short report
`Haematologica 1997; 82:351-353
`
`THE ASSOCIATION OF CYCLOPHOSPHAMIDE AND DEXAMETHASONE IN
`ADVANCED REFRACTORY MULTIPLE MYELOMA PATIENTS
`LIDIA CELESTI, MARINO CLAVIO, ALESSIA POGGI,* SALVATORE CASCIARO,* EMANUELA VALLEBELLA,
`MARCO GOBBI
`Chair of Hematology, Department of Internal Medicine, University of Genoa; *II Division of Internal Medicine, S. Martino
`Hospital, Genoa, Italy
`
`ABSTRACT
`
`VAD is the most active regimen in refractory
`myeloma patients; however, the role of vincristine
`and doxorubicin remains unclear. Relatively high
`doses of cyclophosphamide (3.6 g/sqm) increased
`the response rate and survival in resistant MM.
`Cyclophosphamide and dexamethasone were
`administered to 28 patients with advanced refrac-
`tory myeloma. Thirteen patients received cyclo-
`phosphamide 1.2 g/sqm on days 1 and 3 and
`dexamethasone 40 mg/day from day 1 to day 4,
`every 4 weeks for 6 cycles (schedule A); 15 patients
`were treated with cyclophosphamide 0.5 g/sqm on
`days 1 and 3 and dexamethasone 40 mg/day from
`day 1 to day 4, every two weeks for 12 cycles
`(schedule B). Overall, 21 patients (75%) responded
`
`and 10 achieved an objective response (36%), while
`11 reached a partial response. Twenty patients
`died (68%), most of them of disease progression,
`and 8 are still alive (32%). Median length of
`response and survival is 6 and 8 months, respec-
`tively. Therapy was easily applied and well tolerat-
`ed. The overall response rate (75%) compares
`favorably with the best published results in this set-
`ting. The two schedules proved to be equally effec-
`tive but patients treated with schedule B had more
`infections, which may have been related to the
`higher dosage of steroids.
`©1997, Ferrata Storti Foundation
`
`Key words: cyclophosphamide, dexamethasone, refractory myeloma
`
`About 40% of patients with multiple myeloma
`
`(MM) are refractory either to alkylating
`agents and prednisone or to more complex
`cytotoxic drug combinations.1 Furthermore, virtual-
`ly all patients who initially respond develop resis-
`tance after variable periods of time, usually not
`exceeding 36-40 months. The most active regimen
`in refractory patients is VAD, which includes vin-
`cristine, doxorubicin administered in continuous
`infusion, and high-dose dexamethasone.2 However,
`the role of vincristine and doxorubicin remains
`unclear since it has been shown that comparable
`results can be obtained in this setting with dexam-
`ethasone alone.3 Moreover, VAD increases mul-
`tidrug resistance gene espression in neoplastic plas-
`ma cells, thus worsening the drug resistance phe-
`nomenon.4 As a matter of fact, these patients bene-
`fit for a very short period and their survival does not
`usually exceed 6 months. Recently, relatively high
`doses of cyclophosphamide (3.6 g/sqm) followed
`by G-CSF support increased response rate and sur-
`vival in patients with resistant MM.5
`Here we report on 28 patients with advanced
`refractory disease who received a combination of
`cyclophosphamide and dexamethasone (CY-DEX),
`given with two different schedules.
`
`Patients and Methods
`From January 1992 to June 1996, CY-DEX were administered
`to patients with advanced, alkylating refractory multiple myelo-
`ma as salvage therapy. Refractory status implied disease pro-
`gression during first-line therapy or lack of response after at
`least 3 courses of alkylating agent-containing therapy given for
`relapse. The main treatments employed before CY-DEX were
`MP (n = 12), VAD-VND (n = 6), VMCP (n = 6) and VCAP (n =
`3). Patients over 75 years of age or with severe heart, lung or
`liver impairment were excluded. Two different institutions
`(Chair of Hematology DIMI and II Division of Internal
`Medicine, S. Martino Hospital, Genoa) enrolled patients.
`Clinical and hematological data are reported in Table 1. CY-
`DEX were administered according to two different schedules
`(Table 2). Thirteen patients received cyclophosphamide 1.2
`g/sqm on days 1 and 3 and dexamethasone 40 mg/day from
`day 1 to day 4, every 4 weeks for 6 cycles (schedule A); 15
`patients were treated with cyclophosphamide 0.5 g/sqm on
`days 1 and 3 and dexamethasone 40 mg/day from day 1 to day
`4, every two weeks for 12 cycles (schedule B). Allocation of
`patients to either schedule A or B was not random, but was
`made on the basis of the therapeutic policy of the participating
`institutions; however, the two patient groups were similar as far
`as age, stage and performance status were concerned.
`Responding patients did not receive any maintenance treat-
`ment. Response criteria have already been published.6 Patients
`receiving at least 3 (schedule A) or 6 (schedule B) courses of
`therapy were evaluated for response. The duration of response
`was calculated from the end of therapy to the time the M-pro-
`tein began to rise again. Survival was calculated from the start
`of treatment to the date of death or to December 1996.
`
`Correspondence: Prof. Marco Gobbi, Chair of Hematology DIMI, University of Genoa, viale Benedetto XV 6, 16132 Genoa, Italy. Tel. & Fax. international
`+39.10.3538953.
`Received January 24, 1997; accepted April 8, 1997.
`
`ALVOGEN, Exh. 1022, p. 0001
`
`

`

`352
`
`L. Celesti et al.
`
`Table 1. Characteristics of the patients.
`
`All patients
`
`Schedule A
`
`Schedule B
`
`Number
`
`M/F
`
`28
`
`15/13
`
`13
`
`7/6
`
`15
`
`8/7
`
`Median age
`
`63 (44-74)
`
`69 (44-74)
`
`61 (54-73)
`
`1 (7%)
`
`1 (7%)
`
`1 (7%)
`
`11 ( 72%)
`
`1 (7%)
`
`3 (20%)
`
`4 (27%)
`
`5 (33%)
`
`2 (13%)
`
`1 (7%)
`
`–
`
`4 (31%)
`
`–
`
`8 (62%)
`
`1 (7%)
`
`8 (60%)
`
`1 (8%)
`
`3 (24%)
`
`1 (8%)
`
`1 (3.5%)
`
`5 (18%)
`
`1 (3.5%)
`
`19 (68%)
`
`2 (7%)
`
`11 (40 %)
`
`5 (18 %)
`
`8 (28 %)
`
`3 (10 %)
`
`Stage
`
`IA
`
`IIA
`
`IIB
`
`IIIA
`
`IIIB
`
`Previous therapy
`(number of lines):
`
`1 2 3 4 5
`
`Results
`Therapeutic response was assessed in all 28
`patients. Overall, 21 (75%) responded and 10
`achieved an objective response (36%); 11 reached a
`partial response (39%), while 7 patients showed
`stable or progressive disease (25%). Reduction of
`the M component was always associated with a
`marked improvement of the performance status;
`responsive patients experienced a relevant decrease
`in bone pain.
`The two schedules were well tolerated, as can be
`seen by the low myelotoxicity score and produced
`comparable therapeutic results (Table 2). The max-
`imum grade 2-3 myelotoxicity score, on neutrophils
`was slightly higher in patients treated with schedule
`A than in those receiving schedule B (37% vs. 20%,
`respectively), but infectious complications (mainly
`sepsis and bronchopneumonia) were more fre-
`quent in patients belonging to the latter treatment
`group. Therapy-related myelotoxicity did not
`increase the need for transfusional support.
`As of December 1996, 20 patients have died
`(68%), almost all of them of disease progression,
`and 8 are still alive (32%). Median length of
`response and survival is 6 and 8 months, respective-
`ly.
`
`Comment
`Although the overall response rate in our series
`(75%) compared favorably with the best published
`results in this setting, its duration was short and
`there was no difference in survival between respon-
`ders and nonresponders (8 and 6 months, respec-
`tively).
`These results are in line with previously published
`data3,4 on salvage treatment in MM. The reason for
`this short time is mainly related to the poor prog-
`nosis of these patients, as already mentioned.
`However, it should be emphasized that a marked
`reduction in bone pain as well as an improvement
`in the performance status were achieved in all
`responding patients. Both treatments were easily
`applied and well tolerated, and patients were most-
`ly followed on an outpatient basis.
`The greater number of infections observed in
`patients treated with schedule B may have been due
`to the severe immunosuppression related to the
`higher dosage of glucocorticoids administered with
`this schedule. The higher incidence of sepsis and
`bronchopneumonia may also explain the shorter
`median survival in this same cohort of patients.
`Although cyclophosphamide7 and dexametha-
`sone as single drugs have been widely employed as
`salvage therapy, their association has not yet been
`reported.
`Leoni et al.8 reached an overall response rate of
`73% in advanced refractory myeloma using tenipo-
`side, dexamethasone and cyclophosphamide. Their
`
`11
`
`3 1 –
`
`–
`
`7 5 – 1
`
`13 (100%)
`
`14 (93%)
`
`4 4 7
`
`1 6 6
`
`1 (4 %)
`
`18 (64%)
`
`8 (28%)
`
`1 (3.6%)
`
`1 (3.6%)
`
`27 (96%)
`
`5
`
`10
`
`13
`
`MC:
`
`IgG
`
`IgA
`
`IgD
`
`BJ
`
`Bone disease
`WHO pretreatment
`performance status
`
`1 2 3
`
`Table 2. Response and toxicity.
`
`All patients
`
`Schedule A
`
`Schedule B
`
`5 (34%)
`7 (46%)
`–
`3 (20%)
`
`5.2
`
`7 4
`
`8 (53%)
`4 (27%)
`3 (20%)
`–
`
`2 2 1 –
`
`5 (38%)
`4 (31%)
`3 (23%)
`1 (8%)
`
`7.6
`8.6
`6.5
`
`10 (36%)
`11 (39%)
`3 (11%)
`4 (14%)
`
`6.3
`
`8 5
`
`12 (43%)
`8 (28%)
`7 (25%)
`1 (4%)
`
`4 (31%)
`4 (31%)
`4 (31%)
`1 (7%)
`
`– – 2 2
`
`2 2 3 2
`
`8 / 20
`
`4 / 9
`
`4 /11
`
`20
`7.8
`8.2
`6.2
`
`9
`9.4
`10.5
`7
`
`11
`6.3
`6.5
`5.3
`
`Objective response
`Partial response
`Progression
`Stable disease
`Median duration of:
`-response (months)
`-OR
`-PR
`Toxicity (WHO max):
`
`0 1 2 3
`
`Infections:
`sepsis
`bpn
`fuo
`other infections
`Alive/dead
`Causes of death:
`MM
`Median survival (months)
`surv. responders
`surv. non responders
`
`ALVOGEN, Exh. 1022, p. 0002
`
`

`

`Cyclophosphamide and dexamethasone in refractory myeloma
`
`353
`
`survival was also comparable to that obtained in
`our study, but this complex drug combination
`required at least 7 days of hospitalization every
`month.
`The higher dosage of cyclophosphamide adminis-
`tered by Palumbo et al. (3.6 g/sqm in 2 doses) in
`association with prednisone (2 mg/kg ⫻ 4 days)
`produced a lower response rate and more severe
`myelotoxicity.5
`In conclusion, the combination of intermediate
`doses of cyclophosphamide and dexamethasone
`would appear to be a feasible and effective salvage
`treatment for resistant MM patients, and seems to
`be more effective than highly complex and toxic
`regimen. They should therefore be included within
`the current therapeutic options for multiple myelo-
`ma.9 Extension of survival is still an unresolved issue
`but recent advances in our knowledge of myeloma-
`genesis10 will hopefully be translated into new thera-
`peutic means.
`
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`J Clin Oncol 1988; 6:889-905.
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`3. Alexanian R, Barlogie B, Dixon D. High dose glucocorticoid treat-
`ment of resistant myeloma. Ann Intern Med 1986; 105:8-11.
`4. Epstein J, Xiao H, Koba B. P-glycoprotein expression in plasma cell
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`elderly: clinical features and response to treatment in 113 patients.
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`
`ALVOGEN, Exh. 1022, p. 0003
`
`