Bortezomib (Velcade™) + Adriamycin™ + Thalidomide + Dexamethasone (VATD) as an Effective Regimen in Patients with Refractory or Relapsed Multiple Myeloma (MM).

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 | | | % 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 | | Hematologic Toxicities | | Pre-Treatment | Median WBC Nadir | |:-------------- | --------------------- | ---------------- | ----------- | | Platelet Count | 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 | | |