Background: Bortezomib is one of the most active drugs for the treatment of multiple myeloma and there are evidences that its activity is highly increased when it is used in combination with other drugs. We have already reported the activity of Bortezomib in combination with intravenous Melphalan (5 mg/m2) and Dexamethasone (BMD) in relapsed/refractory myeloma patients (ASH 2007, #2728). However, this scheme resulted in an elevated percentage of haematologic toxicity that prompted us to test the combination of Bortezomib with other less myelotoxic but active drugs such as Cyclophosphamide, and a liposomal Adryamicin.

Methods: Bortezomib was given at dosage 1.3 mg/m2, and Dexamethasone 40 mg i.v. on days 1, 4, 8, 15 plus liposomal Adryamicin 20 mg i.v. on days 1 and 15, and Cyclophosphamide 100 mg per os for 15 days (1à15). An antibiotic and antiviral prophilaxis was guaranted to all patients with Bactrim and Acyclovir, and EPO and G-CSF were used as recommended. So far, 17 previously treated patients have been enrolled in this study, 4 males and 13 females. Median age was 63 (range 51–78), 7/17 patients were IIIA stage according to Durie and Salmon classification and 3/17 had extra-medullary disease. Five patients were resistant to previous therapies and 10 were relapsed. All patients had been already treated with a median of 2 previous lines of treatment (range 1–6). Four patients were in relapse within 12 months of stem-cell transplantation and 12 patients had already received Bortezomib alone or in combination. Six patients had been already treated with BMD (three were refractory, one in partial remission, and two relapsed)

Results: After a median follow up of 5 months (range 1–8) 15/17 were valuable for response since they have received at least 2 cycles of therapy. 6/15 (40%) patients were considered responder: 3 patients had a very good partial remission (M-protein ≤ 90%), 3 patients a partial remission (M-protein >50%), 1 progressed, and 8 were in stable disease according to International Myeloma Working Group Criteria. Side effects were predictable and manageable; the most common grade 3/4 adverse events included hematologic toxicity (thrombocytopenia [18%], neutropenia [6%], anemia [6%]), paresthesia grade 2 in 3 patients and nausea and vomiting grade 3 in only one patient. So far, 1 patient has stopped treatment for progression disease, and only one for toxicity (infectious disease grade III), in both cases after 2courses. In table 1 the comparison of efficacy and toxicity between ABCD and BMD after 3 cycles is reported. ABCD seems to be as effective as BMD (considering that 1/3 of patients had been already treated with BMD) but with higher tolerability.

Conclusion: The combination of liposomal Adryamicin, Bortezomib, Cyclophosphamide, and Dexamethasone (ABCD) is effective and well tolerated treatment even for heavily pretreated patients with poor prognostic features. The dosage of some drugs could be increased in order to maximize the overall response rate.

BMD%ABCD%p-value
* only 1 patient grade 4 
TOXICITY      
#evaluable cycles 152 100 57 100  
witheld or deferred cycles 25 16 2 4 0,03 
Hematological toxicity grade 3–4 53 35 8* 14 0,005 
Extrahematol toxicity grade 3–4 8 5 8* 14 0,05 
of pts w RBC transf 16 11 1 2 0,07 
of pts w PLT transf 12 8 1 2 0,2 
of pts w G-CSF 41 27 1 2 0,0001 
stop Tx for toxicity 6 4 1 2 0,28 
stop Tx for progression 1 0,6 1 2 0,89 
RESPONSE      
Tot pts 34 100 15 100  
PD 3 9 1 7 0,74 
SD 15 44 8 53 0,78 
PR 7 20 3 20 0,69 
VGPR 6 18 3 20 0,81 
CR 3 9 0 0 0,57 
BMD%ABCD%p-value
* only 1 patient grade 4 
TOXICITY      
#evaluable cycles 152 100 57 100  
witheld or deferred cycles 25 16 2 4 0,03 
Hematological toxicity grade 3–4 53 35 8* 14 0,005 
Extrahematol toxicity grade 3–4 8 5 8* 14 0,05 
of pts w RBC transf 16 11 1 2 0,07 
of pts w PLT transf 12 8 1 2 0,2 
of pts w G-CSF 41 27 1 2 0,0001 
stop Tx for toxicity 6 4 1 2 0,28 
stop Tx for progression 1 0,6 1 2 0,89 
RESPONSE      
Tot pts 34 100 15 100  
PD 3 9 1 7 0,74 
SD 15 44 8 53 0,78 
PR 7 20 3 20 0,69 
VGPR 6 18 3 20 0,81 
CR 3 9 0 0 0,57 
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Topics:
bortezomib, cyclophosphamide, dexamethasone, liposomes, multiple myeloma, salvage therapy, toxic effect, brachial plexus neuritis, partial response, granulocyte colony-stimulating factor

Disclosures: No relevant conflicts of interest to declare.

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Corresponding author

2008, The American Society of Hematology
2008
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