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Goals of Therapy in Multiple Myeloma

Insights From:Shaji K. Kumar, MD, Mayo Clinic College of Medicine; Peter Voorhees, MD, UNC School of Medicine at Chapel Hill
Published: Friday, Apr 08, 2016


Transcript:

Shaji Kumar, MD:
Monoclonal antibodies have opened up a new paradigm in treatment of multiple myeloma. The unique thing with monoclonal antibodies is now we have a class of drugs that works through entirely different mechanisms than what proteasome inhibitors, or alkylating agents, or immunomodulatory drugs work through. Now, the goal of therapy in multiple myeloma also has changed along with the availability of new drugs. The primary goal of therapy is to control the disease and reverse the complications of side effects that are related to the disease itself. But, having more effective drugs also allows us to aspire for something more than just controlling the disease, which is having very deep responses to therapy in myeloma. We know that if we can get to very deep responses, the disease can be controlled for a much more prolonged period of time. Not only that, if we can actually get to very minimal amounts of disease or eradicate the minimal amount of disease, we could potentially look at the possibility of curing this disease. So, I think that is where having multiple different classes of drugs can really make a difference.

I think for the future of myeloma therapy, we’re going to be looking at combining these monoclonal antibodies with some of the more effective combinations that we have, such as the combination of proteasome inhibitors and the immunomodulatory drugs. We could be looking at the same paradigm that we have in lymphoma, where rituximab is combined with conventional chemotherapy and can cure a substantial proportion of patients with lymphoma. So, we are hoping that we can probably at least go down that same path by combining these monoclonal antibodies with the effective combinations and get deep responses, with the hope that at least a proportion of those patients would eventually be cured of the disease.

But, in the short-term, the goals or the target for how long or what therapies we use would be based on the conventional measurements of response, which is the stringent complete responses. And more recently, we have been using minimal residual disease negativity. That is increasingly going to be a goal of therapy in myeloma because we know that getting to MRD-negative status translates to better overall survival in the vast majority of these patients. How do we define MRD negativity? That is something that is evolving, and there’s going to be updated response criteria that’s going to be coming out in the next few months that will define MRD negativity in patients with multiple myeloma. So, that is increasingly going to be one of the goals for treating multiple myeloma, especially in the early phases of the disease.

Now, where does a monoclonal antibody fit into this whole thing? The future is going to be in combinations, so identifying which monoclonal antibody will do a better job when combined with the other agents that we have is going to be one of the tasks that we have to engage in, in the next few years. And the clinical trials that are ongoing, as well as some of the new clinical trials that are being planned, will help answer that question. The monoclonal antibodies also give us some flexibility in terms of special patient groups; in particular, patients with renal failure. There are some of the medications that cannot be used in these patients. Especially the immunomodulatory drugs, like lenalidomide and pomalidomide, have to be dose-modified if you’re going to be using them in patients with renal insufficiency. Now, this is not a concern for the proteasome inhibitors, but many of the other drugs, especially the traditional chemotherapy drugs, also have to be modified in patients with renal failure. One of the advantages of the monoclonal antibodies is that they can be given without any dose modifications in patients with renal failure. And that gives us one more class of drugs that can potentially be used in this patient group.

Another group of patients where it could be of particular benefit are the older and the more frail patients. These patients often have many comorbidities, and when you talk about all patients, one has to keep in mind the median age of diagnosis of myeloma is about 67 to 69 years. So, half of these patients are going to be 70 or older, and many of them will have other illnesses, especially the common illnesses like heart disease, hypertension, and diabetes. To navigate all these additional illnesses that these patients have, it can often be very difficult. So, having therapies that are well-tolerated is always of great benefit in patients with myeloma. We know that the current therapies can be given to these patients with decreased doses, but that also often compromises the efficacy of these regimens. The monoclonal antibodies can be very well tolerated, and this also gives us the opportunity to combine the monoclonal antibodies with smaller doses of the other drugs. Or maybe even give the monoclonal antibodies just by themselves, especially in the case of daratumumab where we know it can work all by itself in relapsed myeloma.

One of the difficulties we often face with relapsed myeloma is that many patients can have a very slow rise in their monoclonal protein without actually having any consequences of that monoclonal process. Now, this is the situation akin to what we see in patients with monoclonal gammopathy of undetermined significance or smoldering myeloma, where we are closely watching protein that is slowly rising. But we are not doing anything about it because we know that a significant number of these patients can go for years before they might actually develop any complications of the disease. So, patients with multiple myeloma who have biochemical progression don’t always need therapy right away, especially if these patients present in an indolent fashion in the beginning. These patients can be carefully watched until they start developing some early signs of end-organ damage, and that’s when we may have to intervene with therapies.

Now, the reason why we often adopt this wait-and-watch policy is because most of the drugs that we use for these patients also have side effects. So, it’s always a balance between are we actually giving them side effects when they actually don’t have any symptoms, and that often has dictated why we adopt this late approach. As we have new therapies that are better tolerated—for example, monoclonal antibodies—this is a paradigm that would need to be revisited again. If somebody has just biochemical progression and no symptoms—and if you can give them maybe a monoclonal antibody less often without any significant toxicity, and if you can prove that in clinical trials that this approach of early therapy will change the natural history of the disease, and make patients live longer with a better quality of life—that may be a significant advance in the future. But, at this point, we do not have any data to support that these patients, with just biochemical progression, that by intervening early, we are going to actually make a difference in their overall survival. So, those decisions have to be clearly dictated by data from clinical trials.

There are no clinical trials specifically looking at biochemical progression, but there are clinical trials looking at smoldering multiple myeloma, high-risk smoldering myeloma. I think it will be probably a fair extrapolation to do if we can demonstrate that it works in smoldering myeloma, that maybe we should intervene in biochemical progression.

Transcript Edited for Clarity
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Transcript:

Shaji Kumar, MD:
Monoclonal antibodies have opened up a new paradigm in treatment of multiple myeloma. The unique thing with monoclonal antibodies is now we have a class of drugs that works through entirely different mechanisms than what proteasome inhibitors, or alkylating agents, or immunomodulatory drugs work through. Now, the goal of therapy in multiple myeloma also has changed along with the availability of new drugs. The primary goal of therapy is to control the disease and reverse the complications of side effects that are related to the disease itself. But, having more effective drugs also allows us to aspire for something more than just controlling the disease, which is having very deep responses to therapy in myeloma. We know that if we can get to very deep responses, the disease can be controlled for a much more prolonged period of time. Not only that, if we can actually get to very minimal amounts of disease or eradicate the minimal amount of disease, we could potentially look at the possibility of curing this disease. So, I think that is where having multiple different classes of drugs can really make a difference.

I think for the future of myeloma therapy, we’re going to be looking at combining these monoclonal antibodies with some of the more effective combinations that we have, such as the combination of proteasome inhibitors and the immunomodulatory drugs. We could be looking at the same paradigm that we have in lymphoma, where rituximab is combined with conventional chemotherapy and can cure a substantial proportion of patients with lymphoma. So, we are hoping that we can probably at least go down that same path by combining these monoclonal antibodies with the effective combinations and get deep responses, with the hope that at least a proportion of those patients would eventually be cured of the disease.

But, in the short-term, the goals or the target for how long or what therapies we use would be based on the conventional measurements of response, which is the stringent complete responses. And more recently, we have been using minimal residual disease negativity. That is increasingly going to be a goal of therapy in myeloma because we know that getting to MRD-negative status translates to better overall survival in the vast majority of these patients. How do we define MRD negativity? That is something that is evolving, and there’s going to be updated response criteria that’s going to be coming out in the next few months that will define MRD negativity in patients with multiple myeloma. So, that is increasingly going to be one of the goals for treating multiple myeloma, especially in the early phases of the disease.

Now, where does a monoclonal antibody fit into this whole thing? The future is going to be in combinations, so identifying which monoclonal antibody will do a better job when combined with the other agents that we have is going to be one of the tasks that we have to engage in, in the next few years. And the clinical trials that are ongoing, as well as some of the new clinical trials that are being planned, will help answer that question. The monoclonal antibodies also give us some flexibility in terms of special patient groups; in particular, patients with renal failure. There are some of the medications that cannot be used in these patients. Especially the immunomodulatory drugs, like lenalidomide and pomalidomide, have to be dose-modified if you’re going to be using them in patients with renal insufficiency. Now, this is not a concern for the proteasome inhibitors, but many of the other drugs, especially the traditional chemotherapy drugs, also have to be modified in patients with renal failure. One of the advantages of the monoclonal antibodies is that they can be given without any dose modifications in patients with renal failure. And that gives us one more class of drugs that can potentially be used in this patient group.

Another group of patients where it could be of particular benefit are the older and the more frail patients. These patients often have many comorbidities, and when you talk about all patients, one has to keep in mind the median age of diagnosis of myeloma is about 67 to 69 years. So, half of these patients are going to be 70 or older, and many of them will have other illnesses, especially the common illnesses like heart disease, hypertension, and diabetes. To navigate all these additional illnesses that these patients have, it can often be very difficult. So, having therapies that are well-tolerated is always of great benefit in patients with myeloma. We know that the current therapies can be given to these patients with decreased doses, but that also often compromises the efficacy of these regimens. The monoclonal antibodies can be very well tolerated, and this also gives us the opportunity to combine the monoclonal antibodies with smaller doses of the other drugs. Or maybe even give the monoclonal antibodies just by themselves, especially in the case of daratumumab where we know it can work all by itself in relapsed myeloma.

One of the difficulties we often face with relapsed myeloma is that many patients can have a very slow rise in their monoclonal protein without actually having any consequences of that monoclonal process. Now, this is the situation akin to what we see in patients with monoclonal gammopathy of undetermined significance or smoldering myeloma, where we are closely watching protein that is slowly rising. But we are not doing anything about it because we know that a significant number of these patients can go for years before they might actually develop any complications of the disease. So, patients with multiple myeloma who have biochemical progression don’t always need therapy right away, especially if these patients present in an indolent fashion in the beginning. These patients can be carefully watched until they start developing some early signs of end-organ damage, and that’s when we may have to intervene with therapies.

Now, the reason why we often adopt this wait-and-watch policy is because most of the drugs that we use for these patients also have side effects. So, it’s always a balance between are we actually giving them side effects when they actually don’t have any symptoms, and that often has dictated why we adopt this late approach. As we have new therapies that are better tolerated—for example, monoclonal antibodies—this is a paradigm that would need to be revisited again. If somebody has just biochemical progression and no symptoms—and if you can give them maybe a monoclonal antibody less often without any significant toxicity, and if you can prove that in clinical trials that this approach of early therapy will change the natural history of the disease, and make patients live longer with a better quality of life—that may be a significant advance in the future. But, at this point, we do not have any data to support that these patients, with just biochemical progression, that by intervening early, we are going to actually make a difference in their overall survival. So, those decisions have to be clearly dictated by data from clinical trials.

There are no clinical trials specifically looking at biochemical progression, but there are clinical trials looking at smoldering multiple myeloma, high-risk smoldering myeloma. I think it will be probably a fair extrapolation to do if we can demonstrate that it works in smoldering myeloma, that maybe we should intervene in biochemical progression.

Transcript Edited for Clarity
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