SAN DIEGO – A provocative analysis suggests that a sequence of bortezomib and lenalidomide provides a better survival advantage than regimens with three or more agents in patients with multiple myeloma and high-risk cytogenetics.*

"While the limitations of this retrospective study limit drawing definitive conclusions, it appears that poor cytogenetics and biology trump treatment intensification," Dr. Rachid Baz and his colleagues stated in a poster presentation at the annual meeting of the American Society of Hematology.

The investigators reported on 208 patients with multiple myeloma who received bortezomib (Velcade) and lenalidomide (Revlimid), nonconcurrently between January 2004 and August 2010 at the H. Lee Moffitt Cancer Center and Research Institute in Tampa. The patients were stratified by treatment into six groups: lenalidomide with or without dexamethasone (lenalidomide A) or lenalidomide in combination with two or more agents (lenalidomide B); bortezomib with or with dexamethasone (bortezomib A) or bortezomib in combination with two or more agents (bortezomib B); and finally, only doublets or single agents (nonintensive therapy) or three or more agents in combination (intensive therapy).

No differences were observed between the lenalidomide A and B, bortezomib A and B, or intensive and nonintensive therapy groups in the baseline characteristics of age, International Staging System (ISS) and Durie/Salmon stage, beta2microglobulin or renal function, presence of poor-risk cytogenetics, and frequency of high-dose therapy.

Poor-risk cytogenetics, an increasingly fluid term in the context of growing success with novel myeloma agents, included deletions 13q and 17p, translocations, (4;14) and (14;16) or hypodiploidy.

Lenalidomide A patients had a trend toward improved median overall survival at 72 months, compared with 57 months for the lenalidomide B group receiving more complex regimens (P = .07), reported Dr. Baz, with Moffitt’s hematologic malignancies and experimental therapeutics departments.

Median overall survival, the study’s primary end point, however, was significantly improved in the bortezomib A group at 72 months vs. 45 months in the bortezomib B group (P = .02).

Similarly, the nonintensive therapy group lived significantly longer for 74 months vs. 57 months for the intensive therapy group (P = .03).

Notably, patients with high-risk cytogenetics had significantly worse survival if they received intensive therapy rather than nonintensive therapy (median 44 months vs. 72 months; P = .01), he noted. In contrast, patients without high-risk cytogenetics had similar overall survival regardless of whether they belonged to the intensive therapy or nonintensive therapy groups (median 76 months vs. 75 months).

On multivariate analysis that adjusted for known covariates linked to myeloma survival such as ISS stage and high-dose therapy, the only features predictive of poor outcome were renal failure at baseline and intensive therapy.

Dr. Baz said the investigators were surprised by the counterintuitive results and that they could be due to bias from an unidentified confounding factor. For example, it’s possible that high-risk patients who appeared more ill were more likely to be given more intensive therapy by the practicing physician and may have had poor outcomes nonetheless, whereas high-risk patients who appeared more stable were more likely to be given less intensive therapy, but did well because of more indolent disease characteristics.

A potential biologic explanation for the finding might be related to genomic instabilities more commonly seen in high-risk myeloma.

"Patients with high-risk disease have myeloma cells that are more likely to acquire drug resistance faster," he said in an interview. "As a result, if you expose those myeloma cells to many drugs at once, they may acquire resistance to them faster and you get less mileage than if you spread out the drugs."

Dr. Baz said further study at the molecular level is needed to see how drug resistance develops in myeloma in the context of combination therapy with three or four drugs versus treatment with one or two drugs.

"I think the finding is hypothesis generating," he said. "It doesn’t change my practice with the patients I see today, but it needs more study."

Baseline characteristics of the non-intensive and intensive therapy groups were: age (58.9 years, 58.5 years), heavy chain IgG (60%, 63%), light chain Kappa (58%, 67%), ISS stage II (40%, 38%), ISS III (24%, 33%), Durie/Salmon stage III (75%, 85%), creatinine at least 2.0 mg/dL (12%, 13%), presence of bone disease (67%, 80%), poor-risk cytogenetics (43%, 36%), prior high-dose therapy (64%, 66%), and thalidomide use (59%, 47%).

The only significant difference between two groups was the presence of more males in the intensive group (73% vs. 52%; P = .01).

Dr. Baz reported research funding from Celgene and membership on an entity’s board of directors or advisory committee and research funding from Millennium Pharmaceuticals. His coauthors reported similar relationships with Celgene, Millennium, Novartis, and Allergan.

*CLARIFICATION 1/23/12 The status of bortezomib and lenalidomide in treatment for multiple myeloma was clarified in this sentence.

Less May Be More in Treating High-Risk Myeloma