Velcade™ (Vel) has shown promising activity as single agent and, more recently, in combination with other antimyeloma agents (dexamethasone, thalidomide) in relapsed or refractory multiple myeloma. We have now explored the efficacy and safety of adding Adriamycin™ 2.5–10.0mg/m2 continuous infusion on days 1–4 and days 9–12 to Velcade™ 1.0 or 1.3 mg/m2 administered on days 1, 4, 9 and 11; thalidomide 50 or 100 mg days 1–12; and dexamethasone 20 or 40 mg days 1–4 and 9–12 (VATD). The treatment was administered in an out-patient, ambulatory care setting to 20 patients. Of the 20 patients evaluable for toxicity, 14 are also evaluable for response. Patient characteristics are outlined in Table 1. Prior resistance to Velcade™-based treatment was demonstrated in 19 patients, with progressive disease in 13 and stable disease in 6. All patients have received systemic therapy immediately prior to the initiation of VATD, which included Vel + thal (7), VTD (5), DT-PACE (4), Revlimid (3), and dex + thal (1). Hematologic toxicities were dependent on the pre-VATD platelet count and WBC levels, as outlined in Table 2. Out of 14 evaluable patients, partial response (≤ 75% of serum M protein reduction, ≤ 75% of urinary M excretion) was obtained in 7 (50%); none had a complete response. Serum M protein decreased by a median of 57% (21–90%) and urine M decreased by a median of 93% (21–90%). Bone marrow follow-up examinations were available in 13 patients and revealed a median reduction in monoclonal plasmacytosis of 50% (range 33–94%); none had a normal bone marrow. Pre-VATD PET scans showed evidence of disease in 10 patients. Post VATD PET scans showed improvement in 5, stable disease in 1 and progressive disease in 4 patients. Our results are promising and demonstrate that administration of Adriamycin™ can be safely added to VTD, and that this addition does overcome the resistance to Velcade-based therapy even in metronomic doses. This approach is now being formally evaluated in a randomized trial comparing VTD alone versus added Adriamycin™ 2.5 mg/m2 on days 1–4 and 9–12 as a salvage protocol in patients with recurrent or progressive MM. Patient Characteristics Velcade 1.0 mg/m² Velcade 1.3 mg/m² Parameter Total Adria 2.5 mg/m² Adria 5 mg/m² Adria 10 mg/m² Adria 5 mg/m² 1: Autotransplant; 2: Thalidomide; 3: Velcade; 4: Velcade; Thalidomide, Dexamethasone N 20 7 10 1 2 % Age ≥ 65 14 14 60 100 0 % Abn Cytogen 55 43 60 100 50 % Prior Autotx1 85 86 80 100 100 % Prior Thal2 100 100 100 100 100 % Prior Vel³ 95 100 90 100 100 % Prior VTD[sup4] 45 71 20 100 50 % LDH > 190 U/l 55 57 60 100 0 Hematologic Toxicities Pre-Treatment Median WBC Nadir Platelet Count WBC < 2,000 WBC > 2,000 WBC < 2,000 WBC > 2,000 > 100k (n=6) 1 5 .65 2.07 50k-100k (n=9) 3 6 .94 1.73 < 50k (n=4) 1 3 1.98 3.44 Median Platelet Nadir > 100k 46,000 51,000 50K–100k 11,000 20,000 < 50K 36,000 47,000
Cardiovascular complications during the treatment of patients with multiple myeloma (MM) are not uncommon (10%) and the frequency clearly increases with the use of regimens containing thalidomide (T) in combination with glucocorticosteroids or chemotherapy especially adriamycin. Even with prophylactic anticoagulation, DVT still occurs in 10% of such patients. The use of full anticoagulation treatment raises considerable concern of bleeding, especially during the post chemotherapy thrombocytopenic period. We now report the incidence of DVT in MM patients treated with T containing regimens where VELCADE has been added to dexamethasone (D) and adriamycin. Results are shown in table1. The incidence of DVT was also analyzed in 24 patients enrolled on protocol UARK 2001–37, where VELCADE was administered in combination with thalidomide and dexamethasone (VTD) for a total of 98 cycles without anticoagulation. Review of the literature regarding the incidence of DVT in patients receiving DT reveals reports of 16% (Cavo, et al. Haematologica. 2004 89:826) and 12 % (Rajkumar, et al. JClinOncol. 2002 1;20: 4319). In contrast no thrombotic episodes were documented with any of these cycles. This is the first report of protective antithrombotic effect of VELCADE in a malignancy associated with a hyper-coaguable state. Further studies to elucidate the mechanism of VELCADE anticoagulant activity are currently in progress. Table 1. DVT Rates: DTPACE vs. VDTPACE Protocol Treatment N Pts reporting DVT (%) P=0.0006 UARK 2001–12 (DTPACE) Dexamethasone Thalidomide Cisplatin Adriamycin® Cyclophosphamide Etoposide Lovenox® (40mg sc qd) 98 10 UARK 2003–33 (VDTPACE) Velcade® (1mg/m2) Dexamethasone Thalidomide Cisplatin Adriamycin® Cyclophosphamide Etoposide Lovenox® (40mg sc qd) 69 0
Total Therapy II (TT2), consisting of intensive induction with non-cross resistant VAD, DCEP, CAD (with collection of PBSC) and DCEP.; followed by tandem autotransplants in support of melphalan 200mg/m2; followed by consolidation chemotherapy every 3 months x4 ; followed by interferon maintenance, has complete accrual of 668 patients with upfront randomization to +/− Thalidomide. Collection goal was 20 million CD34+ cells/kg with CAD. This number allows for tandem transplants with support of >5 x 106 CD34 cells/kg, additional cells were stored in case of engraftment problems, additional transplants in the future for relapsed disease and in case of development of MDS. Patient characteristics are outlined in Table 1. 319 patients collected >20 x106 CD 34+ cells/kg with CAD (median 24.9 million, range 20–127), 2 proceeded to second collection with DCEP (median 5.005 million, range 0–10.01. Of this group 310 patients (97%) underwent single and 234 (73%) tandem autotransplant. 135 patients collected 10 – 20 x106 CD 34+ cells/kg with CAD (median 16.35 million, range 10.09–19.93), 13 patients had second collection with DCEP (median 4.92 million, range 1.23–11.68), 5 patients underwent third collection with growth factor (median 2.61million, range 0.12–12.85). Of this group 130 patients (96%) underwent single and 94 (70%) tandem autotransplant. 46 patients collected 5 – 10 x106 CD 34+ cells/kg with CAD (median 7.82 million, range 5.1–9.97), 20 patients had second collection with DCEP (median 9.785 million, range 0.93–27.14), 8 patients underwent third collection with growth factor (median 2.02million, range 0.3–11.8). No patient underwent a fourth collection attempt. Of this group 44 patients (96%) underwent single and 29 (63%) tandem autotransplant. 63 patients collected <5 x106 CD 34+ cells/kg with CAD (median 3.03 million, range 0.01–4.83), 52 patients had second collection with DCEP (median 3.49 million, range 0–21.21), 28 patients underwent third collection with growth factor (median 1.75million, range 0.07–18.99) and 8 patients had a fourth collection attempt with growth factor (median 1.35 million, range 0.22–5.5). Of this group 59 patients (94%) underwent single and 40 (63%) tandem autotransplant. 40 patients collected no CD34+ cells/kg with CAD. 17 patients had second collection with DCEP (median 11.75 million, range 019–36.36), 8 patients underwent third collection with growth factor (median 4.53 million, range 0.11–18.55) and 4 patients had a fourth collection attempt with growth factor (median 2.09 million, range 1.54–12.27). Of this group 25 patients (63%) underwent single and 4 (10%) tandem autotransplant. 53% of patients reached the collection goal with CAD alone. Using additional collection attempts we were able to increase that number to 57% of patients. In the group of the CAD non-collectors additional collection attempts yielded results up to 36 x 106 CD34+ Cells/kg allowing the majority of these patients (> 70%) to proceed to autologous transplant. Table 1: Patients depending on initial collection result with CAD Overall >20* 10–20* 5–10* 0–5* 0* * (x 106 CD34+ cells collected) N 603 319 (53%) 135 (22%) 46 (8%) 63 (10%) 40 (9% Age >65 19% 14% 17% 30% 30% 28% CA 31% 30% 33% 30% 40% 25% Thal Arm 49% 41% 56% 63% 57% 50% CRP >4 8% 7% 10% 7% 8% 10% B2M >4 31% 26% 36% 33% 37% 43% LDH >190 29% 27% 33% 26% 30% 40% BM >30% PC 64% 62% 67% 63% 67% 60%
Between October 1998 and February 2004, a total of 668 recently diagnosed myeloma patients were enrolled in TT-2, of whom 566 completed the first and 417 the second autotransplant. Twenty percent of patients were ≥ 65 years of age and 34% had abnormal metaphase cytogenetics; 24% had received a single cycle of chemotherapy prior to enrollment and 32% had a B2 microglobulin level of ≥ 4mg/L. All patients who completed at least the first transplant could be assessed for response to induction therapy consisting of VAD, DCEP, CAD and DCEP given with hematologic growth factor support at 4 to 5 week intervals. We examined whether the quality of induction response had an impact on event-free (EFS) and overall survival (OS). Responses were defined as complete remission (CR) if serum and urine immunofixation were negative with normal bone marrow plasmacytosis in aspirate and biopsy; partial remission (PR) if serum M protein was reduced by ≥ 75% and urine M-protein ≥ 90% with a normal bone marrow plasmacytosis and < PR for all other responses. Superior EFS (p=.04) and OS (p=.06) from first transplant were observed among the 86 CR patients (15%) with a 4-year estimate of EFS of 69% and OS of 83%, compared with 59% and 72%, respectively, for PR patients (N=214) and 52% and 68%, respectively, for < PR patients (N=266) (Figure 1 and 2). With a median follow-up of 3 years from the first transplant, we conclude that, although a stringently-defined CR after induction therapy resulted in a better EFS and OS, there was no difference in outcome between PR and < PR patients, who had virtually super imposable survival curves. These data, as well as a review of the literature (Vesole et al. Blood1994; 84: 950, Alexanian et al. Blood1994, 84: 4278 and Singhal et al. Bone Marrow Transplant2002, 30: 673) provide a strong argument for change in current Medicare policy, which denies autotransplants to myeloma patients who have failed primary induction therapy. Even with intensive induction therapy as applied in TT-2, more than two-thirds of patients achieving < PR prior to the first transplant are projected to be alive at 4 years after their autotransplant. Figure Figure Figure Figure
Velcade has shown promising activity alone and, more recently, in combination with other anti-myeloma agents (dexamethasone, thalidomide, doxil, standard dose melphalan) for relapsed or refractory multiple myeloma. We have now explored the efficacy and safety of Velcade™ 1.0 or 1.3mg/m2 administered on days -4 and -1 prior to Melphalan, which was given in two fractionated doses for a total of 100–250 mg/m2 on days -4 and -1 or as single dosing on day -1 supported on day 0 by PBSC infusion. Follow-up is now 1–5 months; detailed follow-up data will be available at presentation. Of 37 patients currently evaluable for toxicity, 27 are also evaluable for response. Patient characteristics are outlined in Table 1, depicting a high risk population. The treatment was administered in the out-patient setting in 37 patients, 27 of whom were entirely managed through ambulatory care. Hospital admission was required for pneumonia in 4, sepsis in 3, nausea and vomiting in 2 and ileus in 1 patient. In 37 evaluable patients, hematopoetic recovery depended upon the timing of PBSC collection (prior to the first, second or the Vel-Mel transplant). Neutrophil recovery to > 1,000/μL occurred at a median of 13 days and platelet recovery to 50,000/μl at a median of 17 days. Non-hematologic toxicities included ≥ grade III mucositis in 5, diarrhea in 11, febrile neutropenia in 5, pneumonia/sepsis in 14, and fatigue in 22 patients. No fatal complications were seen. Of 27 evaluable patients, partial response (≥ 75% of serum M protein reduction, ≥ 75% of urinary M excretion) was obtained in 9 (39%) including 6 (26%) who showed a complete disappearance of serum M and urine M. Bone marrow follow-up examinations were available in 17 patients and revealed a median reduction in plasmacytosis of 75% including 2 patients achieving a normal bone marrow plasmocytosis Our results are promising and demonstrate that Vel can be safely added to Mel at doses as high as 250 mg/m2 in fractionated dosing with a high response rate also in high-risk, advanced disease. This approach will be formally evaluated in a randomized trial comparing tandem transplants with Mel 200 mg/m2 alone versus added Vel 1.0 mg/m2 on days 1 and 4 followed on each day by Mel 140 (total 280 mg/m2). Velcade 1.0 mg/m² Velcade 1.3 mg/m² Parameter Mel 250 Mel 220–240 Mel 200 Mel 100–150 Mel 250 Mel 200 Mel 100–150 N 4 4 12 10 4 2 1 % AGE ≥ 65 0 25 33 30 0 0 100 %Abn Cytogen 75 0 8 30 50 50 0 % Prior Autotx 75 25 33 40 75 0 100 % Prior VTD 50 25 25 30 75 50 100
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