High-Dose Chemotherapy with Carboplatin, Cyclophosphamide and Etoposide and Autologous Transplantation for Multiple Myeloma Relapsing After a Previous Transplant

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High-dose chemotherapy with carboplatin, cyclophosphamide and etoposide and autologous transplantation for multiple myeloma relapsing after a previous transplant

J Mehta, G Tricot, S Jagannath, KR Desikan, D Siegel, S Singhal, N Munshi, D Vesole, S Mattox, D Bracy and B Barlogie

University of Arkansas for Medical Sciences, Little Rock, AR, USA

Summary: nancies, autografting is not the final step in the overall man- agement of myeloma,4 and post-autograft relapse can be Eighteen extensively pre-treated patients (35–73 years, treated effectively.3,4 median 46) with relapsed multiple myeloma received Amongst 94 patients receiving salvage therapy for salvage chemotherapy with 6 g/m2 cyclophosphamide, relapse following an autograft, 53 received standard-dose 800 mg/m2 carboplatin, and 1800 mg/m2 etoposide therapy and 41 received transplants.3 With a median follow- (CCV) as a 96-h continuous infusion followed by auto- up of 11 months from salvage therapy, the actuarial overall logous peripheral blood stem cells. The median number survival at 18 months for all patients was 59%, with pre- of prior chemotherapy regimens was five (range 4–10), salvage ␤2-microglobulin р2.5 mg/l and late relapse after including at least one autograft. Four patients died of the preceding transplant (Ͼ12 months) favorably affecting toxicity, and one developed dialysis-dependent renal overall survival in multivariate analysis. Transplantation failure, while the others tolerated CCV well. Three of performed as primary salvage therapy was associated with six patients with pre-transplant creatinine of Ͼ1 mg/dl a significantly prolonged survival,3 although this may be died of toxicity compared with one of 12 with creatinine more a reflection of the way salvage therapy was selected р1 mg/dl (P = 0.083, Fisher’s exact test). Three of four because clinically symptomatic patients usually received patients treated with four previous regimens showed standard-dose therapy whereas asymptomatic patients pro- Ͼ50% reduction in tumor compared with one of 14 ceeded to a transplant immediately.3,4 treated with Ͼ4 regimens (P = 0.02, Fisher’s exact test). Cyclophosphamide is an active drug in myeloma, and is At the last follow-up, five patients were alive at 8–24 included in a number of combination chemotherapy proto- months (median 13) with stable (n = 1) or progressive cols.1,4 However, the experience with etoposide and plati- (n = 4) disease, and nine had died of progressive disease num compounds in myeloma is relatively limited.5–13 at 2.5–15 months (median 7). We conclude that CCV Although single-agent carboplatin in standard doses has chemotherapy with autografting is tolerated well by been disappointing in myeloma,11,13 the combinations extensively pre-treated myeloma patients provided the etoposide–dexamethasone–cytarabine–cisplatin (EDAP)8 pre-transplant creatinine is normal, but toxicity in and cyclophosphamide–etoposide12 have been reported to patients with abnormal renal function is high. The effi- be effective in relapsed/refractory disease. cacy in multiply relapsed disease is poor, with response We have used combination infusional chemotherapy in only 22% of patients. CCV may deserve further comprising carboplatin, cyclophosphamide, and etoposide evaluation early in the course of myeloma in patients with autologous peripheral blood stem cell transplantation with normal renal function. in 18 patients with relapsed myeloma who had received Keywords: autologous transplant; carboplatin; cyclo- extensive previous therapy including at least one auto- phosphamide; etoposide; melphalan; multiple myeloma; transplant. relapse

Patients and methods Despite an excellent response to sequential intensive therapy including tandem autotransplantation in a significant Eighteen patients with relapsed multiple myeloma received 1 number of patients with multiple myeloma, most patients CCV chemotherapy and an autologous peripheral blood eventually experience disease recurrence and require stem cell transplant at the University of Arkansas for Medi- further therapy.2–4 However, unlike most other malig- cal Sciences bone marrow transplant program between Sep- tember 1994 and February 1996. Patient characteristics are shown in Table 1. Two patients, both with high-grade Correspondence: Dr J Mehta, Division of Hematology/Oncology, Univer- 14 sity of Arkansas for Medical Science, 4301 West Markham, Slot 508, immunoblastic transformation of the disease, had menin- Little Rock, Arkansas 72212, USA geal involvement at the time of therapy. The best response Received 25 November 1996; accepted 15 April 1997 to previous therapy was complete remission in five patients, CCV in relapsed myeloma J Mehta et al 114 Table 1 Patient characteristics at the time of salvage chemotherapy remission required tumor mass reduction by at least 75%, with carboplatin–cyclophosphamide–etoposide reduction in Bence–Jones proteinuria to Ͻ100 mg/day, and р5% plasma cells in the marrow on aspirate and biopsy. Age (median) 35–73 years (46) For complete as well as partial response, the findings had Time from diagnosis (median) 7–71 months (20) to be present on at least two occasions with a minimum Stage III (%) 11 (61) interval of 2 months. Development of new osteolytic Central nervous system disease (%) 2 (11) lesions, hypercalcemia, or other new disease manifestations Immunoblastic transformation (%) 2 (11) High-risk chromosomal karyotype No. (%)b 4 of 9 (44) constituted relapse or progressive disease. Refractoriness was defined as Ͻ50% reduction in serum or urine M Number of previous treatment regimens 3–9 (4) (median)a protein. One previous autograft (%) 15 (83) Two previous autografts (%) 2 (11) Previous allograft and autograft (%) 1 (6) C-reactive protein Ͼ4.0 mg/l (%) 9 (50) Results LDH Ͼ190 U/l (%) 8 (44) Creatinine Ͼ1.0 mg/dl (%) 6 (33) + Albumin р3.5 g/dl (%) 14 (78) The number of CD34 cells infused in 17 patients was 6 ␤2-microglobulin Ͼ2.5 mg/l (%) 11 (61) 0.48–34.2 × 10 /kg (median 3.85). One patient died of treatment-related toxicity during the conditioning before aNot including transplantation. Hemibody irradiation is included, but infusion of cryopreserved cells (see below). local/involved field irradiation is excluded. bIncludes any translocations, or any abnormalities involving chromosome 11q or 13. No karyotype results available in nine patients. Toxicity

and partial remission in 13. All patients provided informed All patients developed grade IV hematologic toxicity. consent for the salvage chemotherapy and transplantation. Neutropenic fever requiring broad-spectrum antibiotic therapy developed in all patients; with bacteremia in three (one Fusobacterium and two coagulase-negative Chemotherapy and autograft Staphylococcus) and fungemia (Tinea glabrata) in one. The drugs were administered through an in-dwelling central Variable amounts of gastrointestinal toxicity (nausea, vom- venous catheter as a continuous intravenous infusion over iting, and diarrhea) were seen in all patients, but this was 96 h at the following total doses: 6 g/m2 cyclophosphamide, tolerated well. Mucositis was seen in all patients, and 800 mg/m2 carboplatin, and 1800 mg/m2 etoposide. Mesna required narcotic analgesics; however, it was not a major was administered for uroprotection. Previously cryopre- problem. No graft-versus-host disease was seen in the served autologous peripheral blood stem cells were infused patient receiving the pseudo-autologous graft. 72 h after completion of the chemotherapy infusion. The Four patients died of treatment-related toxicity at days − day of the cell infusion was designated as day 0. All 1, 0, 3 and 10, respectively. The causes of death were patients received G-CSF (usually rounded off to 300 or 480 acute renal failure with congestive heart failure, cardiac ␮g subcutaneously daily) from day +1 after the autograft arrest, fluid overload with respiratory failure, and multi- until myeloid recovery to 2 × 109/l neutrophils on 2 con- organ failure, respectively. Acute renal failure requiring secutive days. dialysis developed in one patient, who had a baseline serum Peripheral blood stem cells were obtained in one patient creatinine of 1.8 mg/dl to start with. Serum creatinine when the patient had relapsed following an allograft in the increased to 2.4 mg/dl in another patient who had received past, and were documented to be of donor origin by karyo- 10 previous treatment regimens including one allograft and typing (male patient, female donor). In the other patients, one autograft, but this improved spontaneously. No sig- stem cells had been obtained prior to the first auto- nificant renal function abnormalities were seen in any of transplant. the other patients who did not die of toxicity. Three of the six patients with pre-transplant creatinine levels of Ͼ1 mg/dl died of toxicity compared with one of Supportive therapy 12 with creatinine р1 mg/dl (P = 0.083, Fisher’s exact All treatment was delivered in single rooms on an in-patient test). Serious toxicity (renal failure or death) was seen in basis. Irradiated and leukocyte-depleted packed red cells four of six patients with pre-transplant creatinine levels of and platelets were transfused to try to maintain a minimum Ͼ1 mg/dl compared with one of 12 with creatinine р1 = hemoglobin of 8 g/dl and a minimum platelet count of mg/dl (P 0.022, Fisher’s exact test). 20 × 109/l. Fever in the neutropenic phase was treated with a combination of broad-spectrum parenteral antibiotics. Hematologic recovery Neutrophils reached 0.5 × 109/l 10–18 days (median 13) Definition of response after autografting. The time to platelet recovery (50 × 109/l) Complete remission was defined by the absence of mono- was 12–288 days (median 18) in patients actually experi- clonal paraprotein in serum and urine using immunofixation encing platelet recovery. Eight patients died of toxicity or with a normal bone marrow aspirate and biopsy. Partial experienced disease progression before recovering platelets. CCV in relapsed myeloma J Mehta et al 115 Disease response requires intensive hydration. The toxic effects of the chemotherapy along with the fluid load contributed to early Fourteen patients not dying within 60 days of CCV and mortality in four patients. Three of these patients had autografting were considered evaluable for response. One abnormal renal function prior to the treatment. Dialysis- patient attained CR, and one attained PR. Overall, four dependent renal failure developed in another patient who patients showed Ͼ50% reduction in disease bulk after had an abnormal renal function to start with. Serious tox- CCV. The best response to previous therapy among the icity (renal failure or death) was associated with pre- responding patients was partial remission in three and com- transplant creatinine levels of Ͼ1 mg/dl (four of six plete remission in one. None of the other patients, including patients), whereas this was seen in only one of 11 with the three who had attained complete remissions in the past, creatinine р1 mg/dl (P = 0.022, Fisher’s exact test). This showed any response to CCV. Three of four patients treated suggests that this treatment should not be used in patients with four previous regimens responded compared with one with compromised kidneys due to the possibility of fatal of 14 treated with more than four regimens (P = 0.02, toxicity or renal failure. Fisher’s exact test). Neither of the patients with immuno- We conclude that although the combination of carbopla- blastic transformation and meningeal infiltration responded tin, cyclophosphamide, and etoposide at the doses used here either locally or systemically. is tolerated well by patients with normal renal function, toxicity in patients with pre-existing renal dysfunction is Outcome substantial, and it should be avoided in patients with compromised renal function. This combination has poor As of July 1996, one of the responding patients was alive activity in the setting of disease relapsing after extensive with stable disease (partial remission) at 18 months, and previous therapy, but it may deserve further evaluation four of the non-responding patients were alive with pro- early in the course of salvage therapy of myeloma. gressive disease at 8, 8, 13 and 18 months. Three of the responding patients and six of the non-responding patients died of relapsed or progressive disease at 2.5–15 months (median 7). References

Prognostic factors 1 Jagannath S, Tricot G, Vesole D et al. Total therapy (TT) with tandem autotransplants (2 Tx) for 231 newly diagnosed Patients with ␤2-microglobulin р2.5, C-reactive protein р4 patients with multiple myeloma (MM). Blood 1996; 88 and LDH р190 appeared to have signiﬁcantly better over- (Suppl. 1): 685a. all survival. However, identiﬁcation of prognostic factors 2 Barlogie B, Vesole DH, Jagannath S. Salvage therapy for mul- in such a small population must be interpreted with caution. tiple myeloma: the University of Arkansas experience. Mayo Clin Proc 1994; 69: 787–795. 3 Tricot G, Jagannath S, Vesole DH et al. Relapse of multiple myeloma after autologous transplantation: survival after sal- Discussion vage therapy. Bone Marrow Transplant 1995; 16: 7–11. 4 Singhal S, Tricot G, Jagannath S et al. Outcome of relapse after transplantation in myeloma. Blood 1996; 88 (Suppl. 1): We found the results of CCV chemotherapy and autotrans- 611a. plantation in myeloma relapsing after extensive previous 5 Broun GO Jr, Petruska PJ, Hiramoto RN, Cohen HJ. Cisplatin, treatment including prior autotransplants disappointing. BCNU, cyclophosphamide, and prednisone in multiple mye- Only three responses (one CR, one PR, one Ͼ50% but not loma. Cancer Treat Rep 1982; 66: 237–242. PR) were seen among the four patients who had received 6 Alexanian R, Dimopoulos M. The treatment of multiple mye- relatively less therapy (four prior regimens), whereas only loma. New Engl J Med 1994; 330: 484–489. one of the 14 patients with a history of Ͼ4 prior regimens 7 Bonnet JD, Alexanian R, Salmon SE et al. Addition of cispla- responded. The latter did not achieve a PR. All other evalu- tin and bleomycin to vincristine-carmustine-doxorubicin- prednisone (VBAP) combination in the treatment of relapsing able patients had refractory disease. 11 or resistant multiple myeloma: a Southwest Oncology Group Barlogie et al treated 19 myeloma patients who were study. Cancer Treat Rep 1984; 68: 481–485. resistant to standard alkylating agent therapy or to VAD 8 Barlogie B, Velasquez WS, Alexanian R, Cabanillas F. Etopo- with 100 mg/m2 carboplatin on 4 consecutive days. Two side, dexamethasone, cytarabine, and cisplatin in vincristine, patients erroneously receiving a four-fold higher drug dose doxorubicin, and dexamethasone-refractory myeloma. J Clin died of bone marrow aplasia, with no antitumor effect in Oncol 1989; 7: 1514–1517. one. None of the other 15 evaluable patients responded. 9 Ventura GJ, Barlogie B, Hester JP et al. High dose cyclophos- Omura et al13 used 400 mg/m2 carboplatin unsuccessfully phamide, BCNU and VP-16 with autologous blood stem cell as a single agent in 15 myeloma patients who had received support for refractory multiple myeloma. Bone Marrow Trans- one prior chemotherapy regimen. The current patient group plant 1990; 5: 265–268. 10 Ohrling M, Bjorkholm M, Osterborg A et al. Etoposide, had generally received much more therapy than these two doxorubicin, cyclophosphamide and high-dose betamethasone groups. It is possible that response rates may have been (EACB) as outpatient salvage therapy for refractory multiple better if patients had received only one previous treatment myeloma. Eur J Haematol 1993; 51: 45–49. regimen as in the study of Omura et al.13 11 Barlogie B, Crowley J, Salmon SE et al. Phase II study of Potentially nephrotoxic chemotherapy such as CCV carboplatin (CBDCA) in refractory multiple myeloma. A CCV in relapsed myeloma J Mehta et al 116 Southwest Oncology Group study. Invest New Drugs 1994; previously treated multiple myeloma. A Cancer and Leukemia 12: 53–55. Group B phase II trial. Am J Clin Oncol 1994; 17: 196–198. 12 Dimopoulos MA, Weber DM, Hester J et al. Intensive sequen- 14 Singhal S, Siegel D, Mattox S et al. Central nervous system tial therapy for VAD-resistant multiple myeloma. Leuk Lym- involvement in multiple myeloma. Blood 1996; 88 (Suppl. phoma 1994; 13: 479–484. 1): 218b. 13 Omura GA, Perri RT, Peterson B, Schiffer CA. Carboplatin in