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© 2003 American Society for Clinical Oncology DTPACE: An Effective, Novel Combination Chemotherapy With Thalidomide for Previously Treated Patients With MyelomaFrom The Myeloma Institute for Research and Therapy, The University of Arkansas for Medical Sciences, Little Rock, AR; Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber Cancer Institute, Boston, MA; Cancer Research and Biostatistics, Seattle, WA. Address reprint requests to Choon-Kee Lee, MD, The Myeloma Institute for Research and Therapy, The University of Arkansas for Medical Sciences, Slot 776, 4301 West Markham, Little Rock, AR 72205; email: leechoonkee{at}uams.edu.
Purpose: To improve outcome in previously treated patients (at least two cycles of standard therapy) with multiple myeloma, thalidomide was combined with cytotoxic chemotherapy as induction therapy. Patients and Methods: The regimen consisted of 4-days of oral dexamethasone, daily thalidomide, and 4 days of continuous-infusion cisplatin, doxorubicin, cyclophosphamide, and etoposide (DTPACE). Response to two cycles of DTPACE for induction was evaluated in 236 patients. Before being treated with DTPACE, 148 patients (63%) had shown progressive disease while receiving standard chemotherapy, and 55 patients (23%) had chromosome 13 abnormalities. Results: The partial remission rate (PR) after two cycles of DTPACE was 32%, with 16% attaining a complete remission (CR) or near-CR (nCR; defined as only immunofixation electrophoresis–positive). Patients with high lactate dehydrogenase (LDH; n = 98) showed a better response than those with normal LDH (n = 138): PR or better, 43% v 27% (P = .01); CR + nCR, 25% v 11% (P = .01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the other patients (n = 181): PR or better, 35% v 33% (P = .84); CR + nCR, 17% v 15% (P = .73). Patients who received 100% dose of DTPACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR or better, 49% v 17% (P < .0001); CR + nCR, 27% v 6% (P < .0001). Conclusion: Combination therapy of oral dexamethasone and thalidomide with infusional chemotherapy is effective as induction therapy before autotransplantation, especially in patients with high-risk features.
FEWER THAN 5% of patients with symptomatic multiple myeloma (MM) treated with melphalan-prednisone achieve a strictly defined complete remission (CR), and the median survival duration generally does not exceed 3 years.1 Combination chemotherapy with additional alkylating agents and anthracyclines has not improved survival beyond results obtained with standard melphalan-based therapy. In contrast, the introduction of high-dose melphalan and autologous stem-cell support has significantly increased CR rates (up to 50%) and doubled the overall survival benefit.2–6 Thalidomide represents the first new class of active agents in the treatment of MM since the introduction of melphalan and glucocorticoids more than 3 decades ago. In a phase II trial at our institution, thalidomide induced a 50% reduction in paraprotein levels in 30% of 169 heavily pretreated patients with advanced MM, including 14% CRs and near-CRs (nCRs).7 The lack of myelosuppression and the presumed multiple potential mechanisms of action, including induction of apoptosis, inhibition of vascular endothelial growth factor and basic fibroblast growth factor production, modulation of immune surveillance, and decreased adherence of myeloma cells to bone marrow stromal cells, make it ideal to test the efficacy of thalidomide in combination with cytotoxic agents earlier in the disease course.8–10 In this study, thalidomide was combined with high-dose dexamethasone and a 4-day continuous infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide (DTPACE). Infusional doxorubicin has been shown to induce a marked response in patients with advanced MM, in combination with dexamethasone.11 Likewise, a combination of high-dose dexamethasone with 4-day continuous infusion of cyclophosphamide, etoposide, and cisplatin has been found to be effective for patients with relapsing myeloma after tandem transplantation, including those presenting with unfavorable cytogenetics.12 This report focuses on the response rates and toxicities of the first two cycles of DTPACE administered as induction therapy before autotransplantation with high-dose melphalan or continuation of additional cycles of DTPACE.
Patients Two hundred thirty-six patients between 31 and 84 years of age with previously treated MM were prospectively enrolled at the Myeloma Institute for Research and Therapy of the University of Arkansas for Medical Sciences (Little Rock, AR) between September 1998 and April 2001, onto trial UARK-98035. The major aim of the study was to evaluate whether DTPACE might be equivalent or even superior to tandem transplantation with high-dose melphalan. Patient characteristics are described in Table 1  . The outcome of these patients was analyzed on September 31, 2002. The Institutional Review Board of the University of Arkansas for Medical Sciences approved the treatment protocol and an informed consent was signed by all patients.
Eligibility Eligible patients were previously treated (with at least two cycles of prior therapy) and had active MM that was measurable (defined as serum monoclonal protein  1.0 g/dL, 24-hour urine monoclonal protein 1.0 g, or BORDER="0"> 20% bone marrow plasmacytosis). Patients had adequate spirometric values of pulmonary function test at least 50% of predicted, carbon monoxide diffusion capacity at least 50% of predicted, and left ventricular ejection fraction more than 45%. Patients with the following conditions were ineligible: serious uncontrolled infection; a poor performance status of Zubrod 3 to 4 except if caused by bone pain; a platelet count less than 100,000/µL except if caused by extensive marrow plasmacytosis; a recent ( 6 months) history of myocardial infarction, unstable angina, uncontrolled symptomatic congestive heart failure, hypertension, or cardiac arrhythmias; or a history of chronic obstructive or restrictive pulmonary disease. Prior malignancy was acceptable, provided there had been no evidence of disease recurrence during the 3 years before entry onto the study and there had been no prior therapy with cytotoxic drugs. Pregnant or nursing women and those who had undergone a prior auto- or allotransplantation were not eligible.
Patients were treated with two cycles of DTPACE as induction therapy (Table 2
DTPACE DTPACE consisted of high-dose dexamethasone 40 mg orally daily for 4 days; thalidomide 400 mg PO at night; 4-day continuous infusion of cisplatin 10 mg/m2/day (total dose per cycle 40 mg/m2), doxorubicin 10 mg/m2/day (total dose per cycle 40 mg/m2), cyclophosphamide 400 mg/m2/day (total dose per cycle 1,600 mg/m2), and etoposide 40 mg/m2/day (total dose per cycle 160 mg/m2). The daily dose of cisplatin, cyclophosphamide, and etoposide was combined in a 1-L bag of 0.9% normal saline, and doxorubicin was infused separately in more than 50 mL of 5% dextrose in water each day. Infusions were administered through a central venous access by using a portable infusion pump. Cycles of DTPACE were repeated at a 4- to 6-week interval provided absolute neutrophil count (ANC) had recovered to more than 1,000/µL and platelet count was more than 100,000/µL. If counts were lower, treatment was delayed until recovery. If patients experienced grades 3 or higher nonhematologic toxicities according to the of the National Cancer Institute common toxicity criteria,13 the next cycle was held until toxicities resolved to grade 2 or less; therapy was then restarted with a 25% to 50% dose reduction. With each cycle, patients were started on a prophylactic regimen of fluconazole 200 mg PO qid, levofloxacin 250 mg PO qid, and acyclovir 400 mg PO bid from the first day of chemotherapy, which was continued until the ANC reached more than 1,000/µL for 2 consecutive days. To prevent Pneumocystis carinii pneumonia, patients received sulfamethoxazole 800 mg and trimethoprim 160 mg (double strength) twice daily for 2 days per week. Patients were also given an H2 antagonist or proton pump inhibitor prophylactically. For peripheral-blood stem-cell mobilization, granulocyte colony-stimulating factor at 10 µg/kg subcutaneously (SC) daily was started on day +5 after the first cycle of DTPACE and continued until completion of stem-cell collection. Granulocyte colony-stimulating factor 300 µg SC a day was administered beginning on day +5 of chemotherapy and continued until the ANC reached more than 1,000/µL for 2 consecutive days for the subsequent cycles of DTPACE.
Statistical Analysis
Variables analyzed were chemosensitivity to preceding standard chemotherapy, prior exposure to doxorubicin, beta2-microglobulin level, plasma cell labeling index (PCLI), cytogenetic findings (chromosome 13 abnormalities), and lactate dehydrogenase (LDH) level. Chemosensitive response before the DTPACE was defined as reduction of more than 50% in the paraprotein level or marrow plasmacytosis achieved by prior treatment. Categorical variables were analyzed by the frequency table with Pearson’s
Patient Characteristics Of the 236 patients, 148 patients (63%) had shown progressive disease after the preceding standard chemotherapy, 107 patients (45%) had PCLI 0.4%, 98 patients (42%) had high LDH levels (greater than normal), and 55 patients (23%) had chromosome 13 abnormalities at the time of study enrollment (Table 1 ). Of the 148 patients with progressive disease, 34 patients had primary refractory myeloma, 83 patients had refractory relapse, and 31 patients experienced relapse while not receiving therapy. Two hundred twelve (90%) patients had at least one of these poor prognostic factors. One hundred fifty-four (65%) patients had received doxorubicin-based regimens before study entry. The median interval was 210 days (range, 13 to 5,430 days) between the last cycle of preceding therapy and DTPACE; 166 days (range, 35 to 5,430 days) for patients with progressive disease, and 416 days (range, 13 to 3,409 days) for those who showed a reduction of at least 50% in paraprotein levels after the preceding chemotherapy.
Of the total number of 236 patients enrolled onto trial UARK-98035, 156 patients received the first cycle at 100% dose. Seven patients who were enrolled never started treatment. Six patients with renal failure who were dependent on dialysis received 100% dose dexamethasone, thalidomide, doxorubicin, cyclophosphamide, and etoposide without cisplatin for two cycles. The remaining 67 patients received the first cycle at
Response After the first cycle of DTPACE (n = 229), 19 patients (8%) achieved either CR (n = 6) or nCR (n = 13), 20 patients (9%) achieved PR, and 124 patients (53%) achieved improvement at a median of 37 days (range, 13 to 120 days). After the second cycle, the response rate increased to 16 patients (7%) with CR, 22 patients (9%) with nCR, 37 patients (16%) with PR, and 127 patients (54%) who showed improvement (Fig 2 ). Additional response was seen in the 63 patients who received more than two cycles of DTPACE, including five patients (2%) with CR, seven patients (3%) with nCR, seven patients (3%) with PR, and nine patients (4%) who showed improvement, with the overall response rate of 40% (n = 94) of PR and 21% (n = 50) of CR (n = 21) + nCR (n = 29).
The response rate was not affected by chemosensitivity to preceding standard chemotherapy, prior exposure to doxorubicin, beta2-microglobulin level, or PCLI (Table 4 ). Patients with high LDH (n = 98) showed a better response than those with normal LDH (n = 138): PR, 43% v 27% (P = .01); CR + nCR, 25% v 11% (P = .01). Patients with chromosome 13 abnormalities (n = 55) responded equally well as the others (n = 181): PR, 35% v 33% (P = .84); CR + nCR, 17% v 15% (P = .73). Patients who received 100% dose DTPACE for two cycles (n = 115) achieved higher response rates than those with less than 100% dose (n = 121): PR, 49% v 17% (P < .0001); CR + nCR, 27% v 6% (P < .0001).
Toxicity Toxicity was monitored up to 3 months after each of the two induction cycles of DTPACE (number of cycles, 435; Table 5 ). Grades 2 neutropenia occurred in 65% of cycles, with a median onset of 7 days (range, 5 to 12 days) to an ANC less than 0.5 x 109/L. Neutropenic fever was observed in 12% of cycles and lasted a median of 5 days (range, 1 to 24 days). Grades 2 thrombocytopenia occurred less frequently (11%) and were associated with 22 episodes of hemorrhage (eight episodes of gastrointestinal mucosal bleeding, eight episodes of hematuria, two episodes of significant epistaxis, and five episodes of catheter site bleeding).
The most common nonhematologic toxicities were nausea and vomiting (21%), followed by mucositis (19%) and hypophosphatemia (17%). Although gastrointestinal toxicity was frequent, it was not associated with serious complications, such as typhlitis or bowel perforation. A number of cardiovascular toxicities occurred, including thromboembolism and arrhythmias. Before routine thrombosis prophylaxis (n = 242 cycles), thromboembolic events occurred after 37 cycles (15%), including deep vein thrombosis of extremities (n = 25) and at the site of the central venous line (n = 12). Three of these patients developed a nonfatal pulmonary embolism. Except for the episode of pulmonary embolism, all events were mild and limited to grade 3 toxicity. All episodes of cardiovascular toxicity resolved at a median of 8 days (range, 1 to 61 days) and included sinus bradycardia (n = 6) and supraventricular arrhythmia (n = 7), which improved after discontinuation of thalidomide. Five episodes of sinus bradycardia were associated with symptomatic syncopal episodes. Pulmonary and renal toxicities and metabolic abnormalities were brief, usually lasting less than a week after completion of 4-day chemotherapy; these toxicities responded well to fluid and electrolyte management. Patients with renal failure (n = 6) who were receiving maintenance dialysis during therapy tolerated the regimen well without cisplatin and had no significant metabolic complications, but grade 3 mucositis occurred. Of note, there was no occurrence of acute tumor lysis syndrome even in patients with high baseline LDH levels. DTPACE produced infrequent but diverse neurologic toxicities. One of the most common neurologic complaints was paresthesias and numbness in hands and feet, which tended to worsen with continuation of thalidomide but improved with dose reduction of thalidomide. Weakness caused by motor neuropathy was most prominent during the first 2 weeks of each chemotherapy cycle. Increase in the level of thyroid-stimulating hormone or decrease in thyroxine was noted after 17 (4%) cycles. Of these, only six episodes were associated with clinical hypothyroidism, which required treatment with levothyroxine. After the first cycle of DTPACE, six patients (3%) died as a result of treatment-related causes, including bacterial sepsis (n = 2), invasive aspergillosis (n = 2), respiratory failure cause by bacterial pneumonia (n = 1), and intracerebral hemorrhage while receiving coumadin (n = 1); one patient died as a result of progressive disease. Three additional patients died of sepsis (n = 2) and cytomegalovirus pneumonia (n = 1) after the second cycle, with a 4% incidence of treatment-related mortality at 3 months after the second cycle.
The combination of thalidomide with chemotherapeutic agents shows outstanding response rates in patients with myeloma who experience relapse after or are completely or partially refractory to standard chemotherapy. Patients who had experienced treatment failure after high-dose dexamethasone and doxorubicin-based regimens, or who had high LDH levels, chromosome 13 changes, or hypodiploid karyotypes, achieved similar response rates as the others. More importantly, two cycles of DTPACE resulted in an excellent tumor reduction before autotransplantation in a group of patients, of whom 90% had at least one poor prognostic factor. The CR and nCR rate (16%) was considerably higher than with conventional chemotherapy, and the rate after two cycles of full-dose DTPACE compares favorably with that achieved with a single autotransplantation in primary refractory or relapsed myeloma.16,17,18 Long-term disease control of myeloma has become possible since high-dose therapy with melphalan was introduced in the mid 1980s, with attainment of CR as a primary goal of therapy. Randomized and historically controlled studies have shown that high-dose therapy combined with autologous stem-cell transplantation produces up to 50% CRs and significantly improves survival in newly diagnosed, symptomatic patients with myeloma.2–5 In contrast, in patients who experience relapse after or are refractory to standard-dose chemotherapy, lower CR rates and shorter overall and event-free survival are observed after autotransplantation.16,17–19 In one multi-institutional study of autotransplantation for patients with refractory myeloma, 27% of patients achieved CR and median overall survival was 19 months.16 Similar observations were made in a study of patients who experienced relapse or were refractory, with a 34% CR rate and a median overall survival of 20 months after transplantation.17 Survival of relapsing or refractory MM patients may improve if more effective cytoreduction can be achieved before autotransplantation, similar to that achieved in newly diagnosed patients.6,19 Although the relative contribution of induction chemotherapy to survival after transplantation requires more randomized trials, in general, better response rates are observed with more intensive chemotherapy before high-dose therapy.19,20 Most conventional pretransplantation induction regimens attain no more than 5% CR (patients are immunofixation-negative) even after multiple cycles of either vincristine, doxorubicin, and dexamethasone or alkylator-based therapy, and the CR rate typically does not increase when such therapy is continued.4,18,21 Improvements in at least PR (as defined) before autotransplantation may not be observed with conventional chemotherapy in patients who experience relapse or are refractory.22 In this context, the response rate of our patients after two induction cycles of DTPACE was quite remarkable, and comparable with those seen with multiple cycles of chemotherapy in newly diagnosed patients who received the total therapy I.6 The excellent response rates in patients with prior doxorubicin or progressive disease, those with a high proliferative disease reflected by high LDH levels and high PCLI, and those with deletion of chromosome 13 indicate that a combination of thalidomide with chemotherapeutic agents and dexamethasone can overcome multidrug resistance induced by either epigenetic or genetic alterations.9,10 DTPACE was well tolerated and given on an outpatient basis in most cases, with a low treatment-related mortality. The regimen caused a wide range of toxicities (although they were infrequent), especially those related to the cardiovascular and neurologic system. Some of these toxicities, such as thromboembolism, sinus bradycardia, supraventricular arrhythmia, somnolence, syncope, and sensory neuropathy, are unique and not usually seen in the context of conventional chemotherapy or high-dose dexamethasone. Thalidomide has been shown to be associated with an increased risk of thromboembolism, especially when combined with doxorubicin.23 Thalidomide appeared to be etiologically related to arrhythmia and syncope because these conditions improved when the dose was reduced or temporarily discontinued.24 Sensory neuropathy was common in the present study, presumably because of a large number of elderly patients, the majority of whom had received prior vincristine therapy.25 At present, patients are routinely given daily low molecular weight heparin 40 to 80 mg to prevent thromboembolism, except when the platelet count is reduced to less than 30,000/µL. Doses of thalidomide are reduced to a range of 100 to 200 mg a day or temporarily withheld if either cardiovascular or neurologic toxicities of grades 3 to 4 occur, until patient’s condition is stabilized and allows re-treatment at a lower dose. This study shows a significant therapeutic potential of the DTPACE regimen and reveals a novel way of managing patients with myeloma, especially those with high-risk features. On the basis of the promising activity of DTPACE, we are currently investigating its role in posttransplantation consolidation therapy and salvage therapy for patients experiencing relapse after autotransplantation. The combination of infusional chemotherapy with PS-341, which induces responses irrespective of presenting disease features, also is planned.
1. Alexanian R, Dimopoulos M: The treatment of multiple myeloma. N Engl J Med 330:484–489, 1994
2. Barlogie B, Hall R, Zander A, et al: High-dose melphalan with autologous bone marrow transplantation for multiple myeloma. Blood 67:1298–1301, 1986 3. Selby PJ, McElwain TJ, Nandi AC, et al: Multiple myeloma treated with high dose intravenous melphalan. Br J Haematol 66:55–62, 1987[Medline]
4. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma: Intergroupe Francais du Myelome. N Engl J Med 335:91–97, 1996 5. Cunningham D, Paz-Ares L, Milan S, et al: High-dose melphalan and autologous bone marrow transplantation as consolidation in previously untreated myeloma. J Clin Oncol 12:759–763, 1994[Abstract]
6. Barlogie B, Jagannath S, Desikan KR, et al: Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood 93:55–65, 1999
7. Barlogie B, Desikan R, Eddlemon P, et al: Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: Identification of prognostic factors in a phase 2 study of 169 patients. Blood 98:492–494, 2001 8. Barlogie B, Tricot G, Anaissie E: Thalidomide in the management of multiple myeloma. Semin Oncol 28:577–582, 2001[CrossRef][Medline]
9. D’Amato RJ, Loughman MS, Flynn E, et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 91:4082–4085, 1994
10. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96:2943–4950, 2000 11. Barlogie B, Smith L, Alexanian R: Effective treatment of advanced multiple myeloma refractory to alkylating agents. N Engl J Med 310:1353–1356, 1984[Abstract] 12. Fassas AB, Spencer T, Desikan R, et al: Cytotoxic chemotherapy following tandem autotransplants in multiple myeloma patients. Br J Haematol 119:164–168, 2002[CrossRef][Medline] 13. National Cancer Institute: Cancer Therapy Evaluation Program: Common Toxicity Criteria, version 2. Bethesda, MD, National Cancer Institute, April 30, 1999 14. Gooley TA, Leisenring W, Crowley J, et al: Estimation of failure probabilities in the presence of competing risks: New representations of old estimators. Stat Med 18:695–706, 1999[CrossRef][Medline] 15. Hintze JL: Number Cruncher Statistical Systems, May 2002, Kaysville, UT
16. Vesole DH, Crowley JJ, Catchatourian R, et al: High-dose melphalan with autotransplantation for refractory multiple myeloma: Results of a Southwest Oncology Group phase II trial. J Clin Oncol 17:2173–2179, 1999 17. Gertz MA, Lacy MQ, Inwards DJ, et al: Delayed stem cell transplantation for the management of relapsed or refractory multiple myeloma. Bone Marrow Transplant 26:45–50, 2000[CrossRef][Medline]
18. Fermand JP, Ravaud P, Chevret S, et al: High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 92:3131–3136, 1998 19. Raje N, Powles R, Kulkarni S, et al: A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma. Br J Haematol 97:153–160, 1997[CrossRef][Medline] 20. Sirohi B, Powles R, Mehta J, et al: Complete remission rate and outcome after intensive treatment of 177 patients under 75 years of age with IgG myeloma defining a circumscribed disease entity with a new staging system. Br J Haematol 107:656–666, 1999[CrossRef][Medline]
21. Moreau P, Facon T, Attal M, et al: Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus 140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: Final analysis of the Intergroupe Francophone du Myelome 9502 randomized trial. Blood 99:731–735, 2002 22. Mineur P, Menard JF, Le Loet X, et al: VAD or VMBCP in multiple myeloma refractory to or relapsing after cyclophosphamide-prednisone therapy (protocol MY 85). Br J Haematol 103:512–517, 1998[CrossRef][Medline]
23. Zangari M, Siegel E, Barlogie B, et al: Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: Implications for therapy. Blood 100:1168–1171, 2002
24. Baidas SM, Winer EP, Fleming GF, et al: Phase II evaluation of thalidomide in patients with metastatic breast cancer. J Clin Oncol 18:2710–2717, 2000 25. Molloy FM, Floeter MK, Syed NA, et al: Thalidomide neuropathy in patients treated for metastatic prostate cancer. Muscle Nerve 24:1050–1057, 2001[CrossRef][Medline] Submitted January 9, 2003; accepted April 30, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Cumulative incidence curves were generated to calculate the probability of responses, using the NCSS statistical software, version 2001 (Kaysville, UT).
