SWOG 0204; Phase 2 Trial of Thalidomide (T) + Dexamethasone (D) Induction Followed by Tandem Autotransplant (TAT) and Prednisone (P) + T Maintenance for Multiple Myeloma (MM).

Background: TAT has recently been shown to double the 7-yr event-free (EFS) & overall survival (OS) rates achieved with a single AT (20% & 40%; IFM94). Completion of TAT in most randomized & phase II trials seldom exceeds 70%, due to toxicities encountered with prolonged induction chemotherapy & posed by the 1^st AT. TD is effective salvage therapy &, when used up-front, effects high response rates including ~15% CR. To reduce induction toxicities & thus deliver TAT in a timely fashion to the majority of pts, SWOG embarked on a trial of TD induction, modest-dose cyclophosphamide (CTX) for PBSC mobilization, melphalan (MEL)-based TAT & subsequent PT maintenance.

Methods: Between 6/15/02 &, as of 7/29/05, 130 eligible & analyzable newly diagnosed pts with active MM have been enrolled. T was administered at a daily dose of 100mg & incremented by 50mg a week to a dose not to exceed 400mg; the start dose of the T was later reduced to 50mg. D was given at 40mg a day on days 1–4, 9–12 & 17–20 & repeated on day 35. Following 3 TD cycles, CTX was administered at 1g/sqm with G-CSF\GM-CSF with an intended minimum PBSC yield of >= 10 x 10⁶ CD34 cells/kg. TAT applied a modest MEL dose of 140mg/sqm for the 1^st AT & the standard MEL 200mg/sqm dose with the 2^nd AT. Maintenance therapy was with P 50mg on alternating days & daily T 200mg with dose reduction as needed for toxicities.

Results: 28 SWOG institutions have enrolled 130 pts; 77 pts have completed the scheduled 3 TD cycles & PBSC collection (median, 8.2 x 10⁶; range, 1.1 x 10⁶ to 21.0 x 10⁶). 18 pts did not proceed past the induction phase: 4 progressed; 3 came off study due to toxicity, 4 due to insurance denial, 6 because of pt preference; & one pt died. 25 pts achieved a response rate (CR+R+PR) of 80% during the induction phase; 1 achieved CR & 19 R/PR. Of 77 pts registered to the transplant step, 35 are currently receiving AT1 & candidates for AT2. Of 27 pts completing AT2, the median time to AT2 was 7.9 months from initial registration & 2.1 months from AT1. 9 pts received AT1 & will not proceed to AT2 because of inadequate collection (6 pts), or unknown reason (3 pts). Toxicity data are available for 102 pts completing induction & mobilization: Grade 3 toxicities were reported for GI (9), fatigue (12), bone pain (7) & hypercoagulability (4); grade 4 toxicity pertaining to hypercoagulable state was noted in 5 pts & bone pain in 2 pts. With an incidence of deep venous thrombosis (DVT) of 21% in the first 23 patients enrolled, the protocol was amended to decrease the start dose of thalidomide to 50mg from 100mg, with a 50mg weekly increment; the current incidence of DVT is less than 10%. No unanticipated toxicities have occurred during the second transplant.

Conclusion: Our preliminary data suggest that TD for induction starting at 50mg of thalidomide & incrementing by 50mg weekly to a target dose of 400mg is well tolerated & allows for all pts to receive AT2 in a timely fashion (2.1 months from AT1) with no increase in toxicity. Larger numbers & longer follow up should clarify if the superior results associated with the timeliness of the AT2 are secondary to a biologic effect or a selection bias.