Predictors of survival outcomes in phase 1 relapsed or refractory multiple myeloma patients.
BACKGROUND
The categories of the International Myeloma Working Group (IMWG) response criteria for multiple myeloma are based on the magnitude of the change in paraprotein and the normalization of the free light chain ratio (rFLC). However, the relationship between the response by these biomarkers and clinical outcomes has not been validated with novel compounds in the phase 1 setting. Early response predictors may have prognostic value and speed development plans for new agents.


METHODS
The relationship between biomarkers of response and clinical outcomes was examined in 87 relapsed or refractory multiple myeloma patients enrolled in nontransplant phase I clinical trials from January 2004 through November 2011 at 4 time landmarks. Progression-free survival (PFS) was the primary outcome, and overall survival (OS) was also assessed.


RESULTS
The normalization of rFLC within 4 months predicted improvement in PFS (11.3 vs 2.8 months, P = .038), whereas the normalization of rFLC within 12 months predicted improvement in PFS (6.1 vs 2.8 months, P = .015) and OS (45 vs 17.4 months, P = .002). The magnitude of response in paraprotein predicted and correlated linearly with PFS at all time landmarks (R(2)  = 0.703-0.943) when it was assessed with 2 different boundaries.


CONCLUSIONS
These findings suggest that the normalization of rFLC and the magnitude of response are viable biomarkers for surrogate endpoints in early-phase clinical trials, validate the use of current IMWG response criteria in the phase 1 setting, and support the use of these biomarkers for drug development endpoints.
Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York, New York.
Meagan S
MS
Barbee
Ajay
A
Nooka
Jonathan L
JL
Kaufman
Sungjin
S
Kim
Zhengjia
Z
Chen
Leonard T
LT
Heffner
Sagar
S
Lonial
R Donald
RD
Harvey
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood / Q000378:metabolism* / Q000652:urine; D017321:Clinical Trials, Phase I as Topic / Q000379:methods; D018572:Disease-Free Survival; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism* / Q000652:urine; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000378:metabolism* / Q000652:urine; D010265:Paraproteinemias / Q000097:blood; D010266:Paraproteins / Q000652:urine; D011379:Prognosis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D007147:Immunoglobulin Light Chains; D010266:Paraproteins
biomarkers; immunoglobulin light chain; multiple myeloma; paraproteins; prognosis; surrogate endpoint