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Smoldering Multiple Myeloma: When to Treat, When to Stick with Monitoring Alone

Carlson, Robert H.

doi: 10.1097/01.COT.0000430607.78287.d3
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NEW YORK—Outside of clinical trials, observation is the current standard of care for patients with smoldering (asymptomatic) multiple myeloma. But that may change, as data accumulate showing that patients with high-risk disease often progress to multiple myeloma and that early intervention may stop that progression or even produce a cure.

A presentation here at the International Congress on Hematological Malignancies reviewed the current status of the existing guidelines from the International Myeloma Working Group, in place since 2010 (Leukemia 2010;24:1121-1127).

As Ola Landgren, PhD, Senior Investigator and Chief of the National Cancer Institute's Multiple Myeloma Section, explained, the guidelines call for use of baseline bone-marrow biopsy and skeletal survey, monitoring with repeat lab tests every two to three months, and then less frequent monitoring if disease becomes stable. But more is known now about risk groups than when the guidelines were written, he said, and two models of risk used today, from the Spanish “PETHEMA” group and the Mayo Clinic, both recognize low-, intermediate-, and high-risk groups.

OLA LANDGREN, PHD: “With the new drugs becoming standard in the myeloma field and more coming that are much less toxic, we can envision a scenario where we could treat patients with smoldering myeloma and actually cure them, and also envision treating patients and controlling the disease very effectively, converting it to a chronic disease.”

“The higher-risk smoldering myeloma groups in both models have an average time to development of multiple myeloma of less than two years, and at five years of follow-up 75 percent of patients had myeloma,” Landgren said. “In my opinion those [high-risk] patients have a very early myeloma disease.”

In a 2011 paper (Clin Cancer Re 2011;17; 1243-1252)—coauthored with Robert A. Kyle and S. Vincent Rajkumar—he wrote that “in the near future, it seems reasonable to believe that high-risk precursor patients will likely become candidates for early treatment strategies.”

“It is obvious that there is a very short time course from diagnosis of high risk to actual onset. And now there is data from the first Phase III trial for smoldering myeloma, using dexamethasone and Revlimid versus observation, showing that progression-free and overall survival are significantly different between treatment and no treatment,” Landgren said, citing an abstract from the 2011 American Society of Hematology Annual Meeting by Maria-Victoria Mateos et al (Abstract 991).

Among the 57 patients receiving treatment in that trial, 82 percent achieved at least a partial response. The hazard ratio for progression in the observation group was 5.67, compared with the treatment group. And with a median follow-up of 47 months from inclusion, the overall survival rate was 94 percent for the treatment group vs. 85% for observation.

Those data do have to be replicated, Landgren said, but they are part of the mounting evidence for treatment in high-risk cases.

Recent functional MRI imaging of bone marrow in patients with smoldering myeloma shows that the bone marrow in about one-third of patients looks very much like that of myeloma patients, and those patients have a much shorter time to develop myeloma, he added.

Envisioning Cure

With the new drugs becoming standard in the myeloma field and more coming that are much less toxic, “we can envision a scenario where we could treat patients [with smoldering myeloma] and actually cure them, and also envision treating patients and controlling the disease very effectively, converting it to a chronic disease,” Landgren said, in an interview after the meeting.

But there is theoretically a chance that treatment of smoldering myeloma could select for more aggressive, resistant cells. “For that reason we should not start treating patients until we have determined the right regimen,” he said, noting that comprehensive treatment will require new diagnostics.

In a recent trial he and colleagues conducted, most patients had at least a 50 percent reduction in clones after therapy, and many had a 75 percent reduction, and no detectable M-spikes.

In the near future, close to 100 percent of patients may have no detectable M-protein after therapy, he said. “The problem is that there could be evidence of cells anyway, so we need other tools to look for minimal residual disease, to really make sure there is no residual disease, or that if there is, to control it to make sure it doesn't progress.”

Patients may have a complete response with no detectable M-spikes, “but you can still find residual cells with the more sensitive technologies.”

Landgren said he recalled testing five million cells from one patient after therapy looking for minimal residual disease, and finding 17 clones—“That was very annoying.”

In an article now online ahead of print in Leukemia & Lymphoma, he and Jens Hillengass review the use of novel imaging techniques in monoclonal plasma cell disorders, including “early myeloma.” One promising technology, they note, is molecular imaging of bone marrow to diagnose focal bone marrow infiltration in smoldering myeloma (doi:10.3109/10428194.2012.740559).

Also of note, Landgren said, is a new test to detect minimal residual disease using polymerase chain reaction to amplify Ig heavy chain VDJ genes, a marker for cells in the myeloma clone.

Landgren has two trials of the carfilzomib-lenalidomide-dexamethasone regimen ongoing at the NIH—one for newly diagnosed patients with multiple myeloma, and the other using the same regimen for high-risk patients with smoldering myeloma.

He emphasized, though, that myeloma is clearly not just one disease, but rather probably 10 or more different diseases molecularly, and so more than one regimen is going to be necessary.

© 2013 Lippincott Williams & Wilkins, Inc.
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