Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization.
OBJECTIVE
This phase II study evaluated bortezomib-based secondary induction and stem cell mobilization in 38 transplant-eligible patients with myeloma who had an incomplete and stalled response to, or had relapsed after, previous immunomodulatory drug-based induction.


METHODS
Patients received up to six 21-day cycles of bortezomib plus dexamethasone, with added liposomal doxorubicin for patients not achieving partial response or better by cycle 2 or very good partial response or better (≥VGPR) by cycle 4 (DoVeD), followed by bortezomib, high-dose cyclophosphamide, and filgrastim mobilization. Gene expression/signaling pathway analyses were conducted in purified CD34+ cells after bortezomib-based mobilization and compared against patients who received only filgrastim ± cyclophosphamide. Plasma samples were similarly analyzed for quantification of associated protein markers.


RESULTS
The response rate to DoVeD relative to the pre-DoVeD baseline was 61%, including 39% ≥ VGPR. Deeper responses were achieved in 10 of 27 patients who received bortezomib-based mobilization; postmobilization response rate was 96%, including 48% ≥ VGPR, relative to the pre-DoVeD baseline. Median CD34+ cell yield was 23.2 × 10(6) cells/kg (median of 1 apheresis session). After a median follow-up of 46.6 months, median progression-free survival was 47.1 months from DoVeD initiation; 5-year overall survival rate was 76.4%. Grade ≥ 3 adverse events included thrombocytopenia (13%), hand-foot syndrome (11%), peripheral neuropathy (8%), and neutropenia (5%). Bortezomib-based mobilization was associated with modulated expression of genes involved in stem cell migration.


CONCLUSIONS
Bortezomib-based secondary induction and mobilization could represent an alternative strategy for elimination of tumor burden in immunomodulatory drug-resistant patients that does not impact stem cell yield.
Center of Excellence for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Weill Cornell Medical College and New York Presbyterian Hospital, New York, New York 10021, USA. run9001@med.cornell.edu
Ruben
R
Niesvizky
Tomer M
TM
Mark
Maureen
M
Ward
David S
DS
Jayabalan
Roger N
RN
Pearse
Megan
M
Manco
Jessica
J
Stern
Paul J
PJ
Christos
Lena
L
Mathews
Tsiporah B
TB
Shore
Faiza
F
Zafar
Karen
K
Pekle
Zhaoying
Z
Xiang
Scott
S
Ely
Donna
D
Skerret
Selina
S
Chen-Kiang
Morton
M
Coleman
Maureen E
ME
Lane
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D003907:Dexamethasone / Q000008:administration & dosage* / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D000069585:Filgrastim; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D011994:Recombinant Proteins / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects
D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D000069286:Bortezomib; D003907:Dexamethasone; D003520:Cyclophosphamide; D000069585:Filgrastim