McCoy, Jason

Abstract The outcome of patients (pts) with WM, a rare B-cell malignancy, varies widely. The international community has convened a panel to develop a prognostically meaningful staging system for survival after treatment initiation. Toward establishing IPSS, we performed multivariate analyses with bootstrap validation in a series of 587 pts (median age 67, range: 28 to 95, M/F ratio: 1.7) diagnosed between September 1979 and December 2001. Diagnostic and treatment criteria fulfilled recommendations of the 2nd international WM workshop. Front-line treatment was initiated at diagnosis in 69% and 4 mo to 164 mo later in the remaining pts. Criteria for initiation of therapy included cytopenia, constitutional symptoms, organomegaly, hyperviscosity, IgM-related disorders, which pertained to 51%, 44%, 35%, 31% and 13%, respectively. Treatment regimens comprised alkylating agents, fludarabine and rituximab in 369, 195 and 23 subjects, respectively. Baseline parameters included age>65 yr in 57%, Hb≤11.5 g/dL in 65%, platelet count ≤100 x109/L in 9%, granulocyte count ≤1.5 x109/L in 9%, B2M >3 mg/L in 56%, albumin ≤3.5 g/dL in 36% and monoclonal protein >7.0 g/dL in 7%. With a median follow-up of 64 mo (range, 6 mo–182 mo), the median survival after treatment initiation was 87 mo (95%CI 79–103) regardless of the type of therapy applied (p=0.3). Using results of univariate survival analyses, recursive partitioning and martingale residuals analyses, 7 adverse characteristics for inclusion in multivariate analyses were identified during an expert meeting: age >65 yr, platelet count ≤ 100x109/L, B2M >3 mg/L, M-protein >7.0 g/dL, granulocytes ≤1.5 x109/L, Hb ≤11.5 g/dL and albumin ≤3.5 g/dL. The Cox proportional hazard model with stepwise selection selected the first 6 covariates. Bootstrap resampling (500 replicates) validated the selection of the first 4 covariates in at least 80% of the replicates. Selection of at least one of the last 2 covariates in more than 80% of the replicates indicated a correlation between these 2 covariates, and validated the inclusion of Hb only. Using the combination of age, Hb, platelet count, B2M and M-protein, low risk was defined by the presence of ≤1 adverse characteristic except age, high risk by the presence of >2 adverse characteristics; the remaining patients with 2 adverse characteristics or age >65yr had intermediate risk, comprising 27%, 38% and 35% of patients with 5-yr survival rates of 87%, 68% and 36% (p<0.0001), independent of treatment and age. IPSS split each subgroup identified by previous scoring systems (Morel, Merlini, Dhodapkar). Conversely, log-rank test was significant only when the latter prognostic system was assessed in low IPSS-risk pts. Thus the combination of age, B2M, M-protein and blood counts provides simple prognostic model for survival in WM, hopefully serving as an objective basis for initiation of therapy and comparison of treatment results.

Abstract ECOG, CALGB and SWOG (coordinating group) enrolled 899 patients with newly diagnosed MM to receive VAD x 4 (813 were considered eligible), followed by randomization to PBSC-supported MEL-TBI (n=261) versus VBMCP (n=255), using CTX 4.5g/m2 + G-CSF for PBSC mobilization in all patients. Responders to VBMCP or MEL-TBI were randomized to IFN (n=121) or no maintenance (n=121). With a median follow-up of alive patients of 60 mos, median EFS and OS from 1st randomization were 25 and 62 mos for MEL-TBI and 21 and 53 mos for VBMCP (p=.14 for EFS, p=.87 for OS). EFS and OS from IFN randomization were also identical at 23/59 mos for IFN versus 18/74 mos for observation (p=.2/.6). 87 VBMCP failures received salvage autotransplants, with a post-relapse median survival of 24 mos which was similar to the 27 mos observed among the remaining 83 VBMCP failures managed with standard salvage therapies. When examined in the context of 2 other randomized trials (IFM 90, MRC VII), OS from baseline of S932, limited to patients <60 yr (as in IFM 90 + MRC VII), is intermediate between the high dose arms of IFM 90/MRC VII and the standard dose arms of these two trials (randomization at baseline) (Figure 1). OS from the time of randomization to high or standard dose therapy on S9321 (again restricted to age <60 yr) was similar to OS timed from transplant for the high dose arms of IFM 90 and MRC VII. (Figure 2). Figure Figure The comparable outcome after high- versus standard-dose therapies on S9321, interpreted in the context of 2 other published randomized clinical trials, may relate to (1) higher dose intensity with VBMCP than with other standard regimens or (2) a detrimental effect of TBI in S9321. We conclude that with the current follow-up MEL-TBI is no better than VAD/VBMCP with the option of salvage transplant and that IFN maintenance is of no benefit in this maintenance setting. Data from this trial will be provided to MRC to be included in their on-going meta-analyses of high-dose therapies and IFN maintenance.

Abstract Recently, many new drugs have been developed for the treatment of Waldenström macroglobulinemia (WM). To optimize the treatment according to the prognosis and to facilitate the comparison of trials, we developed an International Prognostic Scoring System for WM in a series of 587 patients with clearly defined criteria for diagnosis and for initiation of treatment. The median survival after treatment initiation was 87 months. Five adverse covariates were identified: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 × 109/L, β2-microglobulin more than 3 mg/L, and serum monoclonal protein concentration more than 7.0 g/dL. Low-risk patients (27%) presented with no or 1 of the adverse characteristics and advanced age, intermediate-risk patients (38%) with 2 adverse characteristics or only advanced age, and high-risk patients (35%) with more than 2 adverse characteristics. Five-year survival rates were 87%, 68%, and 36%, respectively (P < .001). The ISSWM retained its prognostic significance in subgroups defined by age, treatment with alkylating agent, and purine analog. Thus, the ISSWM may provide a means to design risk-adapted studies. However, independent validation and new biologic markers may enhance its significance.

Purpose Results of a prospective randomized trial conducted by the Intergroupe Francais du Myélome (IFM 90) indicated that autologous hematopoietic cell–supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survial (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM). Patients and Methods In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m 2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (≥ 75%) were randomly assigned to interferon (IFN) or no maintenance treatment. Results With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13). Conclusion The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved ≥ 75% tumor reduction on either arm.