First thalidomide clinical trial in multiple myeloma: a decade later

van Rhee F, Shaughnessy Jr JD, Anaissie E, Siegel D, Hoering A, Zeldis J, Jenkins B, Singhal S, Mehta J, Crowley J, Jagannath S, Barlogie B.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock.

The clinical outcomes of 169 patients, enrolled in the first clinical trial of thalidomide for advanced or refractory myeloma, are updated. Seventeen patients remain alive and 10 event-free, with a median follow-up of 9.2 years. According to multivariate analysis of pre-treatment variables, cytogenetic abnormalities (CA), present in 47% of patients within 3 months of enrollment, and lambda light chain isotype both affected overall survival and event-free survival adversely. Forty percent of the 58 patients lacking these 2 unfavorable features, one-half of whom had no disease recurrence, survived at least 6 years, in contrast to fewer than 5% among those with 1 or 2 risk features (P<0.0001).>

PMID: 18502827 [PubMed - as supplied by publisher]

Lenalidomide raises clot risk in multiple myeloma patients

Thromboembolic events are increased in patients undergoing lenalidomide-based therapy for multiple myeloma. Aspirin prophylaxis appears to reduce this risk.

"There is a real risk of blood clots with the use of lenalidomide in myeloma," according to Dr. S. Vincent Rajkumar, "particularly in combination with other chemotherapeutic drugs."

To investigate these and other risk factors, Dr. Rajkumar of the Mayo Clinic College of Medicine, Rochester, Minnesota and colleagues conducted a pooled analysis of data from three clinical trials involving 125 patients who had previously untreated multiple myeloma.

Along with lenalidomide-based therapy, 52 received high-dose dexamethasone (40 mg 12 days a month) and 73 received prednisolone or dexamethasone 40 mg, 4 times per month. In addition, 110 were given thromboprophylactic treatment, primarily aspirin.

Overall, 10 patients (8%) developed deep vein thrombosis (DVT), the investigators report in the April 1 issue of Cancer. Four were not receiving thromboprophylactic treatment at the time of the event.

There was no significant difference in the incidence of DVT in patients receiving concomitant erythropoietin therapy and those not receiving this treatment. The rate of DVT was higher in the high-dose corticosteroid group compared with the low-dose group (12% versus 6%, respectively), but this difference did not reach statistical significance.

The rate of thrombosis was lower than the range reported in the literature, the investigators point out, possibly because most patients were receiving anticoagulant prophylaxis and 58% received low-dose corticosteroid.

"The best prophylaxis," Dr. Rajkumar concluded, "should take into account all the risks and benefits. By using a low dose of steroids, and using aspirin as a preventive measure, the risk of blood clots can be minimized to less than 10%."

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y, Rice AG, van Abbema A, Wong M, Liu G, Zhan F, Dillon M, Chen S, Rhodes S, Fuh F, Tsurushita N, Kumar S, Vexler V, Shaughnessy JD Jr, Barlogie B, van Rhee F, Hussein M, Afar DE, Williams MB.

Authors' Affiliations: Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.

PURPOSE: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models. EXPERIMENTAL DESIGN: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice. RESULTS: CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice. CONCLUSIONS: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.

PMID: 18451245 [PubMed - in process]

Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma

Barlogie B, Anaissie E, Haessler J, van Rhee F, Pineda-Roman M, Hollmig K, Alsayed Y, Epstein J, Shaughnessy JD Jr, Crowley J.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

BACKGROUND.: Complete response (CR) has been considered a necessary although not sufficient early clinical endpoint for extended survival in multiple myeloma. METHODS.: By using Total Therapy 2 (TT2) clinical outcome data in 668 patients, whether sustained CR (SUS-CR) was potentially a superior surrogate for survival than attaining CR status per se was evaluated. RESULTS.: Compared with not achieving CR (NON-CR) and especially achieving and subsequently losing CR status (LOS-CR) within a 3-year landmark from treatment initiation, SUS-CR was associated with highly superior postlandmark survival (P < .0001). These results were validated in 231 untreated patients enrolled in the predecessor trial, TT1 (hazard ratio [HR] = 0.54, P = .013) and in 1103 previously treated patients on other transplant protocols (HR = 0.49; P < .001). CONCLUSIONS.: In all 3 trial settings the survival benefit of SUS-CR was independent of metaphase abnormalities as a dominant adverse parameter. Given its bleak prognosis despite high CR rates, SUS-CR should be evaluated as a primary trial endpoint in high-risk myeloma. Cancer 2008. (c) 2008 American Cancer Society.

PMID: 18470907 [PubMed - as supplied by publisher]