Melphalan-prednisone versus alternating combination VAD/MP or VND/MP as primary therapy for multiple myeloma: final analysis of a randomized clinical study.
OBJECTIVE
In the absence of a cure for multiple myeloma (MM) with standard-dose therapy, any strategy that can be expected to increase tumor reduction and to extend survival duration is likely to be of clinical relevance. The primary end-point of the present study was to investigate whether the alternating combination of vincristine-doxorubicin-dexamethasone (VAD) and melphalan-prednisone (MP) or vincristine-mitoxantrone-dexamethasone (VND) and MP could improve the clinical outcome of MM patients thus treated in comparison with those receiving MP alone.


METHODS
Between November 1990 and April 1994, 527 previously untreated, stage I-III, MM patients from 29 Italian institutions were randomized to receive one of three remission induction chemotherapy regimens consisting of 8-monthly courses of either MP alone or alternating VAD/MP or VND/MP.


RESULTS
On an intent-to-treat basis, the objective response rates were 53% with MP (objective + minor: 67%), 47% with VAD/MP (objective + minor: 61%) and 49% with VND/MP (objective + minor: 61%). Median survival duration was 36.5 months with MP, 29 months with VAD/MP and 32.5 months with VND/MP. The difference among these groups was not statistically significant, even after stratifying patients into high-risk and low-risk subgroups, as assessed by a multifactor proportional hazard analysis. In both younger and elderly patients, severe granulocytopenia and related infections were significantly more frequent with VND/MP compared to the remaining arms of treatment (p < 0.001 and p = 0.009, respectively). Similarly, the frequency of WHO grade III-IV cardiovascular events was significantly higher for patients receiving anthracycline-containing regimens (VND/MP and VAD/MP) than for those treated with MP alone (p = 0.04).


CONCLUSIONS
Alternating VAD/MP and VND/MP failed to improve the clinical outcome for MM patients, at the cost of increased toxicity and morbidity. Resistance to standard-dose chemotherapy remains a significant obstacle to the treatment of MM.
Cavo
Michele
M
Institute of Hematology and Medical Oncology Seràgnoli, via Massarenti 9, 40138 Bologna, Italy. mcavo@med.unibo.it
Benni
Monica
M
Ronconi
Sonia
S
Fiacchini
Mauro
M
Gozzetti
Alessandro
A
Zamagni
Elena
E
Cellini
Claudia
C
Tosi
Patrizia
P
Baccarani
Michele
M
Tura
Sante
S
D000328:Adult; D000367:Age Factors; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009101:Multiple Myeloma / Q000188:drug therapy*; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016879:Salvage Therapy; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome
D005047:Etoposide; D004317:Doxorubicin; D008942:Mitoxantrone; D008558:Melphalan; D011241:Prednisone