CYCLOPHOSPHAMIDE AND PREDNISONE AS SALVAGE THERAPY FOR MM Weekly Cyclophosphamide and Alternate-Day Prednisone:
An Effective, Convenient, and Well-Tolerated Oral Treatment for
Relapsed Multiple Myeloma After Autologous Stem Cell Transplantation
YOUNG TRIEU, MSC; SUZANNE TRUDEL, MD; GREGORY R. POND, MSC; JOSEPH MIKHAEL, MD; WILFRID JAKSIC, MD; DONNA E. REECE, MD; CHRISTINE I. CHEN, MD; AND A. KEITH STEWART, MBCHB OBJECTIVE: To assess the efficacy and tolerability of weekly stem cell transplantation. By contrast, cyclophosphamide is oral cyclophosphamide in combination with alternate-day pred- unique in that proliferating cells are more sensitive than nisone (CP) as salvage therapy for patients with relapsed multi-ple myeloma (MM) after autologous stem cell transplantation resting ones, with the distinct advantage of reduced toxicity due to myelosuppression.4-6 Furthermore, cyclophospha- PATIENTS AND METHODS: We retrospectively reviewed the medi- mide has been shown to have a lack of cross-resistance to cal records of all patients identified in our clinical database as melphalan in mouse and human myeloma.7,8 As such, the having received CP as treatment for relapsed MM after ASCT at activity of cyclophosphamide should still theoretically be Princess Margaret Hospital between July 1998 and May 2004.
The CP regimen consisted of oral cyclophosphamide at 500 mg retained in patients with MM previously treated with once weekly and oral prednisone at 100 mg on alternate days.
RESULTS: A total of 66 patients received the CP regimen, with a First introduced by Brandes and Israels,9,10 weekly cy- median of 2.0 prior therapies (range, 1.0-5.0) from time of diagno- clophosphamide and alternate-day prednisone resulted in sis to initiation of CP. The median time from relapse after ASCT tostart of CP therapy was 1.5 months (range, 0.0-23.5 months).
response in 3 of 5 patients with refractory myeloma. Later, Because of nonsecretory disease in 7 patients, only 59 patients Wilson et al11 observed that 7 of 28 patients with primary were evaluable for response. The median duration of CP treatment refractory MM and 10 of 29 patients with relapsing refrac- was estimated at 5.8 months (95% confidence interval [CI], 4.6-7.8 months). With a median follow-up of 15.9 months (range, 1.4- tory MM were able to achieve an objective response with a 67.2 months), 36 patients (61%) responded to treatment, 24 mean duration of 10 months. Since then, several other (41%) of whom had a partial response. The 1-year progression-free groups have employed this form of therapy for advanced survival of all evaluable patients was estimated at 66% (95% CI,54%-80%), with a median progression-free survival of 18.6 months MM.12,13 These studies also reported on objective responses (95% CI, 13.9-29.9 months). The median overall survival from time that were comparable to more aggressive regimens, how- of initiation of CP was estimated at 28.6 months (95% CI, 22.1- ever, with significantly less toxicity.
On the basis of this background, we reasoned that CONCLUSION: Our data show that CP is an effective, well-toler- weekly oral cyclophosphamide in combination with alter- ated, and convenient regimen as salvage therapy for MM afterASCT.
nate-day prednisone (CP) would serve as an effective andwell-tolerated orally delivered chemotherapeutic regimen for patients with relapsed MM after ASCT. To our knowl- ASCT = autologous stem cell transplantation; CI = confidence interval; edge, the current study is the first to examine CP as salvage CP = weekly oral cyclophosphamide in combination with alternate-day therapy exclusively in this category of patients; it is par- prednisone; MM = multiple myeloma; NA = not available; PFS = progres-sion-free survival ticularly relevant given recent large multicenter trials ofnovel, but toxic, agents in this setting.14 The use of high-dose chemotherapy followed by autolo- gous stem cell transplantation (ASCT) is now consid- ered standard induction therapy for younger patients with The goal of this retrospective single-center study was to multiple myeloma (MM). Although this treatment strategy examine the tolerability and efficacy of CP in patients with has been shown to improve response, event-free survival,and overall survival in comparative studies of conventional From the Department of Medical Oncology/Hematology (Y.T., S.T., J.M., W.J., chemotherapy, all patients ultimately experience relapse D.E.R., C.I.C., A.K.S.) and Department of Clinical Study Co-ordination andBiostatistics (G.R.P.), Princess Margaret Hospital, University Health Network, after ASCT.1-3 Consequently, salvage therapies are needed.
Toronto, Ontario; and McLaughlin Centre for Molecular Medicine, University of One treatment option is the use of alkylating agents, which Toronto, Toronto, Ontario (S.T., A.K.S.).
are potent therapies for MM. However, most of these Individual reprints of this article are not available. Address correspondence toA. Keith Stewart, MBChB, at his current address: Division of Hematology/ agents are equally toxic to resting and proliferating cells, Oncology, Mayo Clinic College of Medicine, 13400 E Shea Blvd, Scottsdale, resulting in cumulative hematologic toxicity after repeated AZ 85259 (e-mail:
courses and thus severely limiting their application after 2005 Mayo Foundation for Medical Education and Research
Mayo Clin Proc. • December 2005;80(12):1578-1582 • For personal use. Mass reproduce only with permission from Mayo Clinic Pr CYCLOPHOSPHAMIDE AND PREDNISONE AS SALVAGE THERAPY FOR MM TABLE 1. Characteristics of the 66* Patients cycle is 28 days. Patients initially received prednisone at 100 mg on alternate days with subsequent tapering to adose of 50 mg, then 25 mg, depending on toxicity. In the absence of dose-limiting toxicity, treatment was main- tained in responding patients and in patients with stable disease according to serum or urine paraprotein level until signs of progression developed. Patients were considered evaluable for response if they had received a minimum of 1 Other salvage treatments before CP therapy treatment cycle and had at least 1 follow-up MM assess- ment. The primary end point of this study was to determine the response rate at 3 and 6 months after the beginning of therapy, as well as the duration of response and overall survival. Response was graded using the previously pub- lished Blade et al15 criteria for assessment of response.
In addition, toxicity was evaluated in all patients, inde- pendent of the duration of treatment and response. Adverse *Seven of these patients were not evaluable for response because of events were documented through conventional interview nonsecretory disease. CP = weekly oral cyclophosphamide in combina-tion with alternate-day prednisone.
and physical examinations. Toxicity was assessed usingNational Cancer Institute Common Toxicity Criteria.
relapsed MM after ASCT. All patients identified in our clinical database as having received CP treatment for re- Descriptive statistics such as the median, range, and pro- lapsed MM after ASCT at Princess Margaret Hospital be- portions were used to describe the patient population and tween July 1998 and May 2004 were included for analysis.
follow-up. Survival estimates were calculated using the Patient information pertaining to the time of first referral Kaplan-Meier16 method. Patients who were still receiving and detailed clinical and laboratory follow-up information CP treatment had a censoring date as of the last follow-up were obtained from our clinical database approved by the for the duration of CP treatment analysis. Progression-free University Health Network Institutional Review Board.
survival (PFS) estimates were counted from the start dateof CP treatment to the date of progression, date of death, or last follow-up date. Time to progression was measured The CP regimen consisted of oral administration of cyclo- from the start of CP therapy to the date of progression; phosphamide at a 500-mg fixed dose once weekly and oral patients who died of other causes before disease progres- prednisone at 100 mg on alternate days. The duration of 1 sion were censored at that date. Overall survival estimateswere measured from the start date of CP treatment to thedate of death (due to any cause) or the last follow-up datethe patient was known to be alive.
A total of 66 patients at our institution received CP as salvage therapy for relapsed MM after ASCT (Table 1).
The median time from ASCT to treatment was 26.4 months (range, 6.0-66.6 months). The median time from relapaseafter transplantation to start of CP therapy was 1.5 months (range, 0.0-23.5 months). The median number of prior therapies from time of diagnosis to initiation of CP was 2.0 (range, 1.0-5.0). Because of nonsecretory disease in 7 pa- tients, only 59 patients were evaluable for response. The median duration of CP therapy (Figure 1) for the 59 pa-tients was estimated at 5.8 months (range, 0.8-29.9 months;95% confidence interval [CI], 4.6-7.8 months). At the time FIGURE 1. Percentage of patients receiving weekly oral cyclophospha-mide in combination with alternate-day prednisone (CP) treatment.
of analysis, treatment with CP was still ongoing in 3 pa- Mayo Clin Proc. • December 2005;80(12):1578-1582 • For personal use. Mass reproduce only with permission from Mayo Clinic Pr CYCLOPHOSPHAMIDE AND PREDNISONE AS SALVAGE THERAPY FOR MM TABLE 2. Response to Weekly Oral Cyclophosphamide in nonresponders, 19 (32%; 95% CI, 21%-46%) had stable Combination With Alternate-Day Prednisone* disease, whereas 4 (7%; 95% CI, 2%-16%) had disease progression while receiving therapy (Table 2).
Measured from the time of study entry, the 6-month PFS of all evaluable patients was estimated at 78% (95% CI, 68%-89%), and it decreased to 66% (95% CI, 54%-80%) at 1 year (Figure 2). The median PFS was reached at 18.6months (95% CI, 13.9-29.9 months). The median time to *Of the 66 patients, 59 were evaluable for response.
progression was 20.2 months (95% CI, 15.9-NA months).
In 32 patients (54%), the disease had progressed since tients, with a median treatment duration of 8.4 months initiation of CP treatment. Twenty-three patients died at a (range, 7.4-9.4 months). The remaining 56 patients who median of 14.6 months (range, 1.4-61.7 months) after be- were no longer receiving CP therapy were treated for a ginning CP therapy. Progressive disease was attributed to median of 5.5 months (range, 0.8-29.9 months). Reasons the cause of death in 19 patients, whereas 1 patient died of for treatment discontinuation in these patients included the acute respiratory failure; in 3 patients, the cause of death following: disease progression (21 patients [38%]), plateau was unknown because they were lost to follow-up. Thirty- or stable response (20 patients [36%]), proceeding toward a six patients (61%) were alive at last known follow-up. The second salvage transplantation (10 patients [18%]), and median overall survival (Figure 3) from time of initiation toxicities (5 patients [9%]). The median follow-up time for of treatment was estimated at 28.6 months (95% CI, 22.1- all evaluable patients from the start of CP therapy was 15.9 NA months), with a 1-year overall survival rate of 83% With use of the criteria by Blade et al15 for evaluation of All 66 study patients were included in the safety analysis.
response, 36 (61%; 95% CI, 47%-73%) of 59 patients Toxicities were generally minor as the CP regimen was responded to CP treatment. Among these responders, 24 well tolerated by the vast majority of patients (Table 3).
patients (41%; 95% CI, 28%-54%) achieved a partial re- Grade 1 and 2 toxicities were most commonly observed sponse at a median duration of 20.9 months (95% CI, 19.1- and included such symptoms as nausea, fatigue, insomnia, not available [NA] months), whereas a minor response was dyspnea, weight gain, and constipation. The most trouble- observed in 12 patients (20%; 95% CI, 11%-33%). The some documented toxicities were myelosuppression, hy- median time to maximum response was 3.5 months (range, perglycemia, and infections. Myelosuppression attributed 0.9-11.7 months). The other 23 patients (39%; 95% CI, to cyclophosphamide was reversible or improved after the 27%-53%) were not responsive to treatment. Of these dose was reduced in 4 patients and after the drug wastemporarily withheld (for 3 months) in 1 patient. However,in 2 patients, the CP regimen was discontinued because ofmyelosuppression. Prednisone-induced hyperglycemia di- rectly contributed to treatment discontinuation in 3 pa- tients. While receiving therapy, 1 patient experienced a herpes zoster infection, which led to a temporary interrup- tion of treatment (for 2 months); the CP regimen was reinitiated after resolution of the infection. Three patients developed pneumonia, 2 of whom recovered during treat- ment; 1 patient died soon after development of pneumoniabecause of acute respiratory failure.
Despite prolonged PFS and overall survival in patients with MM who have undergone high-dose therapy supported byASCT, relapse is inevitable.1-3 Currently, treatment optionsfor these patients may include the use of pulsed-dose dexa- FIGURE 2. Progression-free survival from time of initiation of cyclo-phosphamide and prednisone.
methasone, thalidomide, or other newer active agents such Mayo Clin Proc. • December 2005;80(12):1578-1582 • For personal use. Mass reproduce only with permission from Mayo Clinic Pr CYCLOPHOSPHAMIDE AND PREDNISONE AS SALVAGE THERAPY FOR MM Previous reports have examined disease outcome at re- lapse. Kumar et al19 reviewed the clinical course of patientswith relapsed MM treated at the Mayo Clinic in Rochester, Minn, and found that the event-free survival for all patientsafter first relapse was 7.3 months. More recent studies of newer agents, such as thalidomide and bortezomib, have reported overall response rates ranging from 31% to 35%, with a median duration of remission of approximately 12months.20-22 In the current study, among patients who achieved at least a partial response, the median duration of Overall sur vival estimate95% Confidence inter val response was 20.9 months. This duration of response com- pares favorably with that reported with the newer agents; also, our CP regimen is more convenient to use and has lower toxicity. However, because this is a retrospective,single-center experience, the results should be interpretedwith caution; prospective, carefully controlled trials com- FIGURE 3. Overall survival from time of initiation of cyclophospha- paring CP to the most active multiple drug combinations in patients with relapsed MM after ASCT are required. Themedian overall survival of 28.6 months for patients re- as bortezomib. The selection of the appropriate salvage sponsive to CP also compares favorably with survival therapy for these patients primarily depends on their toler- rates observed in patients with relapsed MM who re- ability to certain chemotherapies, which in turn is key in ceived thalidomide and bortezomib.20,22 Thus, our CP determining the efficacy of the drug.
regimen seems promising, and we believe it should serve Alkylating agents and corticosteroids are 2 classes of as a basis for further clinical studies. This regimen is now drugs with well-established activity in MM.17,18 However, being studied at our center in combination with bor- the use of melphalan is severely limited by myelosuppres- tezomib as salvage therapy for patients with relapsed MM sion after transplantation. Additionally, its use before or after ASCT is compromised by concerns about stem cellquality. To address these concerns, we have frequently used the CP treatment regimen in patients who requiresalvage therapy for relapse after ASCT.
Our CP treatment is convenient and feasibile for virtually Our data are similar to previously published results all patients, regardless of their age, disease status, prior regarding efficacy and tolerability of the CP regimen.10-13 treatment, or location of residence. Additionally, becauseof its relative lack of myelosuppression, patients who arecandidates for salvage transplantation may benefit from the TABLE 3. Toxicity Associated With Weekly Oral CP regimen since it would allow for recollection of stem cells, and other active second-line agents can be used foreventual relapse. This regimen compares favorably with recent salvage therapies for MM, which are less convenientand have similar or lower efficacy.14 1. Imrie K, Esmail R, Meyer RM, Hematology Disease Site Group of the
Cancer Care Ontario Practice Guidelines Initiative. The role of high-dose chemotherapy and stem-cell transplantation in patients with multiple my- eloma: a practice guideline of the Cancer Care Ontario Practice Guidelines Initiative. Ann Intern Med. 2002;136:619-629.
2. Attal M, Harousseau JL, Stoppa AM, et al, Intergroupe Francais du
Myelome. A prospective, randomized trial of autologous bone marrow trans- plantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97.
3. Child JA, Morgan GJ, Davies FE, et al, Medical Research Council Adult
Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem- *All 66 patients were included in this analysis.
cell rescue for multiple myeloma. N Engl J Med. 2003;348:1875-1883.
Mayo Clin Proc. • December 2005;80(12):1578-1582 • For personal use. Mass reproduce only with permission from Mayo Clinic Pr CYCLOPHOSPHAMIDE AND PREDNISONE AS SALVAGE THERAPY FOR MM 4. Rivers SL, Patno ME. Cyclophosphamide vs melphalan in treatment of
tive and well tolerated in patients with advanced multiple myeloma. Neth J plasma cell myeloma. JAMA. 1969;207:1328-1334.
5. Ringborg U, Lewensohn R. Factors responsible for bone marrow toxicity
14. Richardson PG, Chanan-Khan A, Schlossman RL, et al. Phase II trial of
after treatment of myeloma patients with different alkylating agents. Acta Med single agent bortezomib (VELCADE) in patients with previously untreated multiple myeloma (MM) [abstract]. Blood. 2004;104:100a. Abstract 336.
6. Lenhard RE Jr, Oken MM, Barnes JM, Humphrey RL, Glick JH,
15. Blade J, Samson D, Reece D, et al, Myeloma Subcommittee of the
Silverstein MN. High-dose cyclophosphamide: an effective treatment for ad- European Group for Blood and Marrow Transplant. Criteria for evaluating vanced refractory multiple myeloma. Cancer. 1984;53:1456-1460.
disease response and progression in patients with multiple myeloma treated by 7. Ogawa M, Bergsagel DE, McCulloch EA. Chemotherapy of mouse
high-dose therapy and haemopoietic stem cell transplantation. Br J Haematol. myeloma: quantitative cell cultures predictive of response in vivo. Blood.
16. Kaplan EL, Meier P. Nonparametric estimation from incomplete obser-
8. Bergsagel DE, Cowan DH, Hasselback R. Plasma cell myeloma: re-
vations. J Am Stat Assoc. 1958;53:457-481.
sponse of melphalan-resistant patients to high-dose intermittent cyclophospha- 17. Alexanian R, Haut A, Khan AU, et al. Treatment for multiple myeloma:
mide. Can Med Assoc J. 1972;107:851-855.
combination chemotherapy with different melphalan dose regimens. JAMA.
9. Brandes LJ, Israels LG. Treatment of advanced plasma cell myeloma
with weekly cyclophosphamide and alternate-day prednisone. Cancer Treat 18. Alexanian R, Yap BS, Bodey GP. Prednisone pulse therapy for refrac-
tory myeloma. Blood. 1983;62:572-577.
10. Brandes LJ, Israels LG. Weekly low-dose cyclophosphamide and alter-
19. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients
nate-day prednisone: an effective low toxicity regimen for advanced myeloma.
with relapsed multiple myeloma. Mayo Clin Proc. 2004;79:867-874.
Eur J Haematol. 1987;39:362-368.
20. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in
11. Wilson K, Shelley W, Belch A, et al. Weekly cyclophosphamide and
refractory multiple myeloma [published correction appears in N Engl J Med.
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Cancer Treat Rep. 1987;71:981-982.
21. Kumar S, Gertz MA, Dispenzieri A, et al. Response rate, durability of
12. Lenhard RE, Daniels MJ, Oken MM, et al. An aggressive high dose
response, and survival after thalidomide therapy for relapsed multiple my- cyclophosphamide and prednisone regimen for advanced multiple myeloma.
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Leuk Lymphoma. 1994;13:485-489.
22. Richardson PG, Barlogie B, Berenson J, et al. A phase 2 study of
13. de Weerdt O, van de Donk NW, Veth G, Bloem AC, Hagenbeek A,
bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609- Lokhorst HM. Continuous low-dose cyclophosphamide-prednisone is effec- Mayo Clin Proc. • December 2005;80(12):1578-1582 • For personal use. Mass reproduce only with permission from Mayo Clinic Pr


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