Haematologica 2003 - Supplements
Haematologica 2003 - Supplements Haematologica 2003 - Supplements
initiation of treatment (intent-to-treat), 31% were estimated to have achieved partial response (> 50% myeloma protein reduction, MPR). Most responders could be identified within 2 months using > 25% MPR criteria (Figure 1). Survival was superior among the 52 patients presenting without CA and with low B2M (< 3 mg/ml) prior to therapy; survival shortened progressively in the presence of 1 (n=55) and especially 2 (n=46) adverse parameters; 16 patients lacked cytogenetic and B2M data (Figure 2). Significant myelosuppression was not noted but cumulative and acute dose-related peripheral neuropathy was dose-limiting. REV is another immunomodulatory drug designed to be devoid of neurotoxicity. In an initial phase I/II study, dose escalation was performed, from a starting level of 5 mg q d (n=3), to 10 mg (n=3), 25 mg (n=3) and 50 mg (n=6). All patients had relapsed from prior HDT and most had been exposed to and were resistant to THAL. MPR by > 25%/> 50% occurred overall in 4/4 patients, mainly at >25mg (7 patients). These data formed the basis for a randomized phase II trial for post-HDT relapse patients, comparing REV 25 mg q day x 20 with REV 50 mg daily x 10, with cycles to be repeated in both arms q 28 days. DEX 40mg q day x 4 was added with cycle 3. After entry of 38 patients, the Revimid 50 mg arm appeared inferior in terms of response (21% vs. 42%, p=0.162), prompting modification to an alternating day schedule (50 mg qod x 10 doses). In addition, in both arms, bridging doses were introduced of 5 mg x 8 doses (REV 25 mg arm) and 10 mg qod x 4 doses (REV 50 mg arm). A total of 22 patients have been treated on the 25 mg arm and 25 on the 50 mg arm (19 prior to and 6 after revision). At 8 mos after start of REV, MPR >50% was observed in 25% on the 25mg and 9% on the 50mg arm (p=.16) (Figure 3). No significant sedative or neurotoxic effects were observed. Myelosuppression, especially thrombocytopenia, was dose-limiting. VEL (PS 341) has recently been shown to exhibit marked antimyeloma activity, even in the setting of post-transplant and post- THAL relapse. A phase I/II study was designed to evaluate the combination of PS-341 plus THAL in such high-risk patients (Table 1). Patients were enrolled at a starting level of PS-341 of 1.0 mg/m 2 administered on days 1, 4, 8 and 11 (q 21 days) with thalidomide to be added in a dose escalation fashion from 50 to 100 to 150 to 200 mg, whenever 7 patients had completed the second cycle without evidence of significant worsening of baseline neurotoxicity. DEX pulsing could be added for those patients not achieving at least PR status. Figure 4A displays a representative example of a responding patient and cumulative response rates using different levels of MPR (Figure 4B). It is apparent that 60% achieved PR status (> 50% MPR) at the end of cycle 3. Collectively, these data indicate an important advance in the therapeutic armamentarium of myeloma management. Accompanying gene expression analysis at baseline has been used toward response prediction to PS-341 (Figure 5A). Followup examinations 48 hours after single drug treatment have revealed drug-unique gene expression changes which will aid in the understanding of their molecular mechanisms of action (Figure 5B). Figure 1: Cumulative Incidence of Response to THAL 100% 80% 60% 40% 20% ≥ 25% Response ≥ 50% Response ≥ 75% Response ≥ 99% Response Events / N 79 169 52 169 37 169 16 169 0% 0 2 4 6 8 Figure 2: Overall Survival M o n t h s f r o m S t a r t o f T h e r a p y Figure 3: Cumulative MPR >50% by REV arm 50% 40% 30% 8-Month Estimate 47% 31% 22% 10% Events / N Continuous Dosing 5 / 22 Syncopated Dosing 2 / 25 P = .16 8-Month Estimate 25% 9% 20% 10% 0% 0 2 4 6 8 10 Months After Starting Revimid S6
Figure 5A Table 1: VEL + THAL for Refractory MM (N=30) Prior autotx (99%) 29 Prior THAL (80%) 24 Prior Rx > 5 lines (77%) 23 Abn. Cytogenetics (63%) 19 - del 13 (43%) 13 B2M > 4mg/L (53%) 16 Figure 4A Example of response Figure 5B Figure 4B Cumulative % M-Proteinresponse by cycle S7
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Figure 5A<br />
Table 1: VEL + THAL for Refractory MM (N=30)<br />
Prior autotx (99%) 29<br />
Prior THAL (80%) 24<br />
Prior Rx > 5 lines (77%) 23<br />
Abn. Cytogenetics (63%) 19<br />
- del 13 (43%) 13<br />
B2M > 4mg/L (53%) 16<br />
Figure 4A Example of response<br />
Figure 5B<br />
Figure 4B Cumulative % M-Proteinresponse by cycle<br />
S7
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