ALBERT

Description: Background: Bortezomib (Bz, VELCADE®) is a novel proteasome inhibitor that has demonstrated efficacy and safety in patients (pts) with relapsed and/or refractory multiple myeloma (MM) in clinical trials. In a large randomized phase 3 trial, Bz achieved superior response rates (RR), TTP, and survival compared with high-dose dexamethasone in relapsed MM pts after 1–3 prior therapies. Peripheral neuropathy (PN) has been dose limiting, especially in pts with pre-existing PN. The objective of this multicenter phase 2 trial was to evaluate the activity and safety of Bz as monotherapy in previously untreated MM pts and prospectively examine PN at baseline (BL) and across treatment. Methods: Pts received Bz 1.3 mg/m2 on d 1, 4, 8, 11 of a 21-d cycle, with RR (CR + PR; EBMT) assessed every 2 cycles. Eligible pts had symptomatic MM with measurable disease and no prior chemotherapy. Concomitant steroids (〉 10 mg/d), plt count 〈 30 x 109/L within 14 d of enrollment or 〉 grade (G) 2 PN were exclusion criteria. RR, TTP, safety and incidence/severity of PN were evaluated. The effect on PN of dose modification (DM) and supplements with specified interventions for symptoms was assessed. Neurologic evaluation involving a pt questionnaire and neurologist’s exam was performed before and after treatment. A 33 pt subset had BL nerve conduction studies (NCS), quantitative sensory testing (QST), autonomic testing, and skin biopsy for quantitation of small-diameter neurite densities (ND). Toxicities were assessed by NCI-CTC, v3.0. Results: 63 pts (median age 60 y) have been treated. Data are available for 50 pts; 27 pts had IgG kappa MM and 21 pts had stage III disease. BL small-fiber neuropathy (SFN; normal NCS but abnormal QST or autonomic studies) was seen in 16/33 pts (48%). BL skin biopsy showed that 18/30 pts (60%) had small-fiber ND at the 15th percentile of age-adjusted norms; global mean density was at the 23rd percentile. NCS revealed BL axonal PN in 3/33 pts (9%). Among 46 pts evaluable for response, best response after ≥ 2 cycles was CR in 5 pts (11%) and PR in 9 pts (20%) for a RR of 30%. 13 pts (28%) achieved MR, 17 (37%) had SD, and 2 had PD (4%). The most common adverse events were PN, fatigue and rash. 24 pts (48%) developed PN, including 18 with G1 and 5 with G2. One pt had G3 PN and was discontinued. DM (dose reduction or discontinuation) was required in 9 pts. 23 pts have been studied after treatment. New large-fiber neuropathy (LFN) was seen in 4/23 pts (17%) and new SFN in 8 pts. Of 3 pts with BL LFN, 1 was not restudied, 1 had worsening SFN and 1 was unchanged. Small-fiber neurite counts were increased to the 35th percentile. Of 16 pts with BL SFN, 7 had worsening SFN (by QST). Bz was otherwise generally well tolerated. Conclusion: Bz as monotherapy has shown activity in newly diagnosed MM pts, with a CR of 11% and manageable toxicity. Underlying SFN appears more common in MM than appreciated. Treatment-emergent ≥ G2 PN was observed in 12% of pts and was G3 in 1 pt. Assessment of PN, the effect of interventions and skin biopsy analyses are ongoing.

Description: Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.

Description: Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.