EHA 17

Strategies to improve the tolerability of treatment in patients with multiple myeloma

Professor Michel Delforge – Catholic University, Leuven, Belgium



What strategies are being investigated for optimizing efficacy and improving tolerability?

Well there are three approaches that have proven to be very useful in order to improve the tolerability. First of all, of course, reducing the dose of the drug whenever needed but, in addition to that, for bortezomib-based regimens also prolonging the interval between the injections and a second approach for bortezomib is changing the route of administration from IV to sub-cue.

What are the treatment goals for adapting treatment?

So of course the primary treatment goal is to deliver optimal treatment, in other words to get the best result in terms of response, progression-free and overall survival. But what we have learned is that sometimes by trying to give too much of a drug in a too short period of time you can encounter problems that patients need to discontinue treatment early because of unacceptably high toxicity.

What are the key circumstances where dose modification or route of administration are required?

This is for particular patient subgroups like there are the frail patients, which is frequently associated with age, so in the very elderly patients. But this can also be the case in younger patients if they have, for instance, toxicities from previous treatments and I think about serious peripheral neuropathy. This can also be the case for patients who have poor bone marrow reserve that can be related to extensive myeloma involvement in the bone marrow.

How do you manage peripheral neuropathy?

An important comment I would like to make is that we should try to prevent it and whenever possible because, for instance, for thalidomide induced peripheral neuropathy it is hardly reversible and for bortezomib induced peripheral neuropathy it is reversible in, let’s say, 70-80% of the patients but this means that in 20% of the patients it’s not reversible and also when it’s reversible it usually takes 2-3 months and during that period of time patients can suffer from this peripheral neuropathy. So therefore prevention is the most important approach. In terms of management of intervention, one could do several things but this is not based on strong evidence, this is more like based on personal experience and this could be, if it’s painful neuropathy, to give drugs that reduce the pain, sometimes antidepressant drugs like gabapentin or pregabalin, they can have some activity. But the most important thing is that we really should try to make every effort to prevent neuropathy by frequently evaluating the patients.

Should myeloma physicians routinely involve a nephrologist in the management of patients with renal impairment?

That’s a very important question and the answer is yes, especially in cases when there is severe renal impairment; when a patient, for instance, will need dialysis or is already on dialysis because of acute renal failure. So in that specific situation it can be very helpful to discuss with a nephrologist, for instance, about a renal biopsy and also in terms of trying to optimise the supportive treatment with standard dialysis or eventually in the context of a clinical trial with specific dialysis membranes.

What is your strategy for both the prevention and the management of infections?

Also here I want to emphasise the importance of clinical awareness because myeloma patients, especially patients with active disease, also elderly patients, patients with renal impairment, they are very prone to severe infections, most of the time severe bacterial infections. So clinical awareness is very important because sometimes if these patients are on treatment with high dose dexamethasone, the typical clinical symptoms can not be there so you really need to rely on your clinical experience and on having a low threshold for doing additional examinations and for prompt installation of effective anti-infectious treatment like antibiotics. In a more general situation it is important to be aware that treatment with bortezomib will increase the risk for herpes zoster reactivation in these patients to give the appropriate prophylaxis and to be aware, of course, that some drugs like lenalidomide or combinations with chemotherapy can induce neutropenia and therefore increase the risk for infections.

How do you manage bone disease?

As we know, 80% of the myeloma patients will have some form of bone disease and bone symptoms are the most important symptoms of the disease and more precisely I mean bone pain, pathological fractures resulting in functional impairment. So the management of bone disease also starts with just using the right approach to diagnose the disease which can sometimes be a standard X-ray but if that doesn’t show up with lesions and the patient suffers from bone pain it should be supplemented with more specific exams like a CT scan or MRI or eventually, in specific cases, a PET scan. But if you know that there is bone disease, well the approach can depend on the type of the bone involvement, for instance, if there is a threat for compression on the spinal cord or there is spinal compression, of course, patients need immediate radiotherapy. In the case when there is just the bone disease with limited symptoms then of course you start with the general anti-myeloma treatment. If there is extensive pain of course one should give appropriate drugs and appropriate pain killers. An important class of drugs in treatment of myeloma bone disease are the bisphosphonates and recently there have been very interesting data on the role of one of the amino bisphosphonates, zoledronic acid, not only on the bone disease but also on the myeloma itself, briefly showing that patients treated with zoledronic acid had a longer overall survival compared to patients who were treated with one of the older bisphosphonates, more precisely chlodronate.

A final comment that I would like to make is that there are emerging data that anti-myeloma drugs like bortezomib, they also exert or they can exert a positive effect on the bone. More precisely, they can stimulate bone formation in some patients and it is the subject of on-going clinical studies.

What is your strategy to prevent venous thromboembolism?

We should be aware about the increased risk of venous thromboembolic events in the majority of myeloma patients just because of the disease. But patients who are more at risk are patients who are treated with a thalidomide- or lenalidomide-based regimen when the drugs are used in combination, so lenalidomide is used in combination with dexamethasone, thalidomide combined with dexamethasone, eventually supplemented with a third agent. There have been algorithms published where the type of the anti-coagulant drug that should be given is related to the number of risk factors. So when a patient has a very low risk for venous thromboembolism, then normally it’s sufficient to give a low dose of aspirin. Various patients who have a higher risk should be treated with a prophylactic dose of low molecular weight heparins. When a patient has already got a previous thromboembolic event, then you should judge if this patient should continue on this type of treatment or switch treatment, if not it might be interesting to put the patient on a full dose of anti-coagulation.

What were your main highlights from EHA?

In terms of EHA, I think we had useful repetition of studies that had been previously presented but this repetition or more mature follow-up is very important. There are, of course, new drugs that are pretty close to entering treatment or that will soon be available, so I think drugs like pomalidomide, carfilzomib, there are data on interesting combinations, for instance the combinations with novel antibodies like elotuzumab. There was a very interesting study about a new monoclonal antibody that is called daratumumab, so really many new things but some of these studies need just a more prolonged follow-up to be able to know exactly their activity and also to be able to position them in the whole treatment approach of myeloma patients. In terms of increased tolerability, I think there was some interesting discussion about the sub-cue administration of bortezomib where this will really imply a major change in the near future, where many patients will be switched from IV to sub-cue. Although the published study in relapsed patients showed a nearly identical activity from sub-cue compared to IV, we still need in the future additional studies with sub-cue administration in first line in younger and in elderly patients. This will be for the up-coming meetings.