Renal impairment in mutiple myeloma

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Published: 5 Apr 2013
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Prof Meletios Dimopoulos - Univeristy of Athens, Greece

Prof Meletios Dimopoulos talks to ecancertv at IMW 2013.

Renal impairment is a common complication in multiple myeloma (MM). It is seen in 20-40% of patients with MM. In about 5% of cases, acute renal impairment occurs, which is oliguric and may require haemodialysis.

The reason for this is the production of free light chains in excess to heavy light chains by myeloma cells. These filter through the glomeruli and accumulate in the renal tubules. In some patients cast formation occurs and these can obstruct the renal tubules, leading to deterioration of renal function.

Outside of MM itself, a number of risk factors predispose patients to renal impairment. In around of 10% of patients there is hypercalcaemia, which is a cause of renal impairment. In addition, many patients complain of bone pain prior to diagnosis of MM, which has been treated with nonsteroidal anti-inflammatory drugs.

These agents predispose to renal impairment as well. Furthermore, these patients are often dehydrated, which contributes to renal impairment. Finally, antibiotics used for the treatment of infection and contrasting agents used in imaging are both nephrotoxic.

Renal impairment significantly impacts on prognosis and overall survival in MM patients. It is the most common cause of early mortality in MM patients, with death seen in the first 2 months from diagnosis. It also causes significant morbidity and increases the expense of treating these patients. Before the era of novel agents, renal impairment prevented MM patients from receiving appropriate therapy.

Supportive care is provided to these patients in the form of haemodialysis for oliguric patients. Rehydration is also very important and to avoid procedures that may aggravate renal impairment.

Some mechanical procedures have also be used, including plasma exchange, but have not been very successful. This is because the light chains have a low molecular weight and are not effectively removed with this procedure. Today, however, there are some special haemodialysis filters with large pores that are able to retain the free light chains.

The advent of novel therapies has significantly impacted on the treatment of MM with renal impairment. In combination with high dose steroid therapy, bortezomib is the mainstay of therapy and has been shown to be safe and effective in these patients. In fit patients, a third agent can be added, include cyclophosphamide, doxorubicin or thalidomide. Lenalidomide can be considered with a dose adjustment.

High dose therapy and autologous stem cell transplant (ASCT) has been used in these patients, with a dose adjustment of melphalan. However, with the use of novel agents, the use of high dose therapy in these patients is decreasing.

Carfilzomib can be given to renal patients with no impact on renal function. Pomalidomide can also be used safely in patients with a creatinine clearance above 45 mL/min. However, there are ongoing studies to evaluate the use of pomalidomide in patients with lower creatinine clearance.

This programme has been supported by an unrestricted educational grant from Janssen Pharmaceutica (A Johnson & Johnson Company).

14th International Myeloma Workshop

Renal impairment in multiple myeloma

Professor Meletios Dimopoulos – University of Athens, Greece

Renal impairment is a common complication in MM. Why is this?

Depending on how you define renal impairment, it is seen in 20-40% of patients with myeloma diagnosis and actually in about 5% you have a clinical scenario of acute renal impairment which can be oliguric and may require even haemodialysis. The reason is that the myeloma cells produce free light chains in excess to the heavy light chains and these circulate and they’re filtered through the glomeruli and they accumulate in the renal tubules. In some patients, not in all patients, in some patients there is a cast formation there which obstructs the renal tubules and then the endpoint is deterioration of renal function.

Outside of MM itself, what risk factors predispose to renal impairment in these patients?

As you know, about 10% of patients at presentation, they have hypercalcaemia which per se is a cause of renal impairment. Also many of these patients before the diagnosis of myeloma, they complain of bone pain so even before the diagnosis is made they’re being treated with non-steroidal anti-inflammatories and we know that these agents predispose for renal impairment as well. Furthermore, because of pain, because of hypercalcaemia, they are dehydrated and also this contributes further to renal impairment. Finally, sometimes they present with infection and we know that antibiotics are nephrotoxic; they get imaging procedures to make the diagnosis and we know that some contrasts are also nephrotoxic. So all these parameters may aggravate the renal impairment but the basic and the main problem is the toxic free light chains.

How does renal impairment impact on prognosis and overall survival in MM patients?

Yes, there is a very significant impact on the prognosis of the patient. First of all, renal impairment is the most common cause of early mortality in myeloma and when we say early mortality we’re talking about death within the first two months from diagnosis. Also it affects the overall survival of the patient; it causes significant morbidity; it increases the expense of treating these patients and before the era of novel agents it did not allow patients to get appropriate therapy.

What supportive care is offered to these patients?

Along with prompt institution of anti-myeloma therapy, it is very important to provide the appropriate supportive care. First of all, if the patient is oliguric you need to start him on haemodialysis and also rehydration is very important because these patients are dehydrated. It is important to avoid all types of procedures and medications that may aggravate renal impairment and also today there are some mechanical means to remove these free light chains. Plasma exchange, plasmapheresis, has not been very successful in the past because light chains have low molecular weight and they are not effectively removed with this procedure. However, today there are some special haemodialysis filters with large pores that are able to retain the free light chains. So this is an additional means to reduce acutely the free light chain until there is time for the anti-myeloma treatment to affect the production.

What role can novel therapies play in MM patients with renal impairment?

First of all, we have to use steroids and in most of these patients we need to use a high dose steroid regimen, at least for the first month of treatment, because steroids have single agent activity against myeloma and also they have a quick activity and they have synergism with most of the novel agents. Among the three novel agents that are in clinical use today, bortezomib is the agent that is usually preferred when we’re dealing with a patient with moderate to severe renal impairment. This is due to the fact that bortezomib is metabolised outside the kidneys so it’s not renally excreted. It has a very quick mode of action and it has a significant anti-myeloma activity. So a combination of high dose steroids with bortezomib is the mainstay of treatment. In most patients, if they are in a good condition, we would like to add a third agent which can be cyclophosphamide, it can be doxorubicin or it can be thalidomide. These are the most frequently used regimens to treat patients with myeloma-related renal failure.

Can lenalidomide be used in those patients with a dose adjustment?

Other options when bortezomib is not indicated include thalidomide, which also has activity in myeloma and can be given relatively safely in patients with renal impairment, and also lenalidomide, which is excreted by the kidneys at a significant degree. However, if you adjust the dose of lenalidomide it is quite safe to give lenalidomide and you will avoid overwhelming and myelotoxicity which is seen when you use a standard dose of lenalidomide in patients with renal impairment.

Is high dose therapy with autologous stem cell transplantation a viable option in these patients?

Yes, in the past, before the era of novel agents, a relatively significant number of patients with stable renal impairment were treated with high dose therapy. We know that high dose therapy, when a patient has renal impairment, is usually more toxic, you have to adjust the dose of melphalan, the indicated dose is 140mg/m2 and despite that you will anticipate higher myelosuppression and toxic mucositis. In the era of novel agents I believe that the number of patients that now proceed to high dose therapy with renal impairment is decreasing.

What new proteasome inhibitors are being investigated that could be considered in the future for MM patients with renal impairment?

We have a very recent publication regarding the tolerability and efficacy of carfilzomib, which is a novel non-reversible proteasome inhibitor recently approved in the United States for the treatment of patients with relapsed refractory myeloma resistant to bortezomib and lenalidomide. The recent data indicates that carfilzomib can be given to patients regardless of their renal function and there is no additional toxicity and the activity appears to be the same. So this is very encouraging results because we may have now a fourth novel agent which could be given to these patients.