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High-Risk Smoldering Myeloma

To Treat or Not to Treat Still a Question

Fuerst, Mark

doi: 10.1097/01.COT.0000461133.69794.e4
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NEW YORK—Patients with the highest risk of smoldering myeloma should be treated and those with the lowest risk should be observed, but the question still remains about whether high-risk patients require therapy. That appeared to be the consensus here at the Lymphoma & Myeloma International Congress on Hematologic Malignancies, with two experts debating the overall topic “Should We Treat Smoldering Myeloma? Is the Data Convincing?”

Joseph Mikhael: Yes, Treat High-risk Smoldering Myeloma

Joseph Mikhael, MD, Associate Professor of Medicine, Hematology/Oncology, at the Mayo Clinic in Arizona, explained that myeloma is a unique cancer that is defined by the presence of organ damage, not just by pathology.

“Traditionally, we wait until patients have CRAB [calcium elevation, renal insufficiency, anemia, and bone disease] symptoms. But does that really make sense? Do we have to wait until damage is present to intervene?”

He presented the thesis that there are three patient groups within smoldering myeloma, in accordance with the updated criteria recently issued by the International Myeloma Working Group (IMWG) for the diagnosis of multiple myeloma (Lancet Oncology 2014;15:e538-e548):

  • Group 1 has ultra-high-risk disease, including bone marrow plasmocytes, involved/uninvolved light chains of 100 or more, and one or more focal lesions on MRI or PET: “Treat these patients as if they had true myeloma,” Mikhael said.
  • Group 2 has high-risk disease. “The question is to treat them or not? The whole myeloma community wrestles over this issue. We are all moving toward not waiting for broken bones and kidney disease before we treat these patients.”
  • Group 3 has low-risk disease. “Don't treat these patients. Some of them may upgrade to MGUS [monoclonal gammopathy of undetermined significance]. We don't want to overtreat them. A subset does not need to be treated.”

There has been a paradigm shift in the incidence of high-risk smoldering myeloma, Mikhael said. “The incidence was 10 percent per year over five years, and now it is about one percent per year after 10 years.”

JOSEPH MIKHAEL, MD. JOSEPH MIKHAEL, MD: “Early intervention in high-risk smoldering myeloma prolongs time to progression, improves overall survival, and does not result in appreciable toxicity. Events may develop, such as bone fractures, and renal insufficiency, which is mostly reversible. But treatment will prevent irreversible damage to kidneys and bones that occur on our watch.”

The new IMWG criteria allow the use of early indicators to diagnose myeloma before CRAB symptoms happen, and also allow the use of modern imaging methods to make an early diagnosis. The revised IMWG criteria will allow, in addition to the classic CRAB features, three markers as myeloma-defining events.

These markers are: 60 percent or greater clonal plasma cells on bone marrow examination; serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L; and more than one focal lesion on MRI that is at least 5 mm or greater in size. Each of the three additional markers has been shown in two or more independent studies to be associated with an approximately 80 percent or higher risk of developing myeloma-related organ damage within two years.

Adding in these markers, Mikhael termed the new criteria for smoldering myeloma as “SLiM CRAB.”

To manage high-risk smoldering myeloma, early treatment delays progression to active disease and increases overall survival, he said, citing a Spanish myeloma group study published in 2013 in the New England Journal of Medicine (2013;369:438-447).

This Phase III trial randomized 119 patients to nine four-week cycles of lenalidomide at 25 mg once daily on days 1-21 and dexamethasone at 20 mg once daily on days 1-4 and 12-15 followed by lenalidomide at 10 mg once daily on days 1-21 with seven days off, or observation. The primary endpoint was time to symptomatic disease.

JAMES R. BERENSON, MD. JAMES R. BERENSON, MD: “We need to balance control of disease versus cure. Disease can be controlled for long survival and thus use less toxic drugs and maintain quality of life. Cure leads to lower tumor burden and may be more drug sensitive—that is, it may be easier to eliminate the clone.”

The three-year overall survival rate was higher (94%) in the treatment arm compared with the observation arm (80%). “There is no doubt about the results—survival differed significantly,” Mikhael said. “Some critics had issues with the trial, stating that it was not generalizable since the Spanish criteria for smoldering myeloma were different from Mayo Clinic criteria—but more than 60 percent of the patients met Mayo criteria. I would argue that trial is generalizable.

“Early intervention in high-risk smoldering myeloma prolongs time to progression, improves overall survival, and does not result in appreciable toxicity. Events may develop, such as bone fractures, and renal insufficiency, which is mostly reversible. But treatment will prevent irreversible damage to kidneys and bones that occur on our watch.”

In conclusion, Mikhael said that simply observing those in the low-risk group is acceptable, but cautioned: “I do think you have to be careful with this group moving toward difficulties, and then you have to intervene. The high-risk group is complex. They have a 50 percent chance of progressing.

“Consider therapy in these patients in an individualized manner. Therapy should not be limited to lenalidomide/dexamethasone, but all active therapies, including proteasome inhibitors or immunomodulatory drugs. Ultra-high-risk patients should be treated.”

James Berenson: No, Do Not Treat High-risk Smoldering Myeloma

To treat or not to treat, that is the question, said the other debater, James R. Berenson, MD, President and CEO of the Institute for Myeloma & Bone Cancer Research in West Hollywood, California, who took the negative side of the debate.

He began by outlining the diagnostic criteria for smoldering myeloma, which includes monoclonal protein in serum of more than 3 g/dL and/or monoclonal protein in urine of more than 200 mg over 24 hours plus more than 10 percent bone marrow clonal plasma cells (and/or documented plasmacytoma). The CRAB criteria includes calcium elevation (more than 11.4 mg/dL), renal insufficiency (creatinine more than 2 mg/dL), anemia (Hb under 10g/dL or 2 g/dL below normal), and bone disease (osteolytic lesions or osteopenia or fracture).

Certain risk factors for smoldering myeloma require treatment sooner, Berenson said. The highest risk factors predicting progression are total bone marrow plasma cells more than 60 percent, serum free light chains (SFLC) of more than 100, and MRI findings of more than one—i.e., the same ones mentioned by Mikhael.

The prevalence of high-risk disease shows that smoldering myeloma is uncommon. Overall, smoldering myeloma makes up 15 percent of multiple myeloma cases and only 20 percent of patients have high-risk disease. The definition of high risk depends on the risk factors used in various trials—“Thus, high-risk smoldering myeloma occurs in only three percent of multiple myeloma cases,” Berenson said.

The risk of progression from “asymptomatic” smoldering myeloma to “symptomatic” multiple myeloma, according to the Mayo Clinic, is 10 percent per year during the first five years, three percent per year during years 5-10, and 1.5 percent per year after the first 10 years. “In our practice, the incidence of smoldering myeloma is 14 percent with a median follow-up of 63.5 months, Berenson said.

After 10 years, the risk is not unlike that for MGUS patients: “Progression to symptomatic multiple myeloma is poorly defined. CRAB criteria are not symptoms. Progression based on CRAB may not be related to myeloma.”

Bone disease is “the bane of my existence,” he said, noting that osteopenia/osteoporosis patients with smoldering myeloma do quite well with bisphosphonates. Bone disease includes lytic bone disease, changes on x-ray readings that are not real, osteopenia/osteoporosis from other causes, and vertebral compression fractures that are traumatic or related to osteopenia/osteoporosis.

In his practice, he said, the median five-year overall survival for patients with smoldering myeloma is 87.5 months after median follow-up of 63.5 months. “These patients live a long time. Does treatment improve quality of life?” he asked. “One of the goals of therapy for the smoldering myeloma patient should be the longest life possible with therapy and a disease that has the least impact on quality of life.

“This does not necessarily mean that these patients want treatment. A reduction in paraprotein—that is, responses—may be without meaningful clinical benefit. We need to show prolonged overall survival, whereas responses are of questionable benefit and time to treatment endpoints are also of questionable benefit. We also need to show improved quality of life and prevention of complications.”

When deciding to treat smoldering myeloma, clinicians need to weigh their options, Berenson said. Disease-related issues, such as the risk of death and complications, need to be considered against treatment-related issues, including side effects, tolerability versus improved quality of life, and prolonged survival.

“We need to balance control of disease versus cure. Disease can be controlled for long survival and thus use less toxic drugs and maintain quality of life. Cure leads to lower tumor burden and may be more drug sensitive—that is, it may be easier to eliminate the clone,” he said.

There are risks in treating smoldering myeloma, including toxicity, the negative impact on quality of life, such as neuropathy and somnolence, and production of side effects. Also, secondary malignancies may occur, such as hematologic malignancies induced by lenalidomide and skin cancers by bortezomib. Carfilzomib may cause cardiac complications.

“The effects of treatment on the myeloma may induce or allow clones to take over that are more aggressive, meaning that patients may then be resistant to new therapies in the future.”

Some treatment approaches have been tested in smoldering myeloma, but they are not risk adapted. Exercise was successful in a single case report, and celecoxib in a single-arm study; curcumin has induced small changes in SFLC. Chemotherapy using melphalan-prednisone versus observation showed no differences in progression-free or overall survival. Cytokine inhibitors, such as IL-1RA, in a small trial showed limited activity.

For bisphosphonates alone, there are reports of responses with long progression-free survival. “Larger randomized trials show prolonged time to bony complications, but no impact on time to progression or overall survival,” he said.

Several trials have used thalidomide alone and shown responses, but poor tolerability. However, “in one trial responses actually were associated with shortened survival. Thalidomide with bisphosphonates shows higher response rates and time to progression than use of bisphosphonates alone, but the drug [thalidomide] is too toxic,” Berenson said.

Other treatment approaches for smoldering myeloma are in early phases of development. These include proteasome inhibitors, such as bortezomib alone and carfilzomib with lenalidomide and dexamethasone. “A small NIH trial with carfilzomib with lenalidomide and dexamethasone showed a 100 percent response rate, but the patient numbers are small and the follow-up is short,” he said.

Monoclonal antibodies under investigation include the anti-CS-1 agent elotuzumab, anti-IL-6 agent siltuximab, anti-DKK-1 agent BHQ880, and anti-KIR agent IPH2101.

Berenson also looked at the results of the Spanish group study. The lenalidomide/dexamethasone arm showed prolonged time to symptomatic disease, with a median 21 months in the observation arm versus not reached in the treatment arm. “However, dexamethasone was given only to the treatment arm when progressing biochemically on single-agent lenalidomide maintenance. The researchers waited until patients met CRAB criteria to treat those in the observation arm, which led to a higher rate of death than would be expected.”

He noted that this trial did not have a crossover design, and therefore patients in the observation arm did not receive any lenalidomide/dexamethasone.

His basic message about smoldering myeloma is to “take it slow. Smoldering myeloma is uncommon, and most patients are at low risk to progress. Only a small minority—about one-fifth—of these patients have high-risk disease.” Treatment must have specific goals, including improved quality of life, prevention of complications, and improved overall survival. “No studies have demonstrated an overall survival effect except the Spanish study in high-risk disease, which had significant design problems,” he said.

Berenson suggested treating patients with smoldering myeloma who are in the highest-risk group. “These patients have an 80 percent risk of progression within two years. Therefore, treat them as having active multiple myeloma. But we still don't know if this impacts overall survival or quality of life.”

All other patients should be monitored or placed into a clinical trial, and those with osteopenia or osteoporosis should receive monthly zoledronic acid, he said.


In the question-and-answer session, the debaters were asked about the use of MRI or PET scans for bone disease assessment. “There is no compelling data to show that if we find lesions on imaging, patients will have worse outcome,” Berenson said. “There is no data this makes a difference clinically.”

Mikhael agreed that every myeloma patient should have a skeletal survey, but not necessarily imaging. “How much more does scanning show you? Why do we need a test that is not going to influence patient management?” he asked. One indication for imaging is extramedullary disease, he said.

Another audience member asked about the use of bisphosphonates. The IMWG recommends bisphosphonates for myeloma patients, noted Mikhael, who said: “All patients treated for myeloma should be on bisphosphonates. Treat them for two years, maybe longer. You have to prove there is no bone disease to not give bisphosphonates.

“Of the next 20 myeloma patients I see in my clinic, 19 will go on bisphosphonates. I might not treat that one patient until there is borderline renal insufficiency. For patients with overt bone disease, I recommend the use of bisphosphonates.”

Berenson urged clinicians to be aware of the side effects of bisphosphonates: “I advocate testing bone density before I give bisphosphonates. If a patient has symptomatic disease, then I do further imaging. I use PET/CT scans to know if the disease is elsewhere.”

A survey of the audience after the debate showed that the “Yes” votes increased from 15 percent before the debate to 41 percent afterward, making Mikhael the clear winner.

© 2015 by Lippincott Williams & Wilkins, Inc.
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