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Myeloma: ‘Continued Treatment’ Not Maintenance

Carlson, Robert H.

doi: 10.1097/
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NEW YORK CITY—The scientific agenda at the Lymphoma & Myeloma International Congress on Hematologic Malignancies covered extensive ground over three days. The following are some of the take-home messages regarding multiple myeloma:

Maintenance therapy for myeloma patients is controversial because of its risks, not the least of which is the chance of second malignancy. But Sergio Giralt, MD, Chief of the Adult Bone Marrow Transplant Service at Memorial Sloan-Kettering Cancer Center, put those risks in context: “Prior to continuous therapy regimens, 80 to 90 percent of patients would have to deal with their disease again at an average of two to three years after undergoing autologous stem cell transplant.”

He specifically used the term “continuous therapy,” which he said is more appropriate when an extremely active agent is given for a long period of time.

“That means what we consider our most effective treatment provides only two to three years of control.” Although continuous treatment offers increased remission duration, minimal disease burden, prevention of end organ damage, targeting of tumors leaving dormancy phase, and potential decrease of tumor burden post primary therapy, the impact on overall survival is yet to be determined, he said.

All novel agents appear to have benefits in the longer term, Giralt continued. Unfortunately, all patients receiving continuous therapy are exposed to the side effects but not necessarily to the benefits. In addition to second malignancies, continuous treatment can also result in resistant clones, and the cost can be enormous, he said.

For a low-risk myeloma patient in complete remission (CR) with low tumor burden, “I would put my hands in my pocket, watch that patient carefully, and the moment there is evidence of disease I would probably start to intervene.”

That strategy would spare the patient from lenalidomide for an average of three to four years. “But high-risk patients not in CR, and even those in CR, do need continued therapy,” he said.

Novel Agents for Transplant-Ineligible Patients

Melphalan-prednisone should no longer be used to treat transplant-ineligible myeloma patients, and treatment should include novel agents instead. That was the conclusion of meeting co-chair Ruben Niesvizky, MD, Director of the Multiple Myeloma Service at New York Presbyterian Hospital-Cornell Medical Center.

“We have to learn how to incorporate novel agents that are superior.” There are good data for the use of thalidomide, lenalidomide, and bortezomib, he said, but the strongest option so far is for bortezomib. Needed now are comparisons of bortezomib with lenalidomide-dexamethasone, or with other regimens that do not include melphalan-prednisone.

ClaPD Best for Relapsed/Refractory Myeloma

Tomer Mark, MD, the Morton Coleman Assistant Professor in Multiple Myeloma at Weill-Cornell Medical College, called the combination of clarithromycin, pomalidomide, and dexamethasone (ClaPD) the best regimen for relapsed refractory myeloma.

“ClaPD is highly effective in heavily pretreated patients and has very good clinical activity, whether the patient is refractory to lenalidomide or bortezomib or both,” he said. “And progression-free survival is sustained for more than six months in the majority of patients.”

SCOTT ELY, MD, has developed an assay to help identify myeloma patients at high risk of relapse. He is offering the methods and software free to anyone who will use it and provide feedback.
SERGIO GIRALT, MD: “For low-risk patients in CR with low tumor burden, I would watch carefully, and the moment there is evidence of disease I would probably start to intervene. But high-risk patients do need continued therapy.”

In clinical trials with patients receiving ClaPD, high-risk cytogenetics did not have an impact on progression-free survival or overall survival, he said, adding that a history of being refractory to prior lenalidomide or being double refractory to lenalidomide and bortezomib also did not influence progression-free survival in patients receiving ClaPD.

New Test Assays Proliferation

Also at Weill Cornell Medical College, Scott Ely, MD, Associate Professor of Clinical Pathology and Laboratory Medicine, described a novel assay for myeloma, the plasma cell proliferation index (PCPI), which can help identify myeloma patients at high risk of relapse.

PCPI is the percentage of myeloma cells expressing both the plasma cell marker CD138 and the proliferation marker Ki-67. He noted that although a plasma cell labeling index has been available for calculating proliferation rates since the 1980s, the assay has been available only at one place (the Mayo Clinic) because the assay is time consuming, technically difficult, and very expensive.

PCPI is based on use of core biopsies and a double-immunohistochemistry stain that Ely said is technically feasible in any pathology lab. Proliferating myeloma cells can be counted manually, and the researchers have also developed automated image-analysis software using the MUM1 lymphocyte-specific transcriptional factor.

KEITH STEWART, MB, CHB, recommended that immunomodulatory drugs be renamed “cereblon-binding small molecules” to more accurately reflect the mechanism of action.

To validate the PCPI, Ely is offering the methods and software free to anyone who will use it and provide feedback.

Blocking Cereblon Key to IMiD Activity

Cereblon, the binding protein with which thalidomide initiates its teratogenic effects, appears to be essential to activity of the immunomodulatory drugs (IMiDs) against myeloma and may be a marker for IMiD resistance.

Keith Stewart, MB, ChB, Dean for Research and Professor of Cancer Research at the Mayo Clinic in Scottsdale, Arizona, reviewed research he and colleagues presented at the 2011 American Society of Hematology Annual Meeting (Abstract 127) that showed that myeloma cells with cereblon deletion are resistant to lenalidomide and pomalidomide but not to other therapeutics. (Additional research was subsequently reported at the 2012 ASH Annual Meeting (Abstract 194 and Abstract 1807.)

He said that preliminary data show that low cereblon expression levels predict for poor response to IMiDs and suggested that the IMiDs be renamed “cereblon-binding small molecules” to more accurately reflect the drug classes' mechanism of action.

© 2013 Lippincott Williams & Wilkins, Inc.
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