Vaccination in Multiple Myeloma

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Review

Vaccination in Multiple Myeloma: Review of Current Literature Andinet Alemu,1 John O. Richards,1 Martin K. Oaks,2 Michael A. Thompson1 Abstract Multiple myeloma is a cancer of the immune system. Infection is a major cause of morbidity and mortality in patients with multiple myeloma. Some of these infections are preventable by vaccines available to the general population. However, little is known about the clinical effectiveness of these vaccines in patients with multiple myeloma, and the cellular and humoral immune response to vaccination has not been well characterized, especially in conjunction with modern myeloma therapies. The present report reviews the basics of multiple myeloma and the immune system, the available evidence on the immunologic response of patients with multiple myeloma after vaccination, and current practice recommendations regarding specific vaccines. Understanding the immune response to vaccines could help us understand how immuno-oncologyebased therapies work in multiple myeloma and provide future directions for research. Clinical Lymphoma, Myeloma & Leukemia, Vol. 16, No. 9, 495-502 ª 2016 Elsevier Inc. All rights reserved. Keywords: Immune system, Influenza, Multiple myeloma, Pneumonia, Supportive care

Introduction Vaccines are the first line of prevention for common infectious diseases such as influenza and pneumonia. However, the optimal use of vaccines in the setting of cancers involving the immune system and in patients undergoing treatment for these cancers has not been defined. The purpose of the present review was to compile and clarify the existing data on the effect of vaccines on the immune system of patients diagnosed with multiple myeloma (MM) and the clinical recommendations for appropriate administration of vaccines.

Effect of Pneumonia and Influenza Diseases that are preventable by vaccines still contribute to significant morbidity and mortality in the United States and globally. Among these, influenza and pneumonia account for the largest share of the problem. In 2005, influenza/pneumonia was listed as the eighth most frequent cause of death in the United States, accounting for 63,000 deaths.1,2 The overall national economic 1

Aurora Research Institute, Aurora Health Care, Milwaukee, WI 2 Transplant Research Laboratory, Aurora St. Luke’s Medical Center, Aurora Health Care, Milwaukee, WI Submitted: Mar 24, 2016; Revised: May 13, 2016; Accepted: Jun 1, 2016; Epub: Jun 08, 2016 Address for correspondence: Michael A. Thompson, MD, PhD, Aurora Research Institute, Aurora Health Care, 960 North 12th Street, Suite 4111, Milwaukee, WI 53233 E-mail contact: [email protected]

2152-2650/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clml.2016.06.006

burden of influenza-attributable illness for adults aged 18 years has been reported at $83.3 billion.3 The direct medical costs for influenza in adults totaled $8.7 billion, including $4.5 billion for hospitalization resulting from influenza-attributable illness. Influenza is also responsible for substantial indirect costs ($6.2 billion annually), mainly from lost worker productivity.3 Among adults aged 18 to 64 years, 17 million workdays are lost to influenzarelated illness each year. Thus, the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) has recommended annual influenza vaccination for most age groups and pneumococcal vaccination in certain patient populations and the elderly.4 Despite the theoretical benefit and hope of a preventive supportive care intervention, the effectiveness and utility of such vaccines have not been well characterized in patients with underlying immunosuppression such as MM.

MM and the Immune System MM is a cancer of plasma cells. Plasma cells are terminally differentiated B lymphocytes responsible for the production of antibodies necessary to fight infection. Patients with MM have profound abnormalities in antibody production5,6 and consequently have a significantly increased risk of bacterial infection.2,7-12 MM is most commonly a disease of the elderly, and an age-related decline in both innate and adaptive immunity is common.13 Thus, patients with MM have a compound immunologic deficit of declining overall immunity in the face of abnormal antibody production and

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function. However, the immune system in patients with extended survival has been found to be similar to that of age-matched controls, suggesting that with successful treatment, the immune status will return toward normal.14 Just as with normal plasma cells, myeloma cells are recruited to the bone marrow, where they engraft and grow.15 The growth of myeloma cells has multiple effects on the bone marrow, which is instrumental in multiple immunologic functions, including hematopoiesis, B-cell development, antibody production, secondary lymphoid function, and a repository for memory T cells.16,17 As such, alterations in the bone marrow architecture could affect immunologic outcomes at both a local and a systemic level. Before myeloma engraftment, the bone marrow can be characterized as an immune suppressive or privileged site. Evidence for this has been shown by the isolation of antigen-specific T cells from the bone marrow that become responsive in vitro, which can prevent tumor engraftment when transferred to another host.18 The immune suppressive environment is enhanced in the presence of MM. The interaction of myeloma cells with stromal cells leads to the release of multiple cytokines, such as transforming growth factor-b1 (TGF-b1), vascular endothelial growth factor (VEGF), interleukin (IL)-6, and hepatocyte growth factor (HGF), from the stromal cells or myeloma cells themselves.19 Not only do these cytokines promote myeloma growth, they have been found to suppress immune responsiveness. For instance, HGF has been found to inhibit antigen-presenting cell function and, as a result, inhibits the activation of T cells.20 This inhibition of antigen-presenting cells is associated with the production of indoleamine 2,3-dioxygenase 1, which catabolizes tryptophan into immunosuppressive metabolites.21 Similar to HGF, VEGF inhibits antigen-presenting cell function by blocking dendritic cell maturation,22 thereby blocking T- and B-cell function. Inflammation is one of the hallmarks of cancer. Inflammatory cytokines such as IL-6 and VEGF have also been found to influence the development of myeloid cells and have been implicated in the development of immature myeloid cells (also called myeloid suppressor cells [MDSCs]).23 MDSCs are a heterogeneous population of cells with 2 major subgroups of monocyte and granulocyte lineage. Both types of suppressor cells can be found in the bone marrow or circulation and are very effective at inhibiting lymphocyte activation. Not only can they suppress antigen-specific lymphocytes, they are known to induce regulatory T cells, further enhancing an environment of immune suppression. In a study by Broder et al,5 the removal of phagocytes from culture, obtained from a patient with MM, was able to restore the impaired ability to produce polyclonal antibodies. The ability to obtain MDSCs in the blood and eliminate them to restore lymphocyte function implies that these cells can suppress both local and systemic immune responses. The development of MDSCs in the bone marrow is an indication that hematopoiesis is changed in myeloma, although probably not very noticeably. However, the clinical symptom of normochromicnormocytic anemia has been shown to occur in 75% of MMdiagnosed patients. In a much smaller group of individuals, leukopenia has been observed, showing defects in hematopoiesis and cell number.24 The alteration of hematopoiesis might partially be due to myeloma altering the niche for normal progenitor cells.25 Bruns


et al26 showed that TGF-b1 inhibits hematopoietic stem and progenitor cell renewal. Thus, a small infiltrate of tumor might have much greater effect on hematopoiesis. Immunomodulatory drugs (IMiDs), such as thalidomide, which blocks TGF-b1 signaling, can restore normal hematopoiesis. The engraftment of myeloma in the bone marrow can have farreaching effects, because it modifies hematopoiesis and produces an immunosuppressive environment locally and systemically. Systemic immune deficiencies are associated with the development of suppressor cells and reduced numbers of generated cells in the local environment of the bone marrow. Patients with long-term survival of MM were found to have unique immunologic profiles associated with reduced immunosuppression.27

How Do Vaccines Work? Immunity produced in response to vaccines is largely antibody driven.12 T cells play a significant role in sustaining and maintaining the immune response after vaccination. CD8 T cells (cytotoxic T lymphocytes) are crucial in containing the spread of infection and in recognizing and killing infected cells. Generating and maintaining both B and CD8 T cells requires a signal from CD4 T-helper cells (Th1 and Th2 subtypes). Various vaccine groups induce the immune response through different mechanisms. For example, capsular polysaccharides elicit a B-cell response in a Tcelleindependent manner. In contrast, other vaccines, including toxoids, proteins, and live attenuated vaccines, induce the antibody response and immune memory in a T-celledependent fashion. Immunity generated by a T-celledependent mechanism is highly specific and long-lasting.11,12,28,29 Adaptive immunity can be passive and short term, such as in maternal IgG transported across the placenta or infusion of intravenous immunoglobulin in MM patients. Active immunity/memory is (usually) long term and can be acquired by infection-induced B- and T-cell response or vaccines.11 Immune suppression can result from MM itself or be secondary to MM therapy. Various biologic factors are accountable for innate immune dysfunction in patients with MM. These include a decrease in uninvolved (nonclonal) antibody production from B cells.5,6 The resulting hypogammaglobulinemia or immunoparesis is a poor prognostic feature of MM.30 A functional defect is also present in upregulation of costimulatory molecules (CD80) on dendritic cells, with an inverse CD4/CD8 population ratio and defective natural killer cells.31 Bacterial infections, in particular, those caused by Streptococcus pneumoniae, Escherichia coli, Staphylococcus aureus, and Haemophilus influenzae, are very common. Specifically, the often present underlying polyclonal hypogammaglobulinemia in MM increases the risk of infection from encapsulated pathogens such as S. pneumoniae and H. influenzae.31 A recent population-based study by Blimark et al8 indicated that MM patients have a 7-fold and 10-fold increased risk of bacterial and viral infections, respectively, compared with non-MM patients. Their reported hazard ratios for the risk of infection in MM patients versus matched controls are listed in Table 1. A total of 51 meningitis cases were noted in 9253 MM patients compared with 28 cases in 34,253 controls, for a hazard ratio of 16.6. However, no clinical practice recommendations have been published to provide meningitis vaccinations to patients with MM.

Author's Personal Copy Table 1 Patients With Multiple Myeloma Have a Significantly Increased Risk of Infection Infection

Hazard Ratio

Bacterial Meningitis

16.6

Septicemia

15.6

Pneumonia

7.7

Endocarditis

5.3

Osteomyelitis

3.5

Cellulitis

3.0

Pyelonephritis

2.9

Viral Herpes zoster Influenza

14.8 6.1

Data from Blimark et al.8

Chemotherapy, whether in the form of conventional DNA cytotoxic therapies or newer targeted therapies, inhibits the immune system. The increased use of IMiDs (eg, thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (eg, bortezomib, carfilzomib) has led to an increased number of viral and fungal infections in cancer patients.31 Immunosuppression might be the greatest immediately after diagnosis, with the immune system recovering with response to effective treatment.7 In 2005, Augustson et al7 reported that 45% of the early deaths in MM were due to infections, primarily pneumonia and sepsis. This emphasizes that infection remains a significant cause of morbidity and mortality despite significant advances in treatment strategies and improved long-term survival of patients with MM.

Utility of Vaccination in Immunosuppressed Patients Despite infection remaining a common cause of mortality and morbidity in cancer patients, data are limited regarding the clinical effectiveness of various vaccines in immunosuppressed individuals. In addition, the effectiveness of such vaccines might depend on the degree and nature of the underlying immunosuppression. Thus, the vaccination dose and schedule for otherwise healthy people might not be appropriate for patients with cancer receiving active chemotherapy or other immunosuppressive therapy.32 Issues include understanding when to vaccinate (before, during, or after therapy), because today’s treatments can be more sustained, and which surrogate markers to evaluate (and when) for clinical benefit. Live vaccines are contraindicated for patients with underlying immunosuppression because of the risk of infection from the vaccine.9,32-36

Vaccination Response in Patients With MM Pneumococcal Vaccines Pneumococcal vaccination has been in use for > 30 years. Two types of pneumococcal vaccines are currently available: the polysaccharide vaccine PPV23 (Pneumovax; Merck & Co, West Point, PA) and conjugate vaccines (pneumococcal conjugate vaccines [PCVs]) of differing valences (eg, PCV13, PCV7). Valence refers to

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the number of different serologic strains of S. pneumoniae included in the vaccine. Polysaccharide vaccines induce antibody production in a Tcelleindependent manner. That is, they act directly on B cells without the need for T-cell recognition. PPV23 is very poorly immunogenic in children < 2 years old and largely fails to induce an anamnestic response on revaccination in any age group. This is likely a result of the absence of B1 cells (those responsible for Tcelleindependent responses) in children until approximately 3 years of age. However, PPV23 has demonstrated protection against allcause pneumonia and pneumococcal invasive disease in healthy adults and protection against invasive disease in the elderly. Clinical trials have not conclusively shown efficacy against either invasive disease or all-cause pneumonia in immunosuppressed patients of any age.37 However, its use is generally considered safe in terms of both immediate reactions and long-term adverse effects.38 Thus, although it would appear that PPV23 is unproved in immunosuppressed individuals, age alone might not play a role. Studies designed to separate the effects of age and those of immunosuppression are needed to clarify this issue. PCVs were initially designed to induce immunity in children. They consist of pneumococcal polysaccharides that are chemically coupled to immunogenic protein carriers. The protein engenders the complex with the ability to induce T-celledependent immune responses. T-celledependent responses are generally intact at or near birth; thus, these conjugate vaccines are effective in infancy. In contrast to PPV23, booster doses of conjugate vaccines do provide anamnestic responses, as measured by IgG titers; thus, conjugate vaccines would appear to be indicated for revaccination. The efficacy of either form of the vaccine in immunocompromised individuals is not well understood. This is especially true in the case of hematologic malignancies of B-cell origin, such as chronic lymphocytic leukemia and MM. If immunization using both PPV23 and PCV13 is considered for immunocompromised individuals, the conjugate vaccine (PCV13) should always be administered first to minimize the likelihood of induction of hyporesponsiveness.

Pneumococcal Vaccines in Patients With MM The response of patients with MM to pneumococcal vaccination has been described in few studies. In 1980, Lazarus et al39 reported a 30% antibody response rate (4 of 13 patients) measured 6 weeks after a 14-valent purified polysaccharide vaccine. The response was modest and described as safe and cost-effective. Another study by Chapel et al40 in 1994 reported a 57% response rate (31 of 54 patients) to PPV23 in plateau-phase MM patients. The response was defined as increased pneumococcal IgG by twofold or more. Those “good responders” did not benefit from infusion of intravenous immunoglobulin.40 In a separate study, Yoshida41 found that “specific antibody titers for S. pneumoniae were significantly reduced in patients compared with normal controls” and that “pneumococcal vaccination was effective in 30% to 40% of patients.” In 2013, Karlsson et al42 showed that elderly patients with MM and other B-cell cancers have suboptimal responses to pneumococcal vaccination. They also found that a single dose of PCV7 was not superior to polysaccharide vaccines.42 In addition to considering the IgG antibody levels to pneumococcal serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F by enzyme-linked immunosorbent assay,


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Karlsson et al42 reviewed antibody functional activity versus pneumococcal serotypes 4 and 14 using an opsonophagocytic killing assay (OPA). Prevaccination IgG antibody and OPA titers were lower in B-cell cancer patients than in healthy controls. Factors associated with a poor vaccine response on multivariate analysis included hypogammaglobulinemia and concurrent chemotherapy. In 2016, Karlsson et al43 found a poor correlation between pneumococcal IgG and IgM titers and OPA in vaccinated patients with MM and Waldenström macroglobulinemia. However, that study did not report the IgG subclass mix. The OPA assay was complement dependent, largely because of IgG1 and IgG3 subclasses. IgG1 and IgG3 appear to be the predominant species induced by polysaccharide antigen (PPV23), but IgG2 (which fixes complement poorly) predominates in the response to conjugate vaccines (PCV13). Because Karlsson et al43 administered conjugate vaccine, one might expect that the antibodies elicited were IgG2 (poor fixers of complement). Hence, their findings likely confirmed what is known about subclasses and complement fixation. In early 2014, Pfizer announced in a press release that an 85,000patient study conducted in the Netherlands (Community-Acquired Pneumonia Immunization Trial in Adults [CAPiTA]; ClinicalTrials.gov identifier no. NCT00744263) showed that the PCV13 vaccine prevents pneumonia and invasive bacterial infection in adults aged 65 years.44 Nearly 85,000 participants aged 65 received the PCV13 vaccine or placebo. The PCV13 group had 45% fewer first episodes of vaccine-type community-acquired pneumonia compared with the placebo group. The PCV13 group also had a 75% reduction in vaccine-type invasive pneumococcal disease. That study did not include participants who had previously received the PPSV23 vaccine.44 These data were later reported by Bonten et al.45 Subsequent to this finding, conjugate vaccines have become the vaccine type of choice in the elderly and in the setting of MM. The ACIP has also recommended PCVs at diagnosis for patients with MM, without mention of a revaccination schedule.46

Influenza Vaccines

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Vaccine-preventable diseases are common among patients with hematologic malignancy; however, evidence is limited regarding the effect of vaccination in these patients. A systematic Cochrane review from 2011, which included 8 randomized clinical trials with 305 patients, evaluated the efficacy of inactivated polio, varicella zoster, and influenza vaccine. It showed the effectiveness of the influenza vaccine in reducing the rate of respiratory infection and hospitalization in MM patients; however, the quality of evidence was low.47 Another review by Boehmer et al48 emphasized the recommendation of the ACIP that cancer patients should be given trivalentinactivated vaccine between cycles of chemotherapy. Hahn et al49 studied the effects of boost vaccination on the humoral immune response against influenza in MM patients. In that study, a single shot of seasonal influenza vaccine resulted in 20% to 40% of patients developing “sufficient” titers of neutralizing antibodies to a single antigen. However, we are not aware of any clinical validation of said “sufficiency.” The frequency of protective titers could be roughly doubled by a vaccine boost. The investigators then recommended an influenza vaccine boost for MM patients in general and suggested a prospective, randomized clinical trial to confirm this recommendation.49 We suspect that many MM patients are missing


a single-dose vaccine and that most are not receiving boost vaccines regularly in clinical practice. Also, it is not a standard of care to check immunization responses.

Meningococcal Vaccine Blimark et al8 found a meningitis hazard ratio of 16.6 for MM patients compared with controls. However, no clinical practice recommendations have been published to provide a meningitis vaccination for MM patients (other than in the post-hematopoietic stem cell transplant [HSCT] setting). Given this high risk, studies evaluating the effect of meningococcal vaccination in MM patients are warranted, especially in the context of newer drugs and outside the transplantation setting.

H. influenzae Vaccine H. influenzae is one of the most common bacterial etiologies for recurrent infections in MM patients. Vaccination for H. influenzae has been recommended, although “efficacy is not guaranteed.”50

Varicella Vaccine According to the Centers for Disease Control and Prevention: “because of insufficient experience using varicella vaccine among [HSCT] recipients, physicians should assess the immune status of each recipient on a case-by-case basis and determine the risk [of] infection before using the vaccine. If a decision is made to vaccinate with varicella vaccine, the vaccine should be administered a minimum of 24 months after transplantation if the [HSCT] recipient is presumed to be immunocompetent.”51 With a hazard ratio of 14.8 for the herpes zoster virus, antiviral prophylaxis has been studied and frequently used.8 In the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study), zoster occurred at a rate of 13% in the bortezomib arm compared with 5% in the high-dose dexamethasone arm.52 Thus, although statistically increased in the former, zoster occurred even without the proteasome inhibitor. Vickrey et al53 showed in a retrospective study of 125 MM patients that antiviral prophylaxis was effective at preventing herpes zoster virus in patients with MM who were receiving bortezomib, with or without corticosteroids. This was echoed by Mehta et al,54 who reported “acyclovir prophylaxis virtually eliminates the risk of zoster in patients receiving bortezomib.” A Korean Multiple Myeloma Working Party retrospective study revealed that even acyclovir at a dose of 400 mg once daily during bortezomib therapy provided prophylaxis for herpes zoster, irrespective of the level of MM control and the type of bortezomib-containing chemotherapy regimen.55 Given the risk of zoster and the relatively easy and low-cost treatment, many physicians give antiviral prophylaxis to all MM patients, regardless of the MM therapy used.

Vaccination and Antimyeloma Therapies Stem Cell Transplantation Historical MM studies have included plateau-phase patients (before maintenance therapy was common) or the concurrent therapy was not stated. Guidelines exist for revaccination after stem cell transplantation.56 Tomblyn et al57 reported a comprehensive review of infection prevention in transplantation. They

Author's Personal Copy recommended routine vaccination with inactivated vaccines in postHSCT patients and recommended against the use of live vaccine administration early in the post-transplant period. Individual institutions can modify these template consensus guidelines. Vaccination protocols after autologous stem cell transplantation have largely been based on allogeneic treatment regimens and guidelines. The vaccines should be administered at least after a partial reconstitution of adaptive (T- and B-cell) immunity, which correlates with a minimum waiting period of 3 to 6 months after transplantation.56-59 Similar to the immune response of young children, polysaccharide vaccines are poorly immunogenic and will illicit an antibody response later in HSCT patients than conjugate vaccines. It has been recommended that 3 to 4 doses of PCV vaccination should be administered 3 to 6 months after HSCT. Vaccines for tetanus-diphtheria-pertussis (Tdap), meningococcal conjugate, inactivated polio, H. influenzae, and hepatitis B should be administered 6 to 12 months after transplantation. Measles, mumps, and rubella vaccines should be given to patients serologically negative for measles, mumps, and rubella after HSCT no earlier than 24 months after transplantation. The recommendation for the meningococcal conjugate vaccine is “follow country recommendations for general population” (BII evidence level, which equates to moderate evidence for efficacy and 1 well-designed clinical trial without randomization) and therefore is not universally recommended.

Immunomodulatory Drugs Noonan et al60 showed that lenalidomide-induced immunomodulation augments vaccine responses and endogenous antitumor immunity. Lenalidomide (or other IMiDs) can serve as an immune adjuvant for infectious disease vaccinations and to augment antiMM immunotherapies. Henry et al61 concluded that IMiDs enhance tumor antigen uptake by dendritic cells by increased efficacy of antigen presentation, suggesting the use of these drugs in dendritic cell vaccine therapies.

Proteasome Inhibitors Bortezomib was evaluated as a plasma cell depletion therapy for systemic lupus erythematosus and found to decrease vaccine-induced

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protective antibody titers by w30%.62 Evaluation of MM patients receiving proteasome inhibitors is warranted. The potential IMiD augmentation with proteasome inhibitor decrease for combined therapy has not been evaluated.

Histone Deacetylase Inhibitors Panobinostat is a pan-histone deacetylase inhibitor approved by the US Food and Drug Administration in February 2015 and has been studied for antiviral activity in subjects with human immunodeficiency virus, but we are unaware of any vaccine data for MM patients.

Monoclonal Antibodies The MM monoclonal antibody therapies daratumumab (CD38) and elotuzumab (SLAMF7) were both approved by the Food and Drug Administration in November 2015. We are currently unaware of any vaccine response data regarding these antibodies, but the data should be evaluated as use increases.

Recommendations for MM Patients No universally accepted guideline is available regarding vaccinating cancer patients, including those with MM. Vaccination of close contacts has been recommended. The effectiveness of these vaccinations in patients with MM is questionable when administered during periods of significant immunosuppression and intensive chemotherapy. The many published recommendations from various organizations have been summarized Table 2.46,63-65 The ACIP recommends routine use of PCV13 for patients aged 19 years with conditions of functional or anatomic asplenia, cerebrospinal fluid leak, or cochlear implants. In addition, patients with underlying congenital and acquired immunodeficiency, chronic kidney disease, or hematologic malignancies, including MM and organ transplantation, should receive vaccination with PCV13 at diagnosis, followed by revaccination with PPV23 8 weeks later. Patients aged 65 years without other conditions should receive PCV13, followed by PPV23 within 6 to 12 months.45 The Infectious Diseases Society of America has recommended the routine use of inactivated vaccines in patients with cancer unless they are actively receiving chemotherapy or monoclonal antibody

Table 2 Summary of Vaccination Recommendations Organization

Vaccine Type

Recommendation

Comment

9/2014

PCV

PPSV23 and PCV13 should not be administered together Minimum gap between 2 vaccines should be 6 mo MM patients should receive PCV, followed by revaccination with PPSV23

9/201446

FV

NCCN

201563

PPV/FV

IDSA

201364

PCV

200965

FV

Age < 65 y with preexisting conditions and no previous PPSV23 / PCV-13 now / PPSV23 6-12 mo / PPSV23 every 5 y Age > 65 y with no previous PPSV23 / PCV13 now, then PPSV23 6-12 mo later Annual inactivated FV recommended for all MM patients “Consider Pneumovax and influenza vaccine” in MM patients PCV13 at diagnosis of MM; no mention of revaccination schedules Annual inactivated FV

CDC/ACIP

Date 46

Can be administered together with pneumonia vaccines No clear recommendation regarding vaccination timing and schedule Administration 2 wk before immunosuppression therapy FV likely less effective if given during periods of intense chemotherapy or monoclonal antibody therapy; postponement recommended for such patients

Abbreviations: CDC/ACIP ¼ Centers for Disease Control and Prevention/Advisory Committee for Immunization Practices; FV ¼ influenza vaccine; IDSA ¼ Infectious Disease Society of America; MM ¼ multiple myeloma; NCCN ¼ National Comprehensive Cancer Network; PCV ¼ conjugate pneumococcal vaccine; PPV ¼ polysaccharide vaccine.


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treatment. In such scenarios, vaccination should be postponed until 3 months after completion of chemotherapy and 6 months after completion of monoclonal antibody treatment.64 Recent MM guidelines from the National Comprehensive Cancer Network do not include specific recommendations for vaccination but do note to “consider Pneumovax and influenza vaccine.”63 The Mayo Stratification for Myeloma and Risk-Adapted Therapy supportive care guidelines have suggested prophylactic antimicrobial agents in the induction stage but did not directly address vaccination.66 A review of the treatment of MM patients by Gonsalves et al67 suggested that the evidence for Pneumocystis jiroveci prophylaxis is insufficient unless large doses of sustained steroids have been used. Vaccination for influenza, pneumococcal

pneumonia, and H. influenzae has been recommended, although efficacy is not guaranteed.50 The results from several studies of MM and vaccines are summarized in Table 3.8,39,40,68-71 The vaccination recommendations for patients who have undergone autologous or allogeneic stem cell transplant are provided in the American Society for Blood and Marrow Transplantation’s 2009 guidelines (“Table 6. Vaccinations Recommended for Both Autologous and Allogeneic HCT Recipients”).57

Research Questions Understanding the immune response to vaccines could also help us understand how immuno-oncologyebased therapies (ie, daratumumab, elotuzumab) work in MM. Improved granularity and

Table 3 Historical Timeline of Selected Studies of Vaccination in Multiple Myeloma Investigator Lazarus et al,39 1980

Vaccine

Study Details and Relevance

Design: small prospective trial Subjects: 13 MM patients and 23 age-matched normal controls Intervention: PCV14 vaccination Conclusion: low level of protective immunity among MM patients before and after vaccination of PCV14 injections; overall 30% AB response among MM patients PPV23 (Pneumovax) Design: randomized, double-blind, multicenter, placebo-controlled trial Chapel et al,40 1994 Subjects: 82 patients with stable MM Intervention: Monthly IVIG infusion for 1 y Conclusion: monthly IVIG protected against life-threatening infections and significantly reduced recurrent infection risk Design: small controlled trial Nordøy et al,68 2002 Trivalent influenza vaccine (Fluvirin) and PPV23 Subjects: 35 patients with solid tumors receiving either curative/adjuvant chemotherapy (Pneumovax) or palliative chemotherapy; 38 patients from general medical floor included as controls Intervention: patients and controls received trivalent FV and PSV23 vaccine Results/conclusion: 72% of patients and 87% of controls were serologically protected against 2 or 3 flu strains; most patients and controls achieved protective serum levels of antibodies after PSV23 vaccination; cancer patients achieved an adequate response to influenza virus and streptococcus pneumonia PPV23 Design: small prospective trial Karlsson et al,42 2013 PCV7 Subjects: 56 patients aged 60 y with diagnosis of MM (n ¼ 24), Waldenström macroglobulinemia (n ¼ 15), or nonmalignant B-cell disorder MGUS (n ¼ 17), and 20 age-matched controls Intervention: PPV23 or PCV7 Conclusion: ELISA measurements could overestimate antipneumococcal immunity in elderly subjects with B-cell malignancies; a functional antibody test should be used, particularly for MM and Waldenström macroglobulinemia FV (trivalent) Design: small prospective, responsive adaptive trial Sanada et al,69 2014 Subjects: 109 patients, including 15 with MM Intervention: a second FV (trivalent) given to patients with no response as measured by hemagglutination inhibition titers to all 3 strains after first vaccination Conclusion: Influenza vaccination recommended for cancer patients receiving chemotherapy; 2-dose vaccination might be an effective strategy to augment vaccine efficacy NA Design: retrospective population-based study Blimark et al,8 2015 Subjects: 9253 MM patients and 34,931 matched controls Results/conclusion: specific infections (eg, pneumonia and septicemia), > 10-fold greater than for controls in first year after MM diagnosis; risk of infection has been increasing in recent years; risk of dying from infection is significantly elevated for MM patients compared with age-matched controls NA Design: retrospective survey to explore factors related to early death in MM Hsu et al,70 2015 Subjects: 451 MM patients were included in analysis Conclusion: Two thirds of early mortality in MM is secondary to infection, with pneumonia most predominant; antimicrobial prophylaxis and use of IVIG in early disease course recommended FV (trivalent) Design: retrospective, single-center pilot study Hahn et al,71 2015 Subjects: 48 patients Intervention: second dose of vaccine if insufficient response to first vaccination but without any serious side effects; antibody titers were analyzed using the hemagglutination inhibitory assay Conclusion: double vaccination against influenza in MM patients seemed to enhance protection and should be systematically studied; a larger and stratified cohort of patients needed for systematic assessment of associations between immunization results and clinical parameters; clinical effectiveness should also be studied, particularly with regard to effect on influenza incidence, morbidity, and mortality

500

-

PCV14

Abbreviations: ELISA ¼ enzyme-linked immunosorbent assay; FV ¼ influenza vaccine; IVIG ¼ intravenous immunoglobulin; MGUS ¼ monoclonal gammopathy of undetermined significance; MM ¼ multiple myeloma; NA ¼ not applicable; PCV ¼ pneumococcal conjugate vaccine; PSV ¼ pneumococcal polysaccharide vaccine.


Author's Personal Copy immune function could provide future directions for research to improve supportive care and new immune-targeting therapeutic modalities. Lenalidomide-induced immunomodulation in myeloma augments vaccine responses and endogenous antitumor immunity. Thus, IMiDs can serve as adjuvant supportive therapy, not only for anti-MM, but also for infectious disease vaccination.60 Renowned chronic lymphocytic leukemia researcher Kanti Rai was quoted as saying “If I were truly an expert, the disease would have been cured by now.”72 The questions we can address in the future to improve our expertise regarding vaccination of patients with MM include the following: Do vaccinations provide clinical benefit in patients with mono-

clonal gammopathy of undetermined significance, smoldering multiple myeloma, or MM, with clinical benefit measured as survival, hospitalization, and cost reduction? If clinical benefit exists, what are the surrogate markers for protection? Current arbitrary thresholds for Ig subclass response and OPA have not been validated for clinical endpoints. Should we have an “immunologic dashboard,” followed sequentially, in addition to monitoring MM tumor burden markers? How should we vaccinate (adaptively according to surrogate marker [titer or functional assay] or double/quadruple dosing)? What is the evolution in immune function from monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and MM before, during, and after treatment with various drugs with different mechanisms of action, adjusting for age-related immune function? When is the best time to vaccinate patients with MM (eg, before induction, after induction, after consolidation, during maintenance, after maintenance, or novel strategies, such as less aggressive therapy with co-measurement of cancer response and immune response)? Does maintenance with an IMiD or proteasome inhibitor result in improved immune function during maintenance? Does the minimal residual disease status relate to the vaccine response? Can live vaccines be given and when?

Finally, as new drugs and mechanisms of action are developed for MM, the immune response should be measured as a correlative in clinical trials.

Conclusion Infection remains a significant cause of mortality and morbidity in MM. Some of these infections are preventable by vaccines in nonimmunosuppressed populations. However, the clinical effectiveness of these vaccines in cancer patients is uncertain. Various organizations have recommended administration of influenza and pneumococcal vaccines in patients with MM in accordance with the general population recommendations. However, surrogate marker and clinical outcomes data to support these recommendations are lacking. Some experts have suggested administering these vaccines before initiating chemotherapy or other immune modulators or waiting for at least 3 to 6 months after such therapies. Future studies are needed to assess the surrogate markers and clinically relevant endpoints of efficacy of these vaccines and to

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define specific vaccination schedules and doses for these patients in various clinical scenarios.

Acknowledgments The authors thank Joe Grundle of Aurora Research Institute for editorial assistance.

Disclosure M.A.T. is an advisor/consultant for Takeda/Millenium Multiple Myeloma Registry (honorarium to institution), VIA Oncology (and is Co-Chair on the Medical Oncology Myeloma and Medical Oncology Indolent Lymphoma Committees), AIM Specialty Health (honorarium to institution), MDRing (honorarium to institution), BMS (Elotuzumab) (honorarium to institution), Connect MDS/AML Registry (scientific steering committee member; honorarium to institution), Gilead Sciences (honorarium to institution), and CytRx Corporation Data Safety Monitoring Board. The remaining authors declare that they have no competing interests.

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