Assessment of Tumor Growth (g) and Regression (d) Rate Constants in Patients with Multiple Myeloma (MM) Shows That the Superiority of Bortezomib with Liposomal Doxorubicin (PLD+B) Over Bortezomib Alone (B) Is a Result of Reduced Growth of Refractory Tumor Cells and Not of Higher Regression Rates, and Provides An Earlier Efficacy Endpoint That Allows for Comparison Across Trials
Authors: Manasanch Elisabet E. , Wilkerson Julia , Xiu Liang , Zhuang Sen , Bates Susan , Stein Wilfred , Fojo Antonio T 
Published: October 2019

Abstract
Abstract 5113

Background:
Discerning amongst the many new therapy options in MM would be helped by novel assessment strategies that yield answers from smaller trials and allow for comparisons across trials. M-protein profiles during therapy reflect simultaneous tumor regression and growth. In breast, prostate and renal cell cancer we have validated a novel assessment method that quantifies tumor regression (d) and growth (g) rate constants using tumor quantities obtained while patients are treated in a trial. Unlike incremental measures of efficacy such as PFS/TTP or ORR, g is a continuous variable that accurately assesses differences between treatments. We have shown: (1) the principal effect of active therapies is a slowing of g, (2) g correlates with survival and (3) g can be accurately compared across trials because it is indifferent to assessment intervals and methodologies (Stein et al, Clin Can Res 2010). We utilized this method to evaluate a phase III trial of PLD+B vs B alone in relapsed/refractory MM (Orlowski et al, JCO 2007).

Methods:
Using M-protein values and a two-phase mathematical equation we determined d and g.

Results:
The median g value in pts receiving PLD+B (0.000738) was significantly less (p=0.0012) than that observed in patients receiving B alone (0.00143); however both therapies had similar effects on d (PLD+B=0.01403; B alone=0.01400; p=0.456) indicating the superiority of PLD+B resulted from a greater effect on the growth of residual tumor and not greater cell kill. Consistent with this, the fraction of tumor sensitive to therapy was similar for PLD+B and B. A sustained statistical difference [p<0.05] in median g values between treatment arms was observed after only 370 pts enrolled, compared to 485 for a difference in PFS, suggesting using g, the difference between arms could have been determined in a smaller trial. Furthermore, in an individual patient, reliable, statistically valid g and d values could be estimated early in their evaluation, while M-protein values were still declining, long before M-protein levels increased. Thus, our approach discerns the concomitant growth of resistant clones as sensitive ones are eliminated, providing an earlier indicator of treatment failure.

Conclusions:
The superiority of PLD+B over B alone is shown to be due to an effect on growth of resistant cells; not an acceleration of tumor cell kill. Statistically valid differences between PLD+B and B could be discerned early and the rate of tumor growth in individual patients could be quantitated before increases in M-protein were measured. Further collaborative studies could establish g as a valuable measure of efficacy in MM that allows for cross trial comparisons, the conduct of smaller trials and an earlier assessment of treatment failure.

Disclosures:
Xiu: Johnson and Johnson: Employment, Equity Ownership. Zhuang:Johnson and Johnson: Employment, Equity Ownership.