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Immunotherapy Rationale in Multiple Myeloma

Insights From:Jatin P. Shah, MD, MD Anderson Cancer Center;Ivan Marques Borrello, MD, Johns Hopkins University;James R. Berenson, MD, Institute for Myeloma and Bone Cancer Research
Published: Wednesday, Jul 27, 2016


Transcript:

Jatin P. Shah, MD:
Regarding the rationale for immunotherapy in myeloma, the concept of immunotherapy has already been proven in various solid tumors when we look at melanoma, lung cancer, and breast cancer. I think that the combination, or the rationale, for using immunotherapy has been proven out over the last decade in other various solid tumors. Importantly, we’re starting to see some of that in Hodgkin’s and other hematologic malignancies, as well. And if we go back over the last 20 or 30 years, the use of Rituxan in non-Hodgkin’s lymphoma has really been a proof-of-concept for using monoclonal antibodies and immunotherapy in hematologic malignancies. So, this is not a new concept when we talk about immunotherapy in myeloma. This is really an extension of using immunotherapy both in solid tumors, as well as monoclonal antibodies from non-Hodgkin’s lymphoma for many years now.

There are two important targets that we see on the surface of plasma cells, SLAMF7 and CD38, among others, that are ubiquitously expressed on plasma cells and minimally expressed in other tumor types. This makes an ideal target for developing immunotherapy for this, as well as targeting T cells, which is another aspect of immunotherapy. There are multiple targets that make an ideal disease state to use immunotherapy and monoclonal antibodies.

Ivan Marques Borrello, MD: Immunotherapy success and overall treatment outcomes are very different from those with patients that receive chemotherapy. In general, chemotherapy tends to induce a very quick and rapid response, but the durability of the response is questionable and tends to exhaust itself once the chemotherapeutic agent has been discontinued. This is in sharp contrast to what we see with immunotherapy, where, oftentimes, it’s a very slow response, and, in fact, there may be something called pseudoprogression that will actually show evidence of progression of disease, prior to showing a nice reduction in the overall disease response.

This has been recognized particularly in solid tumors where CT scans show there can be enlargements of the tumor mass, then followed by regression of the disease. And I think, in terms of the depth of response, certainly in myeloma, the criteria for measuring are the same. You measure the M-protein spike, whether it’s in the serum or in the blood, and the depth of that as ultimately defined by immunofixation-negativity. Now we are also entering into the realm of looking at minimal residual disease, whether by flow cytometry or allele-specific PCR (polymerase chain reaction).

James R. Berenson, MD: In assessing the benefit of a drug for an individual patient, it’s important not only to look at median times to progression, progression-free survival, and overall survival, but really, more importantly, what is the shape of that curve? Over time are there sustained differences? It had become more apparent, suggesting ongoing benefit from the treatment that one is using that may be new. And we’re seeing evidence of that in some of the new trials. There’s what we call a plateau, a flattening of the curve, suggesting that these patients are deriving long-term benefit, as opposed to in the past when people were continually progressing in both arms, even though there might be a separation. Now we’re seeing some flattening, suggesting that these drugs are not just working in the short-term, but profoundly affecting the patients over the long term.

Ivan Marques Borrello, MD: As far as response rates with immunotherapy, I think they are still in the genesis of trying to understand how best to interpret these things. That has implications in terms of how clinical trials are designed, and obviously, from a patient-specific perspective, how to judge the overall success of a therapy. The one thing that I think is clear with immunotherapy, as I mentioned earlier, is that you have an ongoing response. Now that response can be a very deep response, and, for example, when one looks at the kinds of responses that are being seen with CAR-T cell therapy, patients are achieving very deep responses to MRD-negativity.

However, there are other therapies, such as vaccine therapies and possibly even monoclonal antibody therapies, where the ability to potentiate or to initiate and have persistence of an immune response may not necessarily translate into a deeper response, but will hopefully translate into a longer response. And so in that situation, a sharp contrast between chemotherapy and immunotherapy. Maybe chemotherapy can give a deeper response, but immunotherapy may give a longer response.

Transcript Edited for Clarity
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Transcript:

Jatin P. Shah, MD:
Regarding the rationale for immunotherapy in myeloma, the concept of immunotherapy has already been proven in various solid tumors when we look at melanoma, lung cancer, and breast cancer. I think that the combination, or the rationale, for using immunotherapy has been proven out over the last decade in other various solid tumors. Importantly, we’re starting to see some of that in Hodgkin’s and other hematologic malignancies, as well. And if we go back over the last 20 or 30 years, the use of Rituxan in non-Hodgkin’s lymphoma has really been a proof-of-concept for using monoclonal antibodies and immunotherapy in hematologic malignancies. So, this is not a new concept when we talk about immunotherapy in myeloma. This is really an extension of using immunotherapy both in solid tumors, as well as monoclonal antibodies from non-Hodgkin’s lymphoma for many years now.

There are two important targets that we see on the surface of plasma cells, SLAMF7 and CD38, among others, that are ubiquitously expressed on plasma cells and minimally expressed in other tumor types. This makes an ideal target for developing immunotherapy for this, as well as targeting T cells, which is another aspect of immunotherapy. There are multiple targets that make an ideal disease state to use immunotherapy and monoclonal antibodies.

Ivan Marques Borrello, MD: Immunotherapy success and overall treatment outcomes are very different from those with patients that receive chemotherapy. In general, chemotherapy tends to induce a very quick and rapid response, but the durability of the response is questionable and tends to exhaust itself once the chemotherapeutic agent has been discontinued. This is in sharp contrast to what we see with immunotherapy, where, oftentimes, it’s a very slow response, and, in fact, there may be something called pseudoprogression that will actually show evidence of progression of disease, prior to showing a nice reduction in the overall disease response.

This has been recognized particularly in solid tumors where CT scans show there can be enlargements of the tumor mass, then followed by regression of the disease. And I think, in terms of the depth of response, certainly in myeloma, the criteria for measuring are the same. You measure the M-protein spike, whether it’s in the serum or in the blood, and the depth of that as ultimately defined by immunofixation-negativity. Now we are also entering into the realm of looking at minimal residual disease, whether by flow cytometry or allele-specific PCR (polymerase chain reaction).

James R. Berenson, MD: In assessing the benefit of a drug for an individual patient, it’s important not only to look at median times to progression, progression-free survival, and overall survival, but really, more importantly, what is the shape of that curve? Over time are there sustained differences? It had become more apparent, suggesting ongoing benefit from the treatment that one is using that may be new. And we’re seeing evidence of that in some of the new trials. There’s what we call a plateau, a flattening of the curve, suggesting that these patients are deriving long-term benefit, as opposed to in the past when people were continually progressing in both arms, even though there might be a separation. Now we’re seeing some flattening, suggesting that these drugs are not just working in the short-term, but profoundly affecting the patients over the long term.

Ivan Marques Borrello, MD: As far as response rates with immunotherapy, I think they are still in the genesis of trying to understand how best to interpret these things. That has implications in terms of how clinical trials are designed, and obviously, from a patient-specific perspective, how to judge the overall success of a therapy. The one thing that I think is clear with immunotherapy, as I mentioned earlier, is that you have an ongoing response. Now that response can be a very deep response, and, for example, when one looks at the kinds of responses that are being seen with CAR-T cell therapy, patients are achieving very deep responses to MRD-negativity.

However, there are other therapies, such as vaccine therapies and possibly even monoclonal antibody therapies, where the ability to potentiate or to initiate and have persistence of an immune response may not necessarily translate into a deeper response, but will hopefully translate into a longer response. And so in that situation, a sharp contrast between chemotherapy and immunotherapy. Maybe chemotherapy can give a deeper response, but immunotherapy may give a longer response.

Transcript Edited for Clarity
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