibility to infections [5]. A randomized, double-blind, placebo-controlled, multicenter trial of intravenous immunoglobulins (IVIg),

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employed as prophylaxis against infections and carried out in 82 MM patients in plateau-phase [6], showed a protective role of IVIg against life-threatening infections, and resulted in a reduced risk of recurrent infections. In

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addition, a Cochrane review [7] suggested that the use of prophylactic IVIg in patients with hypogammaglobulinemia secondary to chronic lymphocytic leukemia (CLL) or MM, who experienced recurrent infections, significantly decreased the rate of infections and the use of antibiotics, thus resulting in a lower need of hospitalization and a lower number of working days lost. Conversely, Blombery et al. [8] showed that the administration of peri-transplant IVIg resulted in no benefit, in terms of reduced infectious complications, in hypogammaglobulinemic MM patients undergoing autologous stem cell transplantation. In addition, compared to patients receiving placebo, those given IVIg showed a higher rate of adverse events [7]. These observations are consistent with the recommendations stemmed from the NIH consensus conference [9] which indicated that, although the use of IVIg is useful in secondary immunodeficiency for the

ACCEPTED MANUSCRIPT prevention of moderate to severe infections, their use is not devoid of adverse events, thus emphasizing the importance of surveillance for long-term adverse events. Subcutaneous Ig (SCIg) have been shown to be safe, cost-effective and compatible with health-related quality of life (HRQoL) [10-12] in patients with primary immunodeficiencies. Additional advantages of SCIg include the possibility for the patient to self-administer the preparations at home, no need of systemic pre-medication, their gradual

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usually mild and do not affect the good tolerability of the treatment [15].

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absorption with slower catabolism and a decreased incidence of systemic adverse events [13, 14]. Local reactions are

In this study, we evaluated the efficacy, safety and HRQoL of a 20% SCIg preparation in a cohort of MM patients with secondary hypogammaglobulinemia. Our data demonstrate that SCIg are an effective and valuable replacement

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treatment in MM patients with secondary Ig defects.

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2. Patients and methods

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2.1 Patients

Forty-six consecutive patients (25 males and 21 females) with MM and secondary hypogammaglobulinemia

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were randomly included in the arm-A (24 patients who wer e given SCIg) or arm-B (22 patients who did not rec eive SCIg and were used as controls) of the present study (Table 1). The following inclusion criteria were established: a)

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diagnosis of MM confirmed by CRAB criteria [16]; b) patients’ age >18 years; c) serum level of normal (nonparaprotein) IgG <500 mg/dL; d) life expectancy >1 year; e) verified ability of SCIg administration at home after

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adequate hospital training to the patient and/or his/her relatives; f) signature of a detailed informed consent form. Exclusion criteria were: a) other causes of immunodeficiency; b) active HCV, and/or HBV, and/or HIV infection; c) difficulties to proceed with home infusions. The study, which was carried out according to the Helsinki Declaration, was approved by the local Ethical Committee.

2.2 Study design

In this prospective, controlled, randomized study, all patients, after signing the informed consent form, underwent a baseline visit and a series of laboratory tests. Follow-up clinical and laboratory data were collected

ACCEPTED MANUSCRIPT monthly. Patients of both arms were asked to refer to our center in case of occurrence of febrile or overt infectious episodes. In patients with IgG MM, serum normal IgG levels were deter mined in arm-A patients with the Hevylite™ assay and the calculation of the Ig heavy/light chain ratio [17] monthly, on the day before the date established for the next SCIg infusion.

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2.3 Dosages and infusion rates

Arm-A patients received a monthly total dose of 0.4 to 0.8 g SCIg/Kg body weight (Hizentra® 200 mg/ml, CSL Behring, Milan, Italy), divided into four weekly infusions to maintain the serum levels of normal IgG above 500 mg/dL. The dosage and frequency of injections were adjusted according to trough nor mal IgG levels. SCIg were infused in the

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subcutaneous of the abdomen or the anterior surface of the thigh (as preferred by the patient), using a suitable infusion pump. The number and location of injection sites were established based on the volume of the total dose.

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The preparation was infused into a maximum of 4 sites simultaneously, at least 3 cm apart, and changing the site of injection with each weekly administration. For the first infusion, a volume of 15 mL per injection site was used, that was increased to 20 mL per site after the fourth infusion and to a maximum of 25 mL per site, if tolerated. The flow

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rate of 15 mL per hour per site was not exceeded for the first infusion, whereas it was increased to a maximum of 25 mL per hour per site according to tolerance in the subsequent infusions. The maximum flow rate did not exceed 50 mL

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per hour for all sites combined at any time.

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2.4 Primary and secondary endpoints

The primary endpoint was the annual rate of severe infections. The diagnosis of infection required the occurrence of at least two of the following features: a) a body temperature >37°C for at least three days; b) symptoms related to the site of infection; c) positive bacterial culture from an appropriate site; d) C-reactive protein >50 mg/L. The secondary endpoints included: a) days of hospitalization due to severe infections; b) days under treatment with antibiotics; c) improvement of HRQoL, evaluated with a Short Form 36 (SF-36) questionnaire [18]. All observational times (including shorter periods due to treatment withdrawal or longer periods due to prolonged treatment courses) were adjusted to a 365-day period.

ACCEPTED MANUSCRIPT 2.5 Statistical methods

Continuous variables, particularly for the rate of total infections, were assessed as mean, median, standard deviation, and range. The differences by groups were evaluated by the Student-Fisher t-test, and Chi-square test. The Wilcoxon correlation and Mann-Whitney U-test were employed to assess the correlation by rate of infection and the

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other variables. The nominal variables included absolute and relative frequency classes, taking into account the

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following variables: patient data (demographics); medical history and concomitant medications; chemotherapy for MM; total serum IgG level; serum protein electrophoresis; rate of infections and related therapy; adverse events.

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2.6 Patient survey for health-related quality of life

The SF-36 health survey was used, that includes 35 items divided into eight subscales: physical function (10

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items); role-physical (4 items); body pain (2 items); general health (5 items); vitality (4 items); social function (2 items); role-emotional (3 items); and mental health (5 items).

To correctly evaluate the score, we calculated SF-36 scale scores by hand for all respondents, and then

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compared the results to those produced by our scale-scoring computer software.

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3. Results

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3.1 General incidence of infections

The overall rate of infections was found to affect approximately 75% of the MM patients. This percentage was lower during the plateau phase compared to the active phase and the treatment periods (58% vs 87%), and was further increased in the advanced phases when almost all patients were affected. Fig. 1, which summarizes the incidence of infections per system, shows that the principal site of infection was the respiratory system, in which almost 70% of all infections were localized.

3.2 Length of SCIg therapy

ACCEPTED MANUSCRIPT At the end of the first six months of treatment, 21 of the 24 patients who were given SCIg accepted to continue the treatment, whereas 3 patients were withdrawn from the study because of the occurrence of side effects. The mean duration of SCIg infusions was 18 months (range 10-28 months).

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3.3 Doses and IgG trough levels

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The mean administered dose of IgG was 80 mg/kg/week. The site of administration was the abdominal wall for all patients. As stated above, trough serum levels of polyclonal IgG (measured on the day prior to infusion) were assessed monthly throughout the study, and were found to be stable, median levels ranging from 8.3 to 9.5 g/L. By comparison, the median serum trough levels of IgG ranged between 2.4 and 5.2 g/L in the control arm-B patients who

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did not receive IgG replacement therapy (Fig. 2).

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3.4 Incidence and types of infections

A significantly lower number of infections (p<0.001) were observed in the SCIg group (p<0.01). An even more

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important observation was the significantly lower incidence of total (p<0.001) as well as severe (p<0.01) infections compared to the arm-B patients (Fig. 3, panel A). As shown in Fig. 3, panel B, a significantly lower number of infectious

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episodes were recorded in the SCIg group, predominantly (85%) affecting the upper respiratory tract. The different

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types of infections are reported Table II.

The total duration of infections, expressed in days and adjusted to a 365-day period, was also analyzed as an

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arbitrary marker of severity. Infections lasted a mean of 62 days (26 –87) for arm-A compared with 135 days (88–194) for arm-B patients, the difference being statistically significant (p <0.01). In addition, mean days/year of hospitalization due to severe infections were 8 in the group of SCIg-receiving patients vs. 121 in the control group (p <0.001; Fig. 3, panel C). Mean days under treatment with antibiotics were 28 for arm-A patients vs. 217 for the control arm-B patients (p <0.001; Fig. 3, panel D).

3.5 Adverse reactions

ACCEPTED MANUSCRIPT The number and types of adverse reactions are summarized in Table III. These were predominantly mild, and in only three patients did their severity require the discontinuation of the SCIg infusion: two of them experienced pain and inflammatory reaction at the site of injection, and one showed an extensive allergic skin reaction after the second administration that resolved following steroid and anti-histamine therapy.

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3.6 Quality of life

Patients receiving SCIg consistently reported improvements in HRQoL measures, including improvements in their feeling of general well-being (SF-36) and in the impact of MM on both their own and their family’s activities (Fig.

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4). Only for incidence of pain were similar responses recorded in both arms of patients (P=n.s.).

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4. Discussion

It is well known that complications of MM include anemia, renal failure, infections, bone disease,

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hypercalcemia, and neurologic involvement [19]. Among them, infections are a frequent cause of morbidity and mortality [5]. In the last several years, the introduction of stem cell transplantation and the anti-angiogenic and

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immunomodulatory agents, such as bortezomib, thalidomide, and lenalidomide, have remarkably improved the outcome of MM patients. These new therapies, however, are consistently responsible for the worsening of the

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immunodeficiency related to MM itself, inevitably resulting in a higher risk of infections [2]. The rate of infections varies in different phases of MM, and seems to be more fr equent during active disease

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and in the first months of induction chemotherapy. In early-stage MM, the most common infections involve the respiratory tract, and are clinically diagnosed as pneumonia and bronchopneumonia. These infections are predominantly caused by Haemophilus influenza e or Strepto coccus pneumoniae, and their occurrence is obviously enhanced by the condition of secondary hypogammaglobulinemia [20]. Only a few studies have addressed the role of Ig replacement therapy in patients with MM and secondary hypogammaglobulinemia, and all of them have been carried out with IVIg. In a randomized, double-blind, placebocontrolled, multicenter trial of IVIg, employed as prophylaxis against infection in 82 patients with stable MM, Chapel et al. [6] demonstrated a protective role of IVIg against life-threatening infections, and a reduced risk of recurrent infections. An additional study, perfor med in patients with hypogammaglobulinemia associated to CLL or MM,

ACCEPTED MANUSCRIPT reached similar results [7]. Conversely, as already mentioned, Blombery et al. [8] showed that the administration of IVIg before, during and after transplant was unable to reduce infectious complications in hypogammaglobulinemic MM patients undergoing autologous stem cell transplantation. Finally, the potential efficacy of IVIg has been evaluated during the plateau-phase of MM, when the serum level of the monoclonal component is low (thus preventing the risk of hyperviscosity syndrome during the active phase of the disease): a significant reduction in both

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frequency and severity of infections has been demonstrated in this condition [6-9, 20].

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SCIg preparations have been shown to be safe, cost-effective, and able to improve HRQoL in patients with primary immunodeficiencies [10, 13, 21-23]. They can be self-administered at home, do not require venous access and systemic premedication, and are characterized by a gradual absorption and a low incidence of systemic adverse events [13, 14]. Local reactions are usually mild and do not affect the good tolerability of the treatment [15]. Their

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safety, efficacy and HRQoL have been assessed in patients with lymphoproliferative disorders and secondary hypogammaglobulinemia [24]. Similar results were obtained in children after hematopoietic stem cell transplantation

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[25], and in patients undergoing lung transplantation [26].

Based on the experience deriving from these studies, guidelines have been proposed to indicate that the r egular Ig administration should be considered in MM patients suffering from life-threatening or recurrent infections, that are

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associated to low levels of non-paraprotein polyclonal IgG [20, 27, 28].

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5. Conclusions

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The main strengths of this study are the determination of normal (non paraprotein) serum IgG levels at short (monthly) intervals, the length of observation prolonged for 18 months or longer for each patient, and the clinical

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assessment of all of them by the same physicians (the present authors). Our results have unequivocally shown that the SCIg administration to MM patients results in a reduced rate of infections, a shorter length of hospitalization and a lower number of days of antibiotic therapy. These preparations were also safe during the active phase of the disease and did not induce additive adverse events when administered in concomitance with anti-myeloma therapy. Whether the prophylactic effects of SCIg administration may eventually result in improvement of overall survival, cannot be established from the present study. Authorship contributions RR planned the study and prepared the draft; CM, AM, AS, AV and RR took care of the patients; IS collected data and assembled the database; RR, AS and IS performed the statistical analysis; FD critically revised the manuscript.

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Conflict of interest

The authors declare they have no conflict of interests.

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Aknowledgement

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This study was supported by the Italian Association for Cancer Research (AIRC, Milan), Investigator grant 2013 (no. 14095), the five per thousand Molecular Clinical Oncology Special Program (grant no. 9965; to A. Vacca), the European Commission's 7th Framework Programme 2007–2013 (EU FPT7) under grant agreement no. 278706 (OVER-MyR; to A.

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Vacca), and grants from MIUR PRIN 2009WCNS5C_004 (to R. Ria) and 2010NECHBX (to A. Vacca).

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ACCEPTED MANUSCRIPT Legends

Figure 1: Incidence of infections in MM patients.

Figure 2: Trough serum levels of polyclonal IgG measured monthly prior to the infusion in the two groups of patients.

Figure 3: Infections in MM patients. Panel A reports the variation in the incidence of infections in the treated groups

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compared to untreated patients. Panel B shows the distribution of infections in the low and high tracts of the

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respiratory system. Panels C and D summarize the days of hospitalization per year, and the days under antibiotic treatment per year in treated and untreated patients.

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Figure 4: Graphic report of patient survey for health-related quality of life (SF-36 questionnaire).

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Table 1: Patients’ characteristics Total

Arm-B: Controls

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71 (56-85)

71 (60-85)

69 (54-88)

25/21

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13 (59) 7 (31.8) 2 (9)

2 (8.3) 20 (83.3) 2 (8.3)

1 (4.5) 19 (86.4) 2 (9.1)

3.2 (1.4-5.7)

3.2 (1.3-5.7)

6 (13) 15 (32.7) 25 (54.3)

3 (12.5) 8 (33.3) 13 (54.2)

3 (13.6) 7 (31.8) 12 (54.6)

13 (28.3)

7 (29.2)

6 (27.3)

19 (41.3) 18 (39.1) 9 (19.6)

8 (33.3) 11 (45.8) 5 (20.9)

11 (50) 7 (31.8) 4 (18.2)

Stage (D&S) IIA: n(%) IIIA: n(%) IIIB: n(%)

3 (6.5) 39 (84.8) 4 (8.7)

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Previous ASCT n(%)

Type of therapy for MM Bortezomib based n (%) IMIDs based n (%) Chemotherapy based n (%)

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3.1 (1.3-5.2)

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Line of therapy for MM First n (%) Second line n (%) Subsequent n (%)

16 (66.6) 6 (25) 2 (8.3)

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29 (63) 13 (28.3) 4 (8.7)

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Isotype of MM IgG: n(%) IgA: n(%) BJ: n(%)

Uninvolved polyclonal IgG, g/L mean (range)

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Sex (M/F)

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Arm-A: SCIg n. Age (mean, range)

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ACCEPTED MANUSCRIPT Table 2: Total number of infectious episodes during the study.

Patients Arm-A: SCIg

Arm-B: Controls

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24 18 43 24 5 12 32 32

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Minor infections:

32 11 6 19 1

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Tracheobronchitis Bacterial skin infection Bacterial stomatitis Lower urinary tract infection Thoracic herpes zoster

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Sepsis Bacterial pneumonia Bronchitis with sepsis Pharyngo-tracheitis with sepsis Acute sinusitis Erysipelas Urinary infection with sepsis Fever of unknown origin

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Major infections:

64 16 12 36 15

ACCEPTED MANUSCRIPT Table 3: Adverse events in SCIg-treated patients.

Number of patients (%) Grade 3/4

Grade 1/2

1 (4)

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Edema of the injection site

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15 (62)

Edema and erythema

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Event

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5 (21)

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3 (12)

2 (8)

3 (12)

Edema and pain Edema and pruritus

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Skin induration and pain

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8 (33)

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Allergic skin reaction

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