Managing Myeloma

Shaji K. Kumar, MD
Associate Professor of Medicine
Mayo Clinic College of Medicine
Consultant, Division of Hematology
Mayo Clinic
Rochester, Minnesota

The opinions contained within this commentary are solely those of Shaji K. Kumar, MD, and are not supported or endorsed by MediCom Worldwide, Inc. or Millennium Pharmaceuticals, Inc. and its affiliates or Cephalon Oncology.

Hello, my name is Shaji Kumar. I am a consultant in the Division of Hematology at Mayo Clinic Cancer Center in Rochester, Minnesota. What I would like to talk about today is the problem of bone disease in multiple myeloma. As you are all aware, it is a common manifestation and ranges all the way from normal bones to osteopenia as well as lytic lesions and pathologic fractures.

The bone disease in myeloma results in considerable morbidity because of the bone pain, the pathological fractures as well as the compression fractures that can lead to neurological compromise. Normally bone formation and bone destruction is a dynamic process that balances each other out. However, in the context of multiple myeloma, there is a significant imbalance with the reduction in the activity of osteoblast that creates bone and osteoclast that results in the bone resorption. The end result of the changes that happens in multiple myeloma is the increased destruction of bone that you often see in the x-rays as lytic lesions or sometimes just as diffuse osteopenia. Clearly, this is one manifestation of myeloma that needs specific therapy in addition to the therapy that is given for management of the disease.

Now one of the things that have proven to be really successful in managing the bone disease in myeloma is bisphosphonates. There are several different bisphosphonates out there and many of them have been used in clinical trials looking at its impact in various malignancies especially in multiple myeloma, and in general what they do is they bind to what we call the calcium hydroxyapatite in the bone and inhibit the osteoclast recruitment and maturation thus preventing bone resumption. There is also some data out there that suggest that maybe it may also have some direct antimyeloma effect and they may also have some anti-angiogenic effect in the context of multiple myeloma. There has been a variety of different clinical trials that have been done looking at the different bisphosphonates especially clodronate, the pamidronate, and the zoledronic acid.

There are several potential benefits of bisphosphonate therapy in multiple myeloma. It can lead to decrease in the bone pain. It can improve the bone density and also have improved quality of life because of the decrease in the skeletal events and the bone pains and there is some suggestion that maybe use of bisphosphonates also might improve the survival in patients with multiple myeloma. So when you talk about bisphosphonate therapy in multiple myeloma, the five questions that always comes up are: who needs it, which bisphosphonate to use, at what dose and frequency, how long do you need to treat patients with myeloma, and what do you monitor while you treat these patients with bisphosphonates. And let us just take each of these questions, one at a time.

Who really needs bisphosphonate therapy? There is no role in patients with monoclonal gammopathy of undetermined significance (MGUS) or patients with asymptomatic myeloma, at this time, based on the data from the different clinical trial sets out there. Clearly, patients with lytic lesions and patients who have had pathological fractures definitely benefit from the use of bisphosphonates. Patients with myeloma who have significant osteopenia will definitely benefit from the use of bisphosphonates. There is some suggestion that maybe any patient with multiple myeloma who is requiring an active myeloma therapy even in the phase of normal
x-rays might benefit from the bisphosphonates; however, there is no conclusive data for this particular group of patients.

Now, which bisphosphonate can be used for treating patients with multiple myeloma? Pamidronate and zoledronic acid are the two that are approved for use in this country and which we commonly use. The zoledronic acid is much more potent. It has a shorter infusion time, but, however, some studies suggest that there is higher risk of complications such as osteonecrosis of the jaw with the use of zoledronic acid. However, what we need to keep in mind is both of them are equally effective in reducing skeletal events based on clinical trials.

Now, how often do you want to actually give the bisphosphonates? The dose of pamidronate is typically given 90 mg IV monthly whereas zoledronic acid is given 4 mg IV monthly. Now, there was one trial that was recently published which demonstrated that 30 mg of pamidronate given monthly is as effective as 90 mg of pamidronate given monthly; however, we need more data before we make any changes in terms of the actual dosing. Now, less frequent administration has not been studied prospectively in comparison to the monthly dosing; however, those kinds of trials are being planned or ongoing. Now, there are some suggestions that may be every 3- to 4-month dosing can be used after the initial 18 months to 2 years of treatment. Now, the doses clearly need to be adjusted for renal failure especially in the context of zoledronic acid and there is enough information out there in terms of dose adjustments in patients with renal insufficiency. Many of us also often tend to use a lower dose of pamidronate in patients with renal insufficiency even though it is not clear how much is really required.

Now, how long do you give the bisphosphonate therapy? This is a question that has been a point of contention for awhile. The current recommendation is to use for 2 years and continued use at a reduced frequency once the 2 years is up may be every 3 to 4 months is often practiced. Now, there is some suggestion that may be we can stop or reduce the frequency of bisphosphonates early on may be at 12 to 18 months especially for patients who have obtained a complete response after stem cell transplantation and in patients whose disease relapsed subsequently, they certainly should be restarted at the time of relapse and in patients who developed skeletal event.

Now, one thing we really do not know much about is how do we monitor patients who are getting bisphosphonate therapy. There are no accepted parameters. There is some suggestion again may be the baseline DEXA scans may be useful in assessing the subsequent improvement; however, this has not been prospectively studied. The role of other imaging studies again had not been clearly studied in studies. The bone resorption markers such as the ICTP or NTx are currently being evaluated in clinical trials and this probably have the best chance of providing useful information in the future. At least in one trial, a high baseline bone alkaline phosphatase predicted for survival improvement when treated with bisphosphonates.

Now what are the common side effects of bisphosphonate therapy in these patients? What you commonly come across is flu-like symptoms such as muscle aches, fever, chills, nausea, and joint pains and most of these can be effectively managed with drugs such as acetaminophen. We can also see IV site reactions with these injections. These again can be very conservatively managed. Hypocalcemia and hypophosphatemia are not very common among patients with multiple myeloma getting bisphosphonates and in this context, again I want to highlight that these patients should always be on calcium supplementation as well as vitamin D supplementation.

Now, one of the side effects that always comes to mind when you hear about bisphosphonates is the osteonecrosis of the jaw. Now this is increasingly being appreciated which I think is for two reasons. One, there is increasing use of bisphosphonates in this patient population and second, patients are clearly living longer with the new therapies and hence are being exposed to a longer duration of treatment with the bisphosphonates. It certainly depends on the duration of therapy and the cumulative dose and it is roughly believed to be about 5% to 15% at about 4 years of treatment. And there is one Greek study which suggested that there may be higher incidence of ONJ occurs with zoledronic acid. Again these two drugs have not been studied head to head in terms of their risk of ONJ. Typically the osteonecrosis is precipitated by dental procedures and trauma in the context of someone getting bisphosphonate therapy.

Now, how do you prevent ONJ? I think it is prudent to say that a comprehensive dental assessment before starting bisphosphonates is a must for patients with multiple myeloma. Now, this should be followed by regular dental care for these patients and there are some recent studies suggesting that may be use of prophylactic antibiotics may prevent the incidence of ONJ. Clearly if somebody develops ONJ, they might need a more detailed evaluation. Surgery is sometimes needed and the other question is whether we should restart bisphosphonates after someone got ONJ. I think if there is complete healing in a patient who has relapsed disease who is at high risk of skeletal events, I think it is reasonable to consider restarting the bisphosphonate therapy and clearly if somebody needs dental procedures, it is always important to hold the bisphosphonate therapy before they proceed to the dental procedure.

The other relatively uncommon toxicity that we see with bisphosphonate is the renal toxicity. Now, it can be either acute or chronic damage and is often related to the dose and infusion rate. There have been reports of acute tubular necrosis and the common renal manifestation that is seen with pamidronate is proteinuria and biopsies in these patients often show a collapsing variant of focal segmental glomerulosclerosis. So it very important that we monitor the creatinine and proteinuria in patients getting bisphosphonates and in someone who actually do develop some increase in the creatinine, I think it is important to hold treatment until we see renal recovery.

So there are a variety of recommendations out there from different bodies including the American Society of Clinical Oncology as well the European Myeloma Network, the International Myeloma Working Group as well the Mayo Clinic. Most of them would agree upon a few common things. One is patients with multiple myeloma with any evidence of bone disease should definitely get bisphosphonate therapy. They should get bisphosphonate therapy for about 18 months to 2 years and following that you can make the decision of continuing bisphosphonate therapy at a reduced frequency depending upon the clinical context.

In conclusion, bisphosphonate therapy is an important component of the supportive care of patients with multiple myeloma. Clearly patients with myeloma and bone disease will benefit from the use of bisphosphonate therapy both in terms of decreasing the symptoms as well as decreasing the risk of skeletal events such as fractures. There are new drugs that are coming through such as denosumab which depends on different mechanisms but again seemed to have activity in the setting and future clinical trials will tell us how to use those new drugs.

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