Experts Publish Treatment Recommendations For Multiple Myeloma-Related Bone Disease
The International Myeloma Working Group, a group of leading myeloma specialists, recently published its recommendations for the treatment of bone disease in multiple myeloma patients.
The researchers recommend that all myeloma patients receiving their first anti-myeloma therapy should also receive treatment with bisphosphonates, regardless of whether the patient shows evidence of bone disease on x-rays. They also note that a minimally invasive procedure known as kyphoplasty, as well as low-dose radiation therapy, may be used to reduce severe pain or bone fractures.
In addition, they explain that most bisphosphonates are well tolerated, but patients may still require preventative strategies to avoid kidney damage and osteonecrosis of the jaw, a rare but serious side effect of bisphosphonate treatment in which the blood supply to the jaw is lost, causing jawbone tissue to die.
Bone Disease And The Use Of Bisphosphonates
Bone disease is a common complication of multiple myeloma. Bone-destroying cells are more active in the bones of myeloma patients than bone-forming cells, which ultimately leads to bone destruction.
To slow down and prevent bone destruction, myeloma patients typically receive treatment with drugs known as bisphosphonates, which reduce the activity of the body’s bone-destroying cells. The most commonly prescribed bisphosphonates in multiple myeloma are Zometa (zoledronic acid) and Aredia (pamidronate).
The experts recommend that bisphosphonate treatment should be started in all multiple myeloma patients receiving anti-myeloma therapy, regardless of whether they show detectable bone lesions on x-rays, and in myeloma patients with osteoporosis or osteopenia (somewhat reduced bone density) resulting from myeloma.
The experts add, however, that it remains unclear whether treatment with bisphosphonates has a clinical benefit in patients who do not show bone lesions on magnetic resonance imaging (MRI) or positron emission tomography/computed tomography (PET-CT).
In patients with active, or symptomatic, myeloma, the experts explain that both Zometa and Aredia are equally effective in reducing bone pain and delaying the time to the first bone lesion or fracture.
They further note that Zometa has been shown in a large clinical trial to be superior to the oral bisphosphonate Bonefos (clodronate; not sold in the United States) in terms of preventing fractures and in terms of overall survival, and that Zometa should therefore be preferred to Bonefos.
The recommendations are unclear, however, as to whether Zometa should be considered the preferred bisphosphonate for treating myeloma patients.
On the one hand, the text of the recommendations includes no specific statement describing Zometa as a preferred bisphosphonate.
There are, on the other hand, regular statements noting, for example, that Zometa "is the only bisphosphonate shown to increase survival in the whole studied population of a prospective randomized trial" -- a reference to the trial in which Zometa was found to be superior to Bonefos.
In addition, a summary table near the end of the recommendations describes Zometa and Aredia as the "first option" and "second option," respectively, for the treatment of newly diagnosed myeloma patients requiring anti-myeloma treatment.
In patients with smoldering, or asymptomatic, myeloma, the experts note that both Zometa and Aredia reduce the risk of developing bone disease, but neither slow progression to multiple myeloma. Thus, they suggest that low- and intermediate-risk asymptomatic patients who have osteoporosis be treated with bisphosphonates at doses used for osteoporosis. For patients with high-risk smoldering myeloma and bone loss that may be myeloma-related, especially if the patients have abnormal MRIs, the experts recommend using bisphosphonates at the doses used for symptomatic myeloma.
According to the experts, patients with the myeloma precursor disease monoclonal gammopathy of undetermined significance (MGUS) are at a higher risk for developing osteoporosis. The authors, however, do not recommend that all MGUS patients be treated with bisphosphonates. Instead, they indicate that MGUS patients with osteoporosis should be treated with bisphosphonates at doses typically used for patients with osteoporosis.
Timing And Administration Of Bisphosphonate Treatment
The experts recommend intravenous administration of bisphosphonates every three to four weeks in patients receiving the drugs during or after anti-myeloma therapy.
Treatment with Zometa should be administered until disease progression for patients who do not achieve a very good partial or complete response to their anti-myeloma therapy, and should be continued after relapse.
According to the experts, the evidence is less clear regarding the duration of therapy with Aredia. They therefore recommend that physician discretion determine the duration of treatment with Aredia, and that treatment be resumed at relapse.
The researchers add that the optimal treatment duration is not clear for patients who achieve a very good partial or complete response to their anti-myeloma therapy. The experts recommend, however, that these patients be treated for at least 12 months and up to 24 months and at their physicians' discretion thereafter.
The experts note that further studies are being conducted to assess the long-term efficacy of reduced bisphosphonate doses in multiple myeloma.
Side Effects Of Bisphosphonates
The recommendations note that bisphosphonates are generally well tolerated and doses can be adjusted based on a patient’s response to the drug.
Common treatment-related side effects include low calcium levels, injection site reactions, and stomach problems.
To prevent low calcium levels, the experts recommend that patients receive calcium and vitamin D3 on a daily basis. However, they point out that calcium supplementation should be used with caution in patients with kidney impairment.
The experts also recommend that physicians monitor patients for the development of serious complications, such as kidney failure and osteonecrosis of the jaw.
To prevent kidney failure, the experts advise that kidney function be measured in patients before each bisphosphonate infusion, and that patients with mild to moderate kidney impairment should receive reduced doses of bisphosphonates.
To prevent osteonecrosis of the jaw, patients treated with bisphosphonates should maintain good dental hygiene and stop bisphosphonate treatment for 90 days before and after invasive dental procedures.
Alternative Treatment Options For Bone Disease
The new recommendations also address several other options for myeloma patients with bone disease that are intended to reduce severe pain or bone fractures.
Kyphoplasty is a minimally invasive procedure in which a physician inserts and inflates a small balloon into the fractured vertebra, creating a space that is then filled with an acrylic cement to stabilize the spinal cord. Vertebroplasty is a procedure in which the cement is injected directly into the fractured vertebra.
According to the experts, kyphoplasty is the treatment of choice to improve the quality of life of patients with fractured vertebrae. They state that the benefits of vertebroplasty are less clear because randomized trials of vertebroplasty have not been carried out yet in myeloma patients.
Radiation therapy may also be used for pain reduction and localized improvements in function. However, the experts advise that it should only be used in urgent cases, depending on a patient’s prior treatment history and response, due to its impact on bone marrow function.
More invasive surgeries are treatment options for the repair of certain fractures, such as fractures of the long bones, spinal cord compression, or vertebral column instability. The experts recommend that patients consult with both their hematologist and an orthopedic surgeon to determine how the surgery may impact the administration of their myeloma therapy.
For more information, please refer to the International Myeloma Working Group’s full recommendations in the Journal of Clinical Oncology.
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I took Zometa monthly for 2 years. I still have back pain and degeneration.... Not sure what to do to stop my pain..
Good evening Myeloma Beacon Staff,
Is there a way to clarify a sentence in the following:
"In patients with smoldering, or asymptomatic, myeloma, the experts note that both Zometa and Aredia reduce the risk of developing bone disease, but neither slow progression to multiple myeloma. Thus, they suggest that low- and intermediate-risk asymptomatic patients who have osteoporosis be treated with bisphosphonates at doses used for osteoporosis. For patients with high-risk smoldering myeloma and bone loss that may be myeloma-related, especially if the patients have abnormal MRIs, the experts recommend using bisphosphonates at the doses used for symptomatic myeloma."
2nd sentence specifically makes note of osteoporsis (and not osteopenia) in low and intermed risk SMM.
Last sentence relates to "bone loss that may be myeloma-related" and "abnormal MRIs".
Three question if you please regarding the last sentence.
1. is the "bone loss" also specifically osteoporosis (and not osteopenia);
2. how does the MM community determine the "bone loss that may be myeloma-related" as being definitively related to myeloma. What diagnostics are used to determine this?
3. What does the reference to "abnormal MRIs" mean? Do MRI determine "bone loss"? "related to myeloma"?
Thank you for clarifying, as this topic is very important to me. I am SMM (HR by PETHEMA, intermediate by MAYO) , osteoPENIA and receiving Zometa every 3 months, so I am not quite sure how my protocol now fits into the IMWG recommendations.
My full spine MRI's have reported normal signal intensity without evidence of suspicious osseous lesion; Full Body PET/CT scan also clean.
I am 7 years postmenopausal and am finding it difficult for anyone to definitively tell me if my osteoPENIA is hormonal related or myeloma related. I was diagnosed MGUS in December, 2010 , SMM in January, 2012, DEXA 9/2010 mild osteopenia, NTx was 29 in 2/2011, DEXA 9/2012 more advanced osteopenia. Zometa commenced in October, 2012 due to the worsening osteopenia in the 2 year time interval and told it would help "protect" my bones. NTx was 13 in 3/2013 reflecting response to Zometa.
I would welcome any comments you may have to help me put my data into context with the IMWG recommendations as I am now left with more questions than answers after reading this article.
All of the very best,
Dana
Hi Dana,
There isn't much in the recommendations relevant to smoldering myeloma beyond what was reported in the article.
The specific recommendation relevant to your case reads: "For high-risk asymptomatic multiple myeloma, or if one cannot differentiate multiple myeloma-related versus age-related bone loss, the treating physician should consider using dosing and schedule of bisphosphonates as with symptomatic multiple myeloma, especially in patients with abnormal MRIs ..."
The experts do not clarify before or after that statement whether "bone loss" means osteoporosis, osteopenia, both ... or something else.
There is, however, a section of the recommendation that may be viewed as clarifying both (a) what the authors mean by "abnormal MRIs" and (b) how to distinguish between myeloma-related and age-related bone loss.
In particular, in the discussion of evidence supporting their recommendations, the authors write that "Several studies have reported the value of MRI (presence of > one focal lesion and presence of diffuse pattern of marrow infiltration) in detecting patients with asymptomatic multiple myeloma at high risk for progression."
In addition, we thought we should mention that, immediately after the above statement, the authors go on to write that "Because there are no data supporting progression-free survival advantage with bisphosphonates in asymptomatic multiple myeloma, bisphosphonates should not be recommended except in a clinical trial of high-risk patients."
This last statement seems somewhat at odds with the recommendation quoted at the beginning of this comment. We do not exactly why that is the case ... but it is. It might be useful for you to know, however, as you discuss your treatment plan with your physicians.
Yes,this is helpful, and thank you very much, I will refer to the recommendations and read more thoroughly.
All the best.
you are right, those sentences are at odds. So the treating physician should consider using bispho with symptomatic MM dosing in HRSMM, esp those with abnormal MRI's BUT in clinical trials settings only.
Is there any way for you to reach out to the authors and bring this to their attention? and clarify it should be MM protocol in clinical trial settings only for HRSMM. Or did we already establish this to be their intended recommendation.
I would like to make certain I fully understand what they are recommending as this would enable me to discuss with my physician the likelihood to have my protocol modified to follow osteoporosis protocol which is important to me. I don't want to misconstrue the recommendation and muddy the already muddied waters that I feel I tread through at times as I amble through my watch and wait limbo.
Thanks again.
Sorry, if you are able/willing to reach out to the authors, could you also clarify "The experts do not clarify before or after that statement whether “bone loss” means osteoporosis, osteopenia, both … or something else."
Hi Dana,
In the case of guidelines and recommendations such as this one, it really does not make sense to reach out to any individual author for interpretation or guidance.
Consensus recommendations by their very nature have been hammered out with great care so that, as much as possible, they reflect the opinions of many people. When there is apparent disagreement, or vagueness, it generally indicates that either the experts themselves could not come to agreement, or they did not devote the necessary time during their development of the guidelines to ensure specificity and consistency.
If we reach out to any of the individual authors to ask for clarification on an issue where there are apparent contradictions, or vagueness, we cannot be assured that the opinion or interpretation we get is that expert's opinion, or truly the opinion of the group.
In cases like this, the only text that can be guaranteed to reflect the opinion of the entire group of experts is the published text of the article, which we have discussed in our review and in our earlier comment.
That said, we do believe the authors paid particular attention to ensuring they were in agreement on the text in the actual "Recommendations" section (rather than the text of the "Evidence" section).
Thus, our suggestion would be to place particular weight on the statement that "For high-risk asymptomatic multiple myeloma, or if one cannot differentiate multiple myeloma-related versus age-related bone loss, the treating physician should consider using dosing and schedule of bisphosphonates as with symptomatic multiple myeloma, especially in patients with abnormal MRIs ..."
This is the recommendation most likely to reflect the consensus opinion of the entire group of authors.
I am on a reduced dose of pamidronate (Aredia) based on a large clinical study done by the Nordic Myeloma Group in Scandinavia which indicated that 30mg. per month is as efficacious as 90mg. per month (the usual prescribed dose) and causes fewer side effects. My doctors at the NIH were well aware of this study and supported the reduced dosage. So far, no problems. Sometimes, less is more, at least, I hope so.... See, http://www.ncbi.nlm.nih.gov/pubmed/20863761
Good morning and thanks so much Beacon Staff for treading through the muddy waters for me...very much appreciated, I fully understand what I need to discuss with my physicians.
Best to you,
Dana
You're welcome, Dana.
Terry - Reflecting what is in the study you reference, the recommendation authors write in the Recommendations section that "Pamidronate [Aredia] 30 and 90 mg have shown comparable effects for preventing [skeletal related events]."
In the Evidence section, they go on to discuss the study comparing the two pamidronate doses, and include some useful commentary.
They write: "A recent study in patients with newly diagnosed multiple myeloma (N=504) demonstrated that pamidronate 30 mg monthly had comparable time to skeletal related events and skeleta related event-free survival time compared to pamidronate 90 mg. Patients received pamidronate for at least 3 years, and patients receiving pamidronate 30 mg showed a trend toward lower risks of osteonecrosis of the jaw and nephrotoxicity [kidney damage] relative to pamidronate 90 mg. However, the study was not powered to show skeletal related event differences between the two pamidronate doses but only to show quality of life differences."
By "was not powered", the authors mean "designed", with an emphasis on the size of the trial (number of trial participants).