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Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
The next section of talks was about new agents under clinical testing for the treatment of multiple myeloma.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
Dr. Noopur Raje from the Dana-Farber Cancer Institute in Boston presented results from a Phase 1 study of LY2127399 (LY) and Velcade (bortezomib) in patients with previously treated myeloma. LY is a human antibody that targets a protein called BAFF, which is present in the myeloma cells of about 60 percent of myeloma patients. The goal of this study was to identify the best dosing for LY in combination with Velcade. The study included 20 patients with a median of three prior therapies (65 percent had prior Velcade, 85 percent Revlimid or thalidomide (Thalomid)). Median time to progression was 4.9 months. All doses were well tolerated, and side effects were similar to Velcade alone. There were a few cases each of severe low blood cell counts, diarrhea, and peripheral neuropathy. However, three patients discontinued therapy due to neuropathy. The overall response rate was 55 percent (10 percent complete response, 15 percent very good partial response, 30 percent partial response). Prior Velcade therapy did not affect response. The 100 mg dose of LY was selected for further study with Velcade. Dr. Raje said that the results suggest further studies of LY plus Velcade compared to Velcade alone are warranted.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
The next talk was given by Dr. Jesus Berdeja from the Sarah Cannon Research Institute in Nashville, Tennessee. Dr. Berdeja presented initial results from an ongoing Phase 1 study of lorvotuzumab mertansine (LM) in combination with Revlimid and dexamethasone in a specific subset of relapsed / refractory myeloma patients whose myeloma cells contain the CD56 protein. LM is a cancer-killing drug bound to an antibody that directs the drug to cancer cells with the CD56 protein. About 70 percent of myeloma patients have myeloma cells with CD56; the protein is not found in normal plasma cells. 16 of the total 52 patients were enrolled at the time of analysis. So far, the overall response has been 62 percent (39 percent very good partial response, 23 percent partial response). Dr. Berdeja also said that LM was active in patients with unfavorable mutations. Additionally, LM was well tolerated. The main severe side effect was peripheral neuropathy. 75 mg/m2 LM is being pursued going forward, and more patients are currently being enrolled at this dose level.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
Dr. Philippe Moreau from the University Hospital in Nantes, France, presented the final study of the session. He presented results from a Phase 2 study of elotuzumab in combination with Revlimid and low-dose dexamethasone in patients with relapsed myeloma. Elotuzumab is an antibody that targets myeloma cells. The study included 63 patients, and two different doses of elotuzumab were tested. The overall response rate was 82 percent (9 percent complete response, 33 percent very good partial response, 40 percent partial response). The overall response rate was actually higher for the lower dose (10 mg/kg) of elotuzumab. Median time to response was 1.0 months, and the median time to best response was 1.9 months. Progression-free survival was not yet reached at a median follow-up of 9 months. The only severe side effects were low blood cell counts due to Revlimid. The most common side effects were infusion reactions that included nausea, dizziness, headache, and fever. Infusion reactions could be well managed by premedication. Dr. Moreau concluded that elotuzumab plus Revlimid and dexamethasone appears to be superior to Revlimid and dexamethasone alone. He also recommended further study of 10 mg/kg elotuzumab. Based on data showing that the overall response rate was 90 percent in patients with only one prior therapy, Dr. Moreau suggested that this combination should also be tested earlier in the disease course.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
These three talks were then followed-up by a discussion led by Dr. Nikhil Munshi from the Dana-Farber Cancer Institute. Dr. Munshi started off by saying that there are more than 10 potential monoclonal antibodies in different stages of clinical development. However, single-agent antitumor activity of antibodies has been modest to date. He said that combination approaches are therefore required.
In regard to the LY study, Dr. Munshi said that BAFF is good target in myeloma and that LY plus Velcade can have a synergistic effect on bones. The strengths of this study, he said, are that the response rates compare favorably with Velcade alone, there were significant responses even in patients with prior exposure to Velcade, and the combination is safe. The questions that remain are: Is there synergy between LY and Velcade? What effect does the combination have on bone? He said that larger studies are needed, and the response in Velcade-refractory patients will determine if the combination can overcome Velcade resistance.
For the LM study, Dr. Munshi said that LM has shown single-agent activity (20 percent response rate), and now LM has been shown to be effective in combination with Revlimid. Now, the combination needs to be compared to Revlimid’s efficacy. He said that several questions remain: Is there synergy between the two agents? Can the dose or schedule be adjusted to reduce the peripheral neuropathy? He said that a larger study is needed, and the combination’s response in Revlimid-refractory patients will tell whether the combination can overcome Revlimid resistance.
For the elotuzumab study, Dr. Munshi said that the strengths are the large patient number, high response rate (including in those with prior Velcade treatment or high-dose therapy), demonstrated safety, and management of infusion reactions with premedication. He said that the questions that remain are: Will elotuzumab have single-agent activity in smoldering myeloma? Is there a biomarker to predict response? He said that a larger study is needed to confirm efficacy. He concluded by saying that this combination is promising.
In regard to the LY study, Dr. Munshi said that BAFF is good target in myeloma and that LY plus Velcade can have a synergistic effect on bones. The strengths of this study, he said, are that the response rates compare favorably with Velcade alone, there were significant responses even in patients with prior exposure to Velcade, and the combination is safe. The questions that remain are: Is there synergy between LY and Velcade? What effect does the combination have on bone? He said that larger studies are needed, and the response in Velcade-refractory patients will determine if the combination can overcome Velcade resistance.
For the LM study, Dr. Munshi said that LM has shown single-agent activity (20 percent response rate), and now LM has been shown to be effective in combination with Revlimid. Now, the combination needs to be compared to Revlimid’s efficacy. He said that several questions remain: Is there synergy between the two agents? Can the dose or schedule be adjusted to reduce the peripheral neuropathy? He said that a larger study is needed, and the combination’s response in Revlimid-refractory patients will tell whether the combination can overcome Revlimid resistance.
For the elotuzumab study, Dr. Munshi said that the strengths are the large patient number, high response rate (including in those with prior Velcade treatment or high-dose therapy), demonstrated safety, and management of infusion reactions with premedication. He said that the questions that remain are: Will elotuzumab have single-agent activity in smoldering myeloma? Is there a biomarker to predict response? He said that a larger study is needed to confirm efficacy. He concluded by saying that this combination is promising.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
The myeloma session of the afternoon was an education session in which myeloma specialists talked about the current understanding of smoldering myeloma, myeloma bone disease, and managing complications from myeloma therapies.
My notes from these talks are fairly long, so I'll come back and post them as soon as possible. In the mean time, I'm going to post a few things from Day 4 first. So check back for more information about the education session.
My notes from these talks are fairly long, so I'll come back and post them as soon as possible. In the mean time, I'm going to post a few things from Day 4 first. So check back for more information about the education session.
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Julie Shilane - Name: Julie Shilane, Beacon Staff
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
Dr. Ivan Borrello from the Johns Hopkins University School of Medicine was the first to speak during the education session. His presentation was on smoldering myeloma.
He began by discussing the clinical definition of smoldering myeloma. The International Myeloma Working Group 2010 diagnostic criteria are as follows: (1) serum monoclonal protein (IgG or IgA) greater than 3g/dL and/or clonal bone marrow plasma cells greater than or equal to 10 percent; AND (2) no organ damage such as lytic bone lesions, anemia, or kidney failure due to myeloma.
If a patient is diagnosed as having smoldering myeloma, they should receive a baseline bone marrow biopsy and skeletal survey, and testing should then be repeated in 2-3 months. If the patient is stable, the testing should be repeated again every 4-6 months for a year. If the patient continues to be stable, testing should then be repeated every 6-12 months.
Statistics calculated by the Mayo Clinic indicate that newly diagnosed smoldering myeloma patients have a 10 percent per year risk of progressing to active myeloma within the first five years after diagnosis. If a patient doesn't progress within the first five years after diagnosis, their risk of progressing in the next five years is three percent per year. Patients who make it 10 years after diagnosis without progressing then have only about a one percent per year risk of progressing.
These varying probabilities over time suggest that there are different groups of smoldering myeloma patients. Additional research by the Mayo Clinic indicates that smoldering myeloma patients are at an increased risk of progressing to active myeloma for each of the following characteristics: the presence of more than 10 percent plasma cells in the bone marrow; M-protein greater than 3 g/dL; free light chain (FLC) ratio either less than 0.125 or greater than 8.
The Spanish Myeloma Group, on the other hand, specifies the factors that increase the risk of progression as being: having 95% or more abnormal plasma cells, and immonoparesis, which is lower than normal levels of one or two immunoglobulins other than the patient's "involved" immunoglobulin (for example, IgA is the "involved" immunoglobulin for patients with IgA myeloma).
Dr. Borrello turned next to the question of whether there is a linear progression from MGUS (monoclonal gammopathy of undetermined significance) to smoldering myeloma to active myeloma to plasma cell leukemia. On this issue, Dr. Borrello mainly focused on the fact that it definitely is now clear that active multiple myeloma is consistently preceded by MGUS.
The final topic that Dr. Borrello considered (at length) during his presentation was whether smoldering myeloma patients should be actively treated, or whether their disease should just be observed and tracked, but not treated.
This issue is being addressed head-on right now during a clinical trial in Spain. It involves two groups of smoldering multiple myeloma patients with high-risk disease. One group is receiving nine cycles of Revlimid and dexamethasone followed by maintenance therapy with Revlimid alone. The other group is just being observed – it is not being actively treated.
Median time-to-progression has not yet been reached in the treated group of patients, while it has been reached – 25 months – for the non-treated group.
Similarly, an overall survival difference may be emerging between the two patient groups. Two year survival is 100 percent in the treated patient group and 96 percent in the untreated group.
At a general level, treating smoldering myeloma might cure some patients and kill of the majority of myeloma cells in other patients to such an extent that the disease is not really an issue for them. By the same token, early treatment could kill off only some myeloma cells in many patients, leaving behind myeloma cells that are much harder to treat.
Dr. Borrello concluded his presentation by saying that, for smoldering myeloma patients, the standard of care is still just observation until the patient progresses to active disease. Furthermore, smoldering myeloma should now be viewed as a varied (“heterogeneous”) disease state, with patients having different risks of progressing to active disease.
Finally, smoldering myeloma patients made aware of the option of participating in clinical trials testing whether or not active treatment is a better option than “watching and waiting.”
Note: The issue of whether smoldering myeloma patients should be actively treated was debated during a very interesting session at the recent International Myeloma Workshop. A detailed summary of the debate can be found in this posting,
https://myelomabeacon.org/forum/imw-2011-multiple-myeloma-discussion-day-2-t392.html#p1508
here in the Myeloma Beacon’s forums.
He began by discussing the clinical definition of smoldering myeloma. The International Myeloma Working Group 2010 diagnostic criteria are as follows: (1) serum monoclonal protein (IgG or IgA) greater than 3g/dL and/or clonal bone marrow plasma cells greater than or equal to 10 percent; AND (2) no organ damage such as lytic bone lesions, anemia, or kidney failure due to myeloma.
If a patient is diagnosed as having smoldering myeloma, they should receive a baseline bone marrow biopsy and skeletal survey, and testing should then be repeated in 2-3 months. If the patient is stable, the testing should be repeated again every 4-6 months for a year. If the patient continues to be stable, testing should then be repeated every 6-12 months.
Statistics calculated by the Mayo Clinic indicate that newly diagnosed smoldering myeloma patients have a 10 percent per year risk of progressing to active myeloma within the first five years after diagnosis. If a patient doesn't progress within the first five years after diagnosis, their risk of progressing in the next five years is three percent per year. Patients who make it 10 years after diagnosis without progressing then have only about a one percent per year risk of progressing.
These varying probabilities over time suggest that there are different groups of smoldering myeloma patients. Additional research by the Mayo Clinic indicates that smoldering myeloma patients are at an increased risk of progressing to active myeloma for each of the following characteristics: the presence of more than 10 percent plasma cells in the bone marrow; M-protein greater than 3 g/dL; free light chain (FLC) ratio either less than 0.125 or greater than 8.
The Spanish Myeloma Group, on the other hand, specifies the factors that increase the risk of progression as being: having 95% or more abnormal plasma cells, and immonoparesis, which is lower than normal levels of one or two immunoglobulins other than the patient's "involved" immunoglobulin (for example, IgA is the "involved" immunoglobulin for patients with IgA myeloma).
Dr. Borrello turned next to the question of whether there is a linear progression from MGUS (monoclonal gammopathy of undetermined significance) to smoldering myeloma to active myeloma to plasma cell leukemia. On this issue, Dr. Borrello mainly focused on the fact that it definitely is now clear that active multiple myeloma is consistently preceded by MGUS.
The final topic that Dr. Borrello considered (at length) during his presentation was whether smoldering myeloma patients should be actively treated, or whether their disease should just be observed and tracked, but not treated.
This issue is being addressed head-on right now during a clinical trial in Spain. It involves two groups of smoldering multiple myeloma patients with high-risk disease. One group is receiving nine cycles of Revlimid and dexamethasone followed by maintenance therapy with Revlimid alone. The other group is just being observed – it is not being actively treated.
Median time-to-progression has not yet been reached in the treated group of patients, while it has been reached – 25 months – for the non-treated group.
Similarly, an overall survival difference may be emerging between the two patient groups. Two year survival is 100 percent in the treated patient group and 96 percent in the untreated group.
At a general level, treating smoldering myeloma might cure some patients and kill of the majority of myeloma cells in other patients to such an extent that the disease is not really an issue for them. By the same token, early treatment could kill off only some myeloma cells in many patients, leaving behind myeloma cells that are much harder to treat.
Dr. Borrello concluded his presentation by saying that, for smoldering myeloma patients, the standard of care is still just observation until the patient progresses to active disease. Furthermore, smoldering myeloma should now be viewed as a varied (“heterogeneous”) disease state, with patients having different risks of progressing to active disease.
Finally, smoldering myeloma patients made aware of the option of participating in clinical trials testing whether or not active treatment is a better option than “watching and waiting.”
Note: The issue of whether smoldering myeloma patients should be actively treated was debated during a very interesting session at the recent International Myeloma Workshop. A detailed summary of the debate can be found in this posting,
https://myelomabeacon.org/forum/imw-2011-multiple-myeloma-discussion-day-2-t392.html#p1508
here in the Myeloma Beacon’s forums.
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
Dr. David Roodman of the University of Pittsburgh gave the next presentation during the afternoon educational session. He spoke on “Bone Disease and Its Management in Multiple Myeloma.”
Dr. Roodman began by noting that 85 percent of multiple myeloma patients will experience myeloma bone disease, which occurs when the bones of myeloma patients become thinner and develop holes, causing bone pain and bone fractures. Dr. Roodman, in fact, believes that bone disease probably would be detected in almost all myeloma patients if more sensitive tests were used to test for the presence of bone disease.
Myeloma bone disease most often affects the bones in the vertebra, followed by the ribs, but the disease’s impact on the bones can also be diffuse (not focused on one particular area).
Within a year after diagnosis, 40% of myeloma patients will experience a bone fracture, and 60% of myeloma patients will experience a fracture at some point during their disease. Unfortunately, patients who experience a fracture are at a higher risk of dying.
There are a variety of options for treating myeloma bone disease, including lifestyle changes (exercise, calcium supplementation, and making an effort to avoid falls), radiotherapy, surgery (vertebroblasty, kyphoplasty, and other options), vitamin D supplementation, treatment with a bisphosphonate (a class of drugs used to prevent bone decay), and the treatment of the patient’s myeloma in and of itself.
Dr. Roodman had quick comments on several of these options …
Regarding radiotherapy, he noted that it can compromise the ability of the patient to respond to drug-based anti-myeloma treatments, and it often doesn’t last very long.
Regarding Vitamin D supplementation, he said that there is no clear consensus on appropriate supplementation in myeloma patients with vitamin D deficiency.
Regarding surgery, he said that, in some cancers, vertebroplasty has been found to be a “sham” (no real improvement or no better control). In myeloma, kyphoplasty definitely has been shown to be helpful.
Dr. Roodman then turned to bisphosphonates and their use in multiple myeloma. He started out this part of his presentation by noting that Zometa (zoledronic acid) and Aredia (pamidronate), two bisphosphonates commonly prescribed for myeloma patients, have been found to be equally potent compared to placebo in reducing “skeletal related events” (SREs) – that is, bone fractures, spinal cord compression, or significant bone pain requiring surgical or radiation-based treatment. Both Aredia and Zometa also bring about an equal delay in a typical patient’s time to first SRE.
There are, however, side effects and limitations to bisphosphonates.
Myeloma patients taking bisphosphonates sometime experience kidney problems and osteonecrosis of the jaw (ONJ), a condition where part of the jaw dies and has to be removed. The incidence of ONJ among myeloma patients being treated with bisphosphonates is dropping, however, due to preventative steps being carried out before and during bisphosphonates treatment. In fact, some estimates indicate the incidence of ONJ may have dropped as much as 75 percent.
In terms of limitations, bisphosphonates do not eliminate SREs; instead, they decrease the incidence of SREs by about 50 percent. Similarly, patients taking bisphosphonates still experience progression of their bone disease, although it happens at a slower pace than if they were not taking bisphosphonates.
Until recently, there also was no indication that bisphosphonates have any anti-myeloma effect. The drugs were viewed as effective at slowing bone disease and preventing fractures, but not necessarily as affecting the progression of a patient’s multiple myeloma.
The recent UK trial comparing the performance of Zometa and Bonefos (clodronate) has suggested, however, that bisphosphonates can have anti-myeloma activity. Compared to Bonefos, Zometa reduced SREs in myeloma patients with or without bone disease, and increased overall survival in patients with bone disease. (At the same time, the incidence of ONJ was 3.5% for patients taking Zometa versus 0.3% for the patients taking Bonefos.)
Dr. Roodman is not convinced, however, that all myeloma patients should be treated with Zometa. Patients in the Zometa trial were in the UK, where the treatment of myeloma is generally perceived to be not as aggressive as it is in the U.S. Would Zometa have as much – or any – anti-myeloma activity in patients already being treated aggressively for their disease?
Dr. Roodman concluded his presentation by emphasizing that it is still important to develop new therapies for myeloma bone disease.
In this regard, he believes there are a number of potential options.
Xgeva (denosumab), for example, has been shown to be more effective than Zometa in preventing SREs. Its side effects are similar to Zometa’s (including the incidence of ONJ). Moreover, Xgeva is given subcutaneously rather than an IV, as Zometa is, and Xgeva doesn’t appear to negatively affect the kidney the way Zometa sometimes can.
Two other drugs that also appear promising as potential treatment for myeloma bone disease are BHQ880 and RAP-011.
Note: For a list of the Myeloma Beacon news articles related to myeloma bone disease, go to this link: https://myelomabeacon.org/tag/bone-disease/ .
Dr. Roodman began by noting that 85 percent of multiple myeloma patients will experience myeloma bone disease, which occurs when the bones of myeloma patients become thinner and develop holes, causing bone pain and bone fractures. Dr. Roodman, in fact, believes that bone disease probably would be detected in almost all myeloma patients if more sensitive tests were used to test for the presence of bone disease.
Myeloma bone disease most often affects the bones in the vertebra, followed by the ribs, but the disease’s impact on the bones can also be diffuse (not focused on one particular area).
Within a year after diagnosis, 40% of myeloma patients will experience a bone fracture, and 60% of myeloma patients will experience a fracture at some point during their disease. Unfortunately, patients who experience a fracture are at a higher risk of dying.
There are a variety of options for treating myeloma bone disease, including lifestyle changes (exercise, calcium supplementation, and making an effort to avoid falls), radiotherapy, surgery (vertebroblasty, kyphoplasty, and other options), vitamin D supplementation, treatment with a bisphosphonate (a class of drugs used to prevent bone decay), and the treatment of the patient’s myeloma in and of itself.
Dr. Roodman had quick comments on several of these options …
Regarding radiotherapy, he noted that it can compromise the ability of the patient to respond to drug-based anti-myeloma treatments, and it often doesn’t last very long.
Regarding Vitamin D supplementation, he said that there is no clear consensus on appropriate supplementation in myeloma patients with vitamin D deficiency.
Regarding surgery, he said that, in some cancers, vertebroplasty has been found to be a “sham” (no real improvement or no better control). In myeloma, kyphoplasty definitely has been shown to be helpful.
Dr. Roodman then turned to bisphosphonates and their use in multiple myeloma. He started out this part of his presentation by noting that Zometa (zoledronic acid) and Aredia (pamidronate), two bisphosphonates commonly prescribed for myeloma patients, have been found to be equally potent compared to placebo in reducing “skeletal related events” (SREs) – that is, bone fractures, spinal cord compression, or significant bone pain requiring surgical or radiation-based treatment. Both Aredia and Zometa also bring about an equal delay in a typical patient’s time to first SRE.
There are, however, side effects and limitations to bisphosphonates.
Myeloma patients taking bisphosphonates sometime experience kidney problems and osteonecrosis of the jaw (ONJ), a condition where part of the jaw dies and has to be removed. The incidence of ONJ among myeloma patients being treated with bisphosphonates is dropping, however, due to preventative steps being carried out before and during bisphosphonates treatment. In fact, some estimates indicate the incidence of ONJ may have dropped as much as 75 percent.
In terms of limitations, bisphosphonates do not eliminate SREs; instead, they decrease the incidence of SREs by about 50 percent. Similarly, patients taking bisphosphonates still experience progression of their bone disease, although it happens at a slower pace than if they were not taking bisphosphonates.
Until recently, there also was no indication that bisphosphonates have any anti-myeloma effect. The drugs were viewed as effective at slowing bone disease and preventing fractures, but not necessarily as affecting the progression of a patient’s multiple myeloma.
The recent UK trial comparing the performance of Zometa and Bonefos (clodronate) has suggested, however, that bisphosphonates can have anti-myeloma activity. Compared to Bonefos, Zometa reduced SREs in myeloma patients with or without bone disease, and increased overall survival in patients with bone disease. (At the same time, the incidence of ONJ was 3.5% for patients taking Zometa versus 0.3% for the patients taking Bonefos.)
Dr. Roodman is not convinced, however, that all myeloma patients should be treated with Zometa. Patients in the Zometa trial were in the UK, where the treatment of myeloma is generally perceived to be not as aggressive as it is in the U.S. Would Zometa have as much – or any – anti-myeloma activity in patients already being treated aggressively for their disease?
Dr. Roodman concluded his presentation by emphasizing that it is still important to develop new therapies for myeloma bone disease.
In this regard, he believes there are a number of potential options.
Xgeva (denosumab), for example, has been shown to be more effective than Zometa in preventing SREs. Its side effects are similar to Zometa’s (including the incidence of ONJ). Moreover, Xgeva is given subcutaneously rather than an IV, as Zometa is, and Xgeva doesn’t appear to negatively affect the kidney the way Zometa sometimes can.
Two other drugs that also appear promising as potential treatment for myeloma bone disease are BHQ880 and RAP-011.
Note: For a list of the Myeloma Beacon news articles related to myeloma bone disease, go to this link: https://myelomabeacon.org/tag/bone-disease/ .
Re: ASCO 2011 Multiple Myeloma Discussion - Day 3
The last educational session of the day was presented by Dr. Sikander Ailawadhi of the University of Southern California. He spoke on “Complications of Anti-Myeloma Therapies.”
Dr. Ailawadhi started his presentation by noting that there are several different classes of anti-myeloma drugs. There are
- Steroids, such as dexamethasone (Decadron) and prednisone
- Alkylating chemotherapy drugs such as melphalan (Alkeran) and cyclophosphamide (Cytoxan)
- Anthracycline chemotherapy drugs such as doxorubicin (Adriamycin) and Doxil (pegylated liposomal doxorubicin).
- Proteasome inhibitors such as Velcade (bortezomib)
- Immunomodulatory agents (IMiDs) such as thalidomide (Thalomid) and Revlimid (lenalidomide)
In terms of the side effects of these treatments, Dr. Ailawadhi started off by discussing the broad group of side effects called “cytopenias”, or low blood-cell counts. These are particularly common in combination drug treatment regimens
Anemia, or low red blood cell counts, is one kind of cytopenia. It can be addressed by giving patients erythropoietin-stimulating agents (ESAs) such as Procrit / Epogen (epoetin alfa) or Aranesp (darbepoetin alfa). These drugs will help eliminate a patient’s anemia, but they also increase a patient’s risk of experiencing internal blood clotting.
A general reduction in all blood cell production – that is, red blood cell, white blood cell, and platelet production – can be a problem when patients are treated with Velcade, although the problem is particularly noticeable immediately after Velcade is given to patients, and the problem typically does not get worse with repeated Velcade dosing.
With Revlimid, the cytopenias that are relevant are reductions in platelets (thrombocytopenia), which is typically more prevalent in patients taking Revlimid who have kidney problems, and reductions in white blood cell counts (neutropenia).
In general, a key approach to handling cytopenias created by anti-myeloma agents is to delay treatment if the cytopenia becomes severe, and, if it recurs, to reduce the dose of the drug causing the cytopenia.
The next side effect Dr. Ailawadhi discussed was peripheral neuropathy (PN), or tingling and numbness in the feet and hands. He began by noting that, in myeloma patients, PN is not always a treatment side effect. Up to 20 percent of myeloma patients get peripheral neuropathy as a result of myeloma itself. This kind of PN, however, is typically mild.
Up to 65 percent of myeloma patients develop treatment-associated PN. It is frequently associated with Velcade, thalidomide, vincristine (Oncovin), and cisplatin. In the case of Velcade, the PN is often reversible.
If a patient experiences PN during their myeloma treatment, one thing to bear in mind is that often the PN is at least partly due to other diseases that the patient may have, such as diabetes. Thus, managing those other diseases is a useful part of managing the treatment-related PN.
For PN related to treatment with Velcade, a physician should consider using an alternative dosing schedule or a different mode of administration (for example, subcutaneous instead of intravenous). For thalidomide-related PN, modifying the dosing is typically a good idea.
There are some drugs that also can be used to reduce the PN associated with myeloma treatment. These include the anticonvulsants gabapentin (Neurontin) and Lyrica (pregabalin) and the “serotonin–norepinephrine reuptake inhibitor” Cymbalta (duloxetine).
Another class of side effects to watch out for with myeloma treatment is “venous thrombolic events” (VTEs), or blood clotting in the veins. This is not typically a risk with Velcade treatment. Instead, it is associated more with treatment using Revlimid or thalidomide. The risk of VTEs increases as the number of anti-myeloma agents a patient is taking increases – that is, combination regimens typically have a greater risk of VTEs than single-agent regimens. On the other hand, there usually is a lower risk of VTEs in patients who are being treated for a relapse in their myeloma.
To prevent VTEs from occurring, consideration should be given to avoiding multi-drug regimens in patients who are at high risk of developing VTEs. Likewise, anti-anemia agents such as Procrit/Epogen and Aranesp should be avoided, when possible, in patients at risk of developing VTEs. Finally, there are drugs that patients can take to prevent the occurrence of VTEs. Aspirin is a good choice for patients at a low risk of developing VTEs. Warfarin or low molecular weight heparin, such as Lovenox (enoxaparin), can be considered for patients who are at a higher risk.
Myeloma patients are also often are at risk of developing infections. This is partly due to myeloma itself, but also is a side effect of certain anti-myeloma agents, particularly steroids and Velcade. Patients taking Velcade frequently develop shingles if they are not taking anything to prevent infection by the herpes zoster virus that causes that infection.
To prevent infections from occurring, patients receiving steroids can be treated during the first three months of steroid treatment with trimethoprim-suphamethoxazole (Bactrim). Patients taking Velcade can be treated with an antiviral agent such as acyclovir (Zovirax) to prevent the onset of shingles. Physicians also generally can consider preventative antibiotic use depending on the individual needs and characteristics of the patient.
Some myeloma patients experience gastrointestinal issues – constipation, diarrhea, nausea, and even vomiting – as a result of their treatment. Physicians need to be aware that these side effects can occur and have appropriate treatment recommendations ready if they do.
For myeloma patients taking bisphosphonates such as Zometa (zoledronic acid) or Aredia (pamidronate), there is a risk of jaw bone decay (osteonecrosis of the jaw, or ONJ). This occurs most often after a patient being treated with a bisphosphonates has some sort of dental procedure. Thus, if a myeloma patient intends to have any dental work, they should stop their bisphosphonates treatment, and that treatment also should be stopped immediately if any signs of ONJ develop at any time. The progression of ONJ sometimes can be halted by administering antibiotics and by carrying out various interventions, including debridement (removing the dead tissue around the decaying jaw) and resection (removing the dead parts of the jaw).
Dr. Ailawadhi ended his presentation by quickly discussing a few other side effects sometimes seen with anti-myeloma treatment.
In the case of thalidomide, there are a number of side effects that can occur: fatigue (which can be managed through the timing of when the drug is taken); confusion or a reduced ability to concentrate; excessive potassium in the blood (hyperkalemia) (which mainly occurs in patients with decreased kidney function); and increases in the level of thyroid specific hormone (TSH), which can overstimulate the metabolism, leading to nervousness, irritability, and other additional side effects.
In the case of Velcade, some patients experience lightheadedness, which sometimes can be avoided by ensuring the patients receive more fluids when the drug is administered.
Dr. Ailawadhi started his presentation by noting that there are several different classes of anti-myeloma drugs. There are
- Steroids, such as dexamethasone (Decadron) and prednisone
- Alkylating chemotherapy drugs such as melphalan (Alkeran) and cyclophosphamide (Cytoxan)
- Anthracycline chemotherapy drugs such as doxorubicin (Adriamycin) and Doxil (pegylated liposomal doxorubicin).
- Proteasome inhibitors such as Velcade (bortezomib)
- Immunomodulatory agents (IMiDs) such as thalidomide (Thalomid) and Revlimid (lenalidomide)
In terms of the side effects of these treatments, Dr. Ailawadhi started off by discussing the broad group of side effects called “cytopenias”, or low blood-cell counts. These are particularly common in combination drug treatment regimens
Anemia, or low red blood cell counts, is one kind of cytopenia. It can be addressed by giving patients erythropoietin-stimulating agents (ESAs) such as Procrit / Epogen (epoetin alfa) or Aranesp (darbepoetin alfa). These drugs will help eliminate a patient’s anemia, but they also increase a patient’s risk of experiencing internal blood clotting.
A general reduction in all blood cell production – that is, red blood cell, white blood cell, and platelet production – can be a problem when patients are treated with Velcade, although the problem is particularly noticeable immediately after Velcade is given to patients, and the problem typically does not get worse with repeated Velcade dosing.
With Revlimid, the cytopenias that are relevant are reductions in platelets (thrombocytopenia), which is typically more prevalent in patients taking Revlimid who have kidney problems, and reductions in white blood cell counts (neutropenia).
In general, a key approach to handling cytopenias created by anti-myeloma agents is to delay treatment if the cytopenia becomes severe, and, if it recurs, to reduce the dose of the drug causing the cytopenia.
The next side effect Dr. Ailawadhi discussed was peripheral neuropathy (PN), or tingling and numbness in the feet and hands. He began by noting that, in myeloma patients, PN is not always a treatment side effect. Up to 20 percent of myeloma patients get peripheral neuropathy as a result of myeloma itself. This kind of PN, however, is typically mild.
Up to 65 percent of myeloma patients develop treatment-associated PN. It is frequently associated with Velcade, thalidomide, vincristine (Oncovin), and cisplatin. In the case of Velcade, the PN is often reversible.
If a patient experiences PN during their myeloma treatment, one thing to bear in mind is that often the PN is at least partly due to other diseases that the patient may have, such as diabetes. Thus, managing those other diseases is a useful part of managing the treatment-related PN.
For PN related to treatment with Velcade, a physician should consider using an alternative dosing schedule or a different mode of administration (for example, subcutaneous instead of intravenous). For thalidomide-related PN, modifying the dosing is typically a good idea.
There are some drugs that also can be used to reduce the PN associated with myeloma treatment. These include the anticonvulsants gabapentin (Neurontin) and Lyrica (pregabalin) and the “serotonin–norepinephrine reuptake inhibitor” Cymbalta (duloxetine).
Another class of side effects to watch out for with myeloma treatment is “venous thrombolic events” (VTEs), or blood clotting in the veins. This is not typically a risk with Velcade treatment. Instead, it is associated more with treatment using Revlimid or thalidomide. The risk of VTEs increases as the number of anti-myeloma agents a patient is taking increases – that is, combination regimens typically have a greater risk of VTEs than single-agent regimens. On the other hand, there usually is a lower risk of VTEs in patients who are being treated for a relapse in their myeloma.
To prevent VTEs from occurring, consideration should be given to avoiding multi-drug regimens in patients who are at high risk of developing VTEs. Likewise, anti-anemia agents such as Procrit/Epogen and Aranesp should be avoided, when possible, in patients at risk of developing VTEs. Finally, there are drugs that patients can take to prevent the occurrence of VTEs. Aspirin is a good choice for patients at a low risk of developing VTEs. Warfarin or low molecular weight heparin, such as Lovenox (enoxaparin), can be considered for patients who are at a higher risk.
Myeloma patients are also often are at risk of developing infections. This is partly due to myeloma itself, but also is a side effect of certain anti-myeloma agents, particularly steroids and Velcade. Patients taking Velcade frequently develop shingles if they are not taking anything to prevent infection by the herpes zoster virus that causes that infection.
To prevent infections from occurring, patients receiving steroids can be treated during the first three months of steroid treatment with trimethoprim-suphamethoxazole (Bactrim). Patients taking Velcade can be treated with an antiviral agent such as acyclovir (Zovirax) to prevent the onset of shingles. Physicians also generally can consider preventative antibiotic use depending on the individual needs and characteristics of the patient.
Some myeloma patients experience gastrointestinal issues – constipation, diarrhea, nausea, and even vomiting – as a result of their treatment. Physicians need to be aware that these side effects can occur and have appropriate treatment recommendations ready if they do.
For myeloma patients taking bisphosphonates such as Zometa (zoledronic acid) or Aredia (pamidronate), there is a risk of jaw bone decay (osteonecrosis of the jaw, or ONJ). This occurs most often after a patient being treated with a bisphosphonates has some sort of dental procedure. Thus, if a myeloma patient intends to have any dental work, they should stop their bisphosphonates treatment, and that treatment also should be stopped immediately if any signs of ONJ develop at any time. The progression of ONJ sometimes can be halted by administering antibiotics and by carrying out various interventions, including debridement (removing the dead tissue around the decaying jaw) and resection (removing the dead parts of the jaw).
Dr. Ailawadhi ended his presentation by quickly discussing a few other side effects sometimes seen with anti-myeloma treatment.
In the case of thalidomide, there are a number of side effects that can occur: fatigue (which can be managed through the timing of when the drug is taken); confusion or a reduced ability to concentrate; excessive potassium in the blood (hyperkalemia) (which mainly occurs in patients with decreased kidney function); and increases in the level of thyroid specific hormone (TSH), which can overstimulate the metabolism, leading to nervousness, irritability, and other additional side effects.
In the case of Velcade, some patients experience lightheadedness, which sometimes can be avoided by ensuring the patients receive more fluids when the drug is administered.
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