Supportive care: managing infection in myeloma | An interview with Heinz Ludwig

Professor Heinz Ludwig is a multiple myeloma (MM) specialist working at the Wilhelminen Cancer Research Institute in Vienna, Austria. He is a leading figure in new treatment strategies with wide-ranging research interests. He holds patient care at the forefront of his endeavors and has a strong treatment philosophy that the physician-patient relationship should be one of trust, with the central focus on the patient.

Following Professor Ludwig’s presentation at the 4th World Congress on Controversies in Multiple Myeloma (COMy) on the topic of ‘Supportive Care’, I spoke to him in person to follow up on some of the more interesting discussion points from his talk. The interview, detailed below, focuses specifically on the supportive care required to effectively manage infection.

FC: Fiona Chaplin and HL: Heinz Ludwig.

FC: What do we mean by supportive care and why is it so essential in myeloma?

HL: Supportive care is all the care, which is provided, and needed for managing a patient’s disease, with the exception of direct anti-myeloma therapy. This includes prophylaxis against viral infections, bacterial infections, and other complications. Supportive care also includes palliative care, though this is reserved for patients in later stages of the disease. It is also taking care of patients’ psychological needs, emotional needs, and symptom treatment. Appropriate supportive care is needed to prevent disease complications a priori and, if they do occur, to manage them accordingly to reduce symptoms and mortality. 

FC: About psychological support, do you have specialists to help with this, or does this support come from you directly?

HL: Yes, we are working with psychologists that we can ask for support, but the person providing medical care, in other words the physician, should have some professional qualification in this area as well. Good communication is essential for informing patients on the many facets of the disease and therapy and for building a respect and a trustful partnership. This will reduce unfounded anxiety and improve compliance. It is understood, that this communication should be respectful, honest and empathetic. Cancer patients in general, and myeloma patients in particular desire this type of care and studies from other cancers suggest that this may even affect the outcome of their disease. Psychologists support patients in coping with the diagnosis and the social, physical, and emotional consequences of the disease and its treatment. They empower patients to better master the burdens of their situation, to reflect their life, and to focus on activities which are joyful and give a sense of meaning to their life.

FC: Do all clinicians in your institute have access to additional support? Do you feel that this support is adequate?

HL: Yes, as mentioned we can refer our patients to psychologists, social workers, physiotherapists and self-help groups, although not every patient is open for such activities. However, I deem it helpful to illustrate to patients how they can get more out of their consultations with their physicians or other caregivers. They need to prepare themselves for these interactions. They need to assess their symptoms and concerns and to communicate them with their care team. They need to reflect what they want to find out during the conversation in order to maximize the use of their time and the caregiver’s time. We encourage patients to make notes beforehand with the questions they want answers to and issues they want to discuss and to come with their partners, because afterwards it will be easier to recall and to interpret the content of the consultation. All this improves the depth and quality of the consultations and a patient’s satisfaction with the interactions.

FC: What are the main risk factors for infection in myeloma, and can these be used to identify patients at high- and low- risk? Would you manage patients that fall into these two categories differently?

HL: There are a number of risk factors, which include myeloma-related innate immunodeficiency in terms of the level of B-cell dysfunction (hypogammaglobulinemia) and immunoparesis, side effects from myeloma therapies, which include neutropenia, lymphopenia, mucositis, and catheter-related infections. Myeloma and/or treatment-associated organ dysfunction can also put a patient at a higher risk for infection, and this encompasses renal failure, pulmonary impairment, severe malnutrition, mucosal damage, hyperglycemia, transfusional iron overload, and rarely, myeloma-associated amyloidosis. Gender also appears to play a role, with a 20% higher risk in males.   

There is one additional important risk factor, and that is age, as elderly people in general have a much higher risk of infection. Another risk factor is a history of frequent previous infections, particularly if these infections occurred around the time when myeloma became an issue. This increased risk of infection, due to the malignant disease itself or its complications such as renal failure is important to recognize, because those patients benefit most from preventive measures.  

In terms of prevention of infections, vaccination offers significant benefit, but unfortunately this is grossly underused in patients with myeloma. In some countries such as the UK, people over the age of 65 are now offered pneumococcal vaccine, because the risk of infection increases with age and this is an important pathogen to prevent. However, myeloma patients frequently develop viral infections of the upper respiratory tract. If this infection cannot be contained by the patient’s immune system, it will often serve as a catalyst for other bacterial infections, frequently leading to severe lower pulmonary tract infections such as pneumonia.

FC: I was intrigued by the fact that men have a 20% higher risk of infection. Is there any research to explain this increased risk?

HL: Yes, this is a fact, but I am afraid I do not have a good answer here. Obviously, it could be related to the different equilibrium of sex hormones. Men also have a slightly higher risk of developing myeloma or other cancers, and a higher risk of infection. Altogether, this results in shorter life expectancy, indicating discrimination and neglect of men by nature. In evolutionary terms, they enjoy their best time when they contribute to the propagation of their species, but lose their importance after birth of a new individual.

FC: What exactly is the level of increased risk for myeloma patients?

HL: Interestingly, people with monoclonal gammopathy of undetermined significance (MGUS) have a higher risk for infection, both viral and bacterial. This was unknown for a long time, but was shown in population-based studies in Scandinavia. Clearly, MGUS is a spectrum of disease with some patients having a low-, and others having a high- risk of transformation [high-risk MGUS]. Patients with MGUS also have a higher risk of mortality than the age-matched population and it would be helpful to understand the underlying pathophysiology.

If a person feels unwell, he or she seeks medical advice, which often leads to a blood test as well, which may lead to the detection of MGUS by chance. Therefore, patients might be selected with a higher likelihood for diseases with MGUS as an innocent bystander; or alternatively MGUS might, per se, be a condition associated with shorter life expectancy. This may in part be due to transformation into MM or other lymphoproliferative disorders and possibly due to hitherto unknown negative health consequences.

Now, when talking about other important vaccinations, influenza needs to be discussed.  All patients in stable disease, or even better during the MGUS or SMM state, should be vaccinated against influenza. This applies also to their partners, family members, and healthcare professionals (HCPs). However, this is not so easy to execute, as many people are reluctant to become vaccinated. Those people do not realize the evident benefits of vaccination and often make false conclusions about their own risks, but what bothers me, is that they put others at risk. People carrying influenza virus may infect myeloma patients who have a higher risk for becoming infected. Importantly, the response to vaccination is markedly lower in myeloma than in healthy people. Hence, the ensuing antibody response should be checked after vaccination, and patients should be revaccinated if there is an insufficient response.

Other vaccinations to consider, include pneumococcal infections, haemophilus influenzae and in selected patients, namely in those with splenectomy or certain complement deficiencies, meningococcal vaccination should be considered. Hepatitis is also something to think about, though this is more relevant in areas of high risk, while in Europe it is not a big problem. When you notice an increase in liver enzymes during treatment with proteasome inhibitors, you should check whether this is due to re-activation of subclinical virus infection.

The vaccines currently available for herpes zoster and herpes simplex, are live attenuated. There is some concern that those viruses may result in clinical infection in patients with severe immunosuppression. New genetically engineered vaccines will certainly replace these preparations in a couple of years, but we have to work with the preparations that are available today. Hence, attenuated vaccines may, in my opinion, be used in patients with well-controlled disease, but I would not administer them to patients with active myeloma. Anti-viral drugs such as acyclovir are mandatory in patients on proteasome inhibitors and are recommended in patients during monoclonal antibody treatment.

FC: Myeloma patients will clearly be more susceptible to seasonal infections such as influenza virus. How do current vaccination programs deal with this in Austria?

HL: There are clear recommendations available in Austria but compliance with the program is not optimal, due to both perception and organizational hurdles. Unfortunately, you cannot easily change perception, especially when people believe that the vaccines can do them harm, even though this goes against common knowledge and expert recommendations. The other issue is the logistics, as patients are prescribed the vaccine and must come to collect this from the pharmacy before being administered in the clinic. Providing the vaccines directly in the clinic without this hurdle would make things much easier.

FC: Can you comment on how vaccination regimens for MM patients differ worldwide and whether other countries follow similar guidelines?

HL: I do not have very solid data but the recommended programs are similar worldwide, although some countries seem to neglect these issues. In general, our attitudes towards prevention of infections is suboptimal.

FC: In your talk, you detailed your personal recommendations for diagnostic measures to assess infection. Could you please outline these briefly and explain how they should fit into patient assessments?

HL: If a patient has an increased risk for infection, and has successfully been vaccinated, she/he is still at increased risk for developing infections caused by other viruses or bacteria. In case of early symptoms of upper respiratory tract infection in patients not immune against influenza virus, inhaling a drug [Relenza® (zanamivir)], which blocks neuramidase receptors used by viruses to enter the cell, may be helpful. This drug seems to have a protective effect against viruses other than influenza as well.

For diagnosis of a suspected viral infection, one should use the available diagnostic machinery, in particular, polymerase chain reaction (PCR) tests to directly detect viral antigens. By using antibody testing only, you may miss the detection of viruses, because of the frequently impaired antibody response in myeloma patients. Essentially, one should test for viruses that are quite frequent in myeloma, including herpes simplex (HSV), herpes zoster virus (HSV), adenovirus, influenza and parainfluenza virus, respiratory syncytial virus (RSV), cytomegalovirus (CMV), vesicular stomatitis virus (VZV), and Epstein-Barr virus (EBV), which may be re-activated. However, we need to acknowledge that even with this extended panel we can fail to diagnose infections with other viruses. Quite often physicians are still in the dark, because they miss the virus. Multiplex PCR can detect a lot more viruses (20 or 32 different strains) and will give a better clue as to what is going on in your patients. Therefore, if your PCR is negative you cannot exclude an ongoing viral infection, due to the limitations of our current diagnostic machinery.

Fungal infections are usually only a problem during high-dose therapy (HD-Dex) and allo-transplantation. Candida often infects the oropharyngeal cavity and can be diagnosed by both visual inspection and blood cultures and Aspergillus can be diagnosed with remarkable sensitivity using a CT thorax, as well as by blood cultures and using the galactomannan assay.

FC: When and how often should these assessments be carried out?

HL: Ordinarily they should be carried out when an infection is suspected and/or when the patient presents with symptoms associated with infection. Usually I send blood samples to the laboratory and request a mouthwash in the case of upper respiratory tract infections. The samples are analyzed using a molecular assay (LightCycler® SeptiFast) that tests for more than 20 bacteria, and a few fungi, and gives results after about six hours. This kind of diagnostic test is likely to revolutionize how we detect infections.

FC: Your recommendations for vaccinations are quite extensive and were summarized in a table. Thank you for allowing us to reproduce this.

FC: These recommendations are predominantly for transplant-eligible patients, as you use post-transplant for the timing. Can this be extrapolated into a program for transplant-ineligible patients? Would they also need the full repertoire of vaccinations?

HL: When a patient receives a transplant, their immune system will be suppressed, putting them at increased risk for developing infections. In this situation, recommendations have been issued, but we should keep in mind that these are expert recommendations only, with limited data from solid clinical studies supporting them. Nevertheless, it seems worthwhile to follow them. In this regard, it may be important to test for viral infections in those patients who do very poorly after transplant and suffer from extreme weakness and fatigue. I would postulate that many of these patients are affected by re-activation of latent viral infections, which presently go undetected. But to answer your question, yes the vaccination program applies as well to the transplant-ineligible patients.

FC: You referred to Andrew Brangan’s data presented at ASH 2017 regarding two influenza vaccinations being better than one. Would you advocate a change in the guidelines to consider this or do we need more evidence?

HL: I think it is logical to vaccinate twice against influenza. You could vaccinate once and then check the antibody titer, but in practice that is not usually done, so it may be easier and better to plan for two vaccinations from the outset. Importantly, influenza vaccines have been improved lately and now cover three to four different strains.  

FC: What is the indication for prophylactic intravenous (IV) immunoglobulins in myeloma?

HL: The current data is very limited, but it has been shown that IV immunoglobulins (Ig) do reduce the risk of bacterial infections and perhaps some viral infections as well. However, you should carefully select the patients which might benefit from therapy. I would only do this [IV Ig] primarily in patients with a history of an increased incidence of infection. In those patients, I check carefully whether IV immunoglobulins provide any benefit. This can be recognized quite quickly (in the first few weeks) after initiation of therapy. If there is no relevant reduction in infection, and in infection risk, I discontinue treatment after a few months at the latest.

Some authors argue that the indication for IV immunoglobulins should be based on the level of polyclonal immunoglobulins. Although some of those patients have a higher risk of infection, there is quite a significant proportion of patients without an increased risk. Hence, I orient myself mainly on the clinical history and on the clinical findings and much less so on levels from laboratory tests. To summarize, I give those patients with frequent bacterial infections a try with IV immunoglobulins.

Thank you so much for talking to the MM Hub!