Feature

Clinical trials key to determining best approach for patients with smoldering myeloma

Elisabet E. Manasanch

A team of researchers at The University of Texas MD Anderson Cancer Center is aiming to learn more about smoldering myeloma, also known as asymptomatic myeloma.

The question of whether to treat individuals with smoldering myeloma or simply monitor their lab reports every few months has been the subject of considerable debate.

However, because the average risk for progression to full-blown myeloma is about 50% at 5 years, there is increased interest in treating patients with smoldering myeloma in hopes of either delaying progression or possibly curing patients.

HemOnc Today spoke with Elisabet E. Manasanch, MD, assistant professor in the department of lymphoma/myeloma in the division of cancer medicine at MD Anderson, about smoldering myeloma, which treatments seem to be most effective, and efforts to identify the most appropriate therapies for these patients.

 

Question: What is smoldering myeloma?

Answer: Smoldering myeloma is a precursor stage of multiple myeloma. Individuals with smoldering myeloma exhibit slightly increased levels of monoclonal protein in the blood or urine and also have a slightly increased number of plasma cells in the bone marrow. However, these patients have no true myeloma symptoms. Most patients who have smoldering myeloma and live long enough most likely will develop multiple myeloma. Yet, other patients may never go on to develop multiple myeloma. The risk for progression to multiple myeloma varies widely. It depends on the quantity of abnormal plasma cells in the bone marrow, as well as the proteins they produce, which can be found in blood and urine. We know, for example, that having more tumor — or abnormal plasma cells — usually is worse and may indicate that the patient has a higher risk for progression to multiple myeloma. So, if the monoclonal protein associated with smoldering myeloma in the blood is high, the risk for progression to multiple myeloma is perceived to be higher. Other factors that play a role in the progression from smoldering myeloma to multiple myeloma include the immune system and other cells that surround the abnormal plasma cells in the bone marrow, the genetic abnormalities of the abnormal plasma cells, and how fast the increase in monoclonal protein is in the blood.

 

Q: If a person has this condition, should family members or first-degree relatives be screened?

A: Overall, the risk for multiple myeloma is very low, even when someone has a first-degree relative with the disease. Because of this, the standard recommendation is to not screen. Despite this, there is evidence suggesting that the sooner we know about patients having multiple myeloma or its precursors — such as smoldering myeloma — their clinical outcomes are better in the long term. This becomes tricky because the only way to diagnose smoldering myeloma, because patients have no symptoms, is to perform blood work or urine tests and search for the abnormal proteins that smoldering myeloma produces. In the clinic, if a patient with multiple myeloma has family members who want to be screened, we usually facilitate this.

 

Q: What are the typical outcomes for patients with smoldering myeloma? Is there a standard for how these patients are treated?

A: Scientists and clinicians have tried to predict the risk for progression to multiple myeloma, and this has led to several risk classification models that can be used in the clinic. The first is the Mayo Clinic model. This model came out of a retrospective study, and it consists of three risk factors: having at least 10% plasma cells in the bone marrow; having at least 3 grams of the monoclonal protein in the blood; and having an abnormal free light chain ratio. The 5-year progression risk is 25% for patients with one risk factor, 51% for those with two risk factors, and 76% for those with three risk factors.

A second risk model was evaluated by researchers who found the percentage of abnormal plasma cells in the bone marrow aspirate, as assessed by flow cytometry, could predict risk for progression. At least 95% abnormal plasma cells is a risk factor. They incorporated this risk factor in their model. The other risk factor identified by this group is low uninvolved immunoglobulins, or immunoparesis. In this model, if a patient has both risk factors, the risk for progression was estimated at about 75% at 5 years; however, if they had no risk factors, the estimate was only about 5%.

The third model is from SWOG. This is the most modern model, which incorporates gene expression. It looks at the plasma cells and which genes are expressed in these plasma cells. It also uses the monoclonal protein and the light chains in the blood. If these are higher, the risk for progression is higher. In addition, if a person has a gene expression score that is higher than a certain threshold, this also is a risk factor. In this model, if a patient has one of these risk factors, their estimated risk for progression is 29% at 5 years. If they have two or more of these factors, the risk is about 70% at 5 years. However, the SWOG model is difficult to implement in the clinic, as gene expression is not available everywhere.

The jury is still out on which prognostic model is best, and there are major international efforts to evaluate all of the risk factors for progression and integrate them in a single model that could be used widely in the clinic and which also may help us determine which patients should be treated. The standard practice for the management of smoldering myeloma is ‘watch and wait.’ If there is a clinical trial, we should offer patients to be included. As we obtain results from clinical trials, the watch-and-wait approach may become obsolete and there may be a new recommendation to treat these patients. Clinical trial outcomes will determine how we treat these patients. This is why it is so important to promote clinical research.

 

Q: What research are you and your team conducting now?

A: We are working on several studies. We started two studies a couple years ago, one of which is completed and another that is still underway. A third study initiated about a year ago is ongoing. The completed study used the anti-PD-1 antibody pembrolizumab (Keytruda, Merck) as an immune prevention strategy to avoid progression to multiple myeloma among patients with smoldering myeloma. Previous studies had shown patients who had more PD-1 on their myeloma cells were at increased risk for progression to multiple myeloma. Thus, the rationale was to test a PD-1 inhibitor in smoldering myeloma. The initial results of this study were presented at last year’s ASH Annual Meeting and Exposition. We treated 13 patients. Of these, one patient progressed to multiple myeloma while on the study; another patient had a complete remission; and all other patients had stable disease. We are thrilled that one patient achieved a complete response after only three infusions of pembrolizumab, and this response is still ongoing more than 1 year after his last treatment. This patient’s prognostic factors suggested that she not only had a very high risk for progressing quickly to multiple myeloma, but that once she progressed, she likely would be classified as having high-risk multiple myeloma. High-risk multiple myeloma does not usually respond well to the available treatments and is characterized by quick relapse after initial response. Thus, this was a truly fantastic response for this patient.

We do not yet fully understand why this patient responded when most patients seemed to have stable disease. Correlative studies looking into this are being analyzed. We additionally have a 200-patient prospective study in monoclonal gammopathy of unknown significance and smoldering myeloma that is still open to accrual. We already screened more than 100 patients. The goal of this study is to find new risk models that can predict risk for progression and find new markers to target the precursors of multiple myeloma. Another ongoing study evaluated the anti-CD38 antibody isatuximab (SAR650984, Sanofi Genzyme) in smoldering myeloma. We are aiming to submit preliminary results of this study at ASH in December.

 

Q: Is there a potential role for immunotherapy for these patients?

A: Based on results discussed above, as well as results using anti-CD38 antibodies, immunotherapy has a role and can alter the natural history of smoldering myeloma. Continued research will determine how immunotherapy will impact smoldering myeloma and what immunotherapy combinations might be best to use in clinical trials. – by Jennifer Southall

 

For more information:

Elisabet E. Manasanch, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: eemanasanch@mdanderson.org.

 

Disclosure: Manasanch reports no relevant financial disclosures.

Elisabet E. Manasanch

A team of researchers at The University of Texas MD Anderson Cancer Center is aiming to learn more about smoldering myeloma, also known as asymptomatic myeloma.

The question of whether to treat individuals with smoldering myeloma or simply monitor their lab reports every few months has been the subject of considerable debate.

However, because the average risk for progression to full-blown myeloma is about 50% at 5 years, there is increased interest in treating patients with smoldering myeloma in hopes of either delaying progression or possibly curing patients.

HemOnc Today spoke with Elisabet E. Manasanch, MD, assistant professor in the department of lymphoma/myeloma in the division of cancer medicine at MD Anderson, about smoldering myeloma, which treatments seem to be most effective, and efforts to identify the most appropriate therapies for these patients.

 

Question: What is smoldering myeloma?

Answer: Smoldering myeloma is a precursor stage of multiple myeloma. Individuals with smoldering myeloma exhibit slightly increased levels of monoclonal protein in the blood or urine and also have a slightly increased number of plasma cells in the bone marrow. However, these patients have no true myeloma symptoms. Most patients who have smoldering myeloma and live long enough most likely will develop multiple myeloma. Yet, other patients may never go on to develop multiple myeloma. The risk for progression to multiple myeloma varies widely. It depends on the quantity of abnormal plasma cells in the bone marrow, as well as the proteins they produce, which can be found in blood and urine. We know, for example, that having more tumor — or abnormal plasma cells — usually is worse and may indicate that the patient has a higher risk for progression to multiple myeloma. So, if the monoclonal protein associated with smoldering myeloma in the blood is high, the risk for progression to multiple myeloma is perceived to be higher. Other factors that play a role in the progression from smoldering myeloma to multiple myeloma include the immune system and other cells that surround the abnormal plasma cells in the bone marrow, the genetic abnormalities of the abnormal plasma cells, and how fast the increase in monoclonal protein is in the blood.

 

Q: If a person has this condition, should family members or first-degree relatives be screened?

A: Overall, the risk for multiple myeloma is very low, even when someone has a first-degree relative with the disease. Because of this, the standard recommendation is to not screen. Despite this, there is evidence suggesting that the sooner we know about patients having multiple myeloma or its precursors — such as smoldering myeloma — their clinical outcomes are better in the long term. This becomes tricky because the only way to diagnose smoldering myeloma, because patients have no symptoms, is to perform blood work or urine tests and search for the abnormal proteins that smoldering myeloma produces. In the clinic, if a patient with multiple myeloma has family members who want to be screened, we usually facilitate this.

 

Q: What are the typical outcomes for patients with smoldering myeloma? Is there a standard for how these patients are treated?

A: Scientists and clinicians have tried to predict the risk for progression to multiple myeloma, and this has led to several risk classification models that can be used in the clinic. The first is the Mayo Clinic model. This model came out of a retrospective study, and it consists of three risk factors: having at least 10% plasma cells in the bone marrow; having at least 3 grams of the monoclonal protein in the blood; and having an abnormal free light chain ratio. The 5-year progression risk is 25% for patients with one risk factor, 51% for those with two risk factors, and 76% for those with three risk factors.

A second risk model was evaluated by researchers who found the percentage of abnormal plasma cells in the bone marrow aspirate, as assessed by flow cytometry, could predict risk for progression. At least 95% abnormal plasma cells is a risk factor. They incorporated this risk factor in their model. The other risk factor identified by this group is low uninvolved immunoglobulins, or immunoparesis. In this model, if a patient has both risk factors, the risk for progression was estimated at about 75% at 5 years; however, if they had no risk factors, the estimate was only about 5%.

The third model is from SWOG. This is the most modern model, which incorporates gene expression. It looks at the plasma cells and which genes are expressed in these plasma cells. It also uses the monoclonal protein and the light chains in the blood. If these are higher, the risk for progression is higher. In addition, if a person has a gene expression score that is higher than a certain threshold, this also is a risk factor. In this model, if a patient has one of these risk factors, their estimated risk for progression is 29% at 5 years. If they have two or more of these factors, the risk is about 70% at 5 years. However, the SWOG model is difficult to implement in the clinic, as gene expression is not available everywhere.

The jury is still out on which prognostic model is best, and there are major international efforts to evaluate all of the risk factors for progression and integrate them in a single model that could be used widely in the clinic and which also may help us determine which patients should be treated. The standard practice for the management of smoldering myeloma is ‘watch and wait.’ If there is a clinical trial, we should offer patients to be included. As we obtain results from clinical trials, the watch-and-wait approach may become obsolete and there may be a new recommendation to treat these patients. Clinical trial outcomes will determine how we treat these patients. This is why it is so important to promote clinical research.

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Q: What research are you and your team conducting now?

A: We are working on several studies. We started two studies a couple years ago, one of which is completed and another that is still underway. A third study initiated about a year ago is ongoing. The completed study used the anti-PD-1 antibody pembrolizumab (Keytruda, Merck) as an immune prevention strategy to avoid progression to multiple myeloma among patients with smoldering myeloma. Previous studies had shown patients who had more PD-1 on their myeloma cells were at increased risk for progression to multiple myeloma. Thus, the rationale was to test a PD-1 inhibitor in smoldering myeloma. The initial results of this study were presented at last year’s ASH Annual Meeting and Exposition. We treated 13 patients. Of these, one patient progressed to multiple myeloma while on the study; another patient had a complete remission; and all other patients had stable disease. We are thrilled that one patient achieved a complete response after only three infusions of pembrolizumab, and this response is still ongoing more than 1 year after his last treatment. This patient’s prognostic factors suggested that she not only had a very high risk for progressing quickly to multiple myeloma, but that once she progressed, she likely would be classified as having high-risk multiple myeloma. High-risk multiple myeloma does not usually respond well to the available treatments and is characterized by quick relapse after initial response. Thus, this was a truly fantastic response for this patient.

We do not yet fully understand why this patient responded when most patients seemed to have stable disease. Correlative studies looking into this are being analyzed. We additionally have a 200-patient prospective study in monoclonal gammopathy of unknown significance and smoldering myeloma that is still open to accrual. We already screened more than 100 patients. The goal of this study is to find new risk models that can predict risk for progression and find new markers to target the precursors of multiple myeloma. Another ongoing study evaluated the anti-CD38 antibody isatuximab (SAR650984, Sanofi Genzyme) in smoldering myeloma. We are aiming to submit preliminary results of this study at ASH in December.

 

Q: Is there a potential role for immunotherapy for these patients?

A: Based on results discussed above, as well as results using anti-CD38 antibodies, immunotherapy has a role and can alter the natural history of smoldering myeloma. Continued research will determine how immunotherapy will impact smoldering myeloma and what immunotherapy combinations might be best to use in clinical trials. – by Jennifer Southall

 

For more information:

Elisabet E. Manasanch, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: eemanasanch@mdanderson.org.

 

Disclosure: Manasanch reports no relevant financial disclosures.

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