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American Journal of Hematology 52:77-81 (1996) HyperCVAD for VAD-Resistant Multiple Myeloma Meletios A. Dimopoulos, Donna Weber, Hagop Kantarjian, Kay 6. Delasalle, and Raymond Alexanian University of Texas M. D. Anderson Cancer Center, Houston, Texas More effective and safer regimens are needed for patients who have advanced multiple myeloma resistantto or relapsingdespiteprior treatment with alkylating agents and VAD. We treated58 such patients using the combinationof twice daily cyclophosphamide(total dose 1.8 g/mz)and VAD (hyperCVAD). Treatment was given to outpatients followed by G-CSF at 5 pg/kg/d until granulocyte recovery. Twenty-three patients responded (40%), with a median duration of granulocyte depression to less than 500/pl of 4 days and a mortality rate of 2%. The median survival time for all patients was 15 months, and the median remissiontime of responding patientswas 8 months. Patients who had low LDH, low BzM, or primary resistant disease lived significantly longer than patients without these features. The combination of fractionated cyclophosphamide and VAD provided an effective and safe rescuetreatment for many patients who had advancedmyeloma resistant to standard therapies. Q 199s Wiley-Liss, Inc. Key words: chemotherapy for myeloma, resistant multiple myeloma, VAD INTRODUCTION MATERIALS AND METHODS Few effective treatments are available for patients who Clinical Features have advanced multiple myeloma that is resistant to both Fifty-eight consecutive patients who had multiple rny- alkylating agents and vincristine-doxorubicin-dexameth- eloma resistant to both standard melphalan-prednisone asone (VAD). Myeloablative therapy for myeloma has and VAD chemotherapy were treated. There were no been associated with significant morbidity and limited exclusions because of age, performance status, or the sustained effect against late-phase disease [1,2]. Several presence of other medical disorders. The median age was useful regimens of high-dose alkylating agents have been 58 and 14 patients were older than 65. The myeloma associated with significant toxic effects and therefore protein type was IgG in 47% of patients, IgA in 34%, have been restricted to younger patients in good medical and only light chains in 19%. Poor risk factors, such as condition [3-51. a high serum level of lactate dehydrogenase (LDH 1300 In an effort to develop an effective but less toxic therapy UA, normal <22S UA) or beta2microglobulin (B2M> 4.0 for patients with VAD-resistant disease, we studied a mgfl), were present in 52% of patients (Table I). combination of high-dose fractionated cyclophosphamide In 25 patients, the disease was relapsing after a previous with vincristine, doxorubicin and dexamethasone (hyper- remission despite continued chemotherapy with VAD (re- CVAD). Fifty-eight consecutive patients who had ad- sistant relapse) (Table I); hyperCVAD was third-line or vanced and resistant myeloma and who had not received more therapy for all patients. Primary resistant disease a prior intensive alkylating agent program were treated that had not responded to any prior therapy, including on an outpatient basis. This regimen was given regardless of age, performance status or organ dysfunction, with daily granulocyte colony-stimulating factor (G-CSF) and Received for publication June 2, 1995; accepted January 17, 1996. prophylactic antibiotics during the neutropenic period. Addressreprint requests to Dr. Raymond Alexanian,Box 1,The UniverThe goal was to achieve an acceptable frequency of re- sity of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., sponse with few complications. Houston, TX 77030. 01996Wiley-Liss, Inc. 78 Dimopoulos et al. TABLE 1. Patient Characteristics HyperCVAD (1 993-1994) No. patients Median age (range) Male (%) Laboratory studies (%) Hemoglobin <8.5 g/dl Creatinine >2.0 mgldl Calcium >11.5 mg/dl B,microglobulin >4.0 mg/l LDH >300 U/l Disease status (%) Primary resistance Resistant relaose 58 58 (40-76) 59 26 12 15 43 22 57 43 Cyclophosphamide-etoposide (1990-1993) 72 56 (39-71) 58 24 14 20 55 22 74 26 VAD or intermittent high-dose dexamethasone, affected 33 patients. HyperCVAD was second-line therapy for 15 patients and third-line or more therapy for 18 patients. Primary resistance included 3 patients with tumor growth of at least 25%, 11 patients with stable disease as defined by less than 25% tumor reduction, and 19 patients with a prior tumor reduction of 26-70% that was insufficient to consider responsive. The median interval from initial chemotherapy was 9 months for all patients who had primary resistant disease (range 3 4 2 months) and 30 months for those who had relapsing myeloma (range 9-23 1 months). Treatment A central venous catheter was inserted through an antecubital vein by the outpatient nursing service. Treatment consisted of cyclophosphamide (300 mg/mYi.v.) over 3 hr every 12 hr for 6 doses on days 1 through 3 (total dose = 1,800 mg/m2) with oral fluids of at least 2.0 1/ day; mesna was given simultaneously by continuous infusion at a dose of 600 mg/m2/dayfor 3 days. Twelve hours after the completion of cyclophosphamide, vincristine (2.0 mg) and doxorubicin (50 mg/m') were given by continuous infusion over 48 hr; on day 11, vincristine (2.0 mg) was given by rapid i.v. injection. Dexamethasone (20 mg/m2 p.0.) was administered in a single morning dose for 5 days beginning on day 1 and for 4 days beginning on day 11. G-CSF was started on day 6 at a dose of 5 ugkglday sc and repeated daily until the patient's granulocyte level exceeded 2,0OO/p1 for 2 consecutive days. Between days 8 and 18, all patients received ciprofloxacin (500 mg p.0. twice daily), fluconazole (100 mg p.0. daily), and acyclovir (200 mg p.0. three times daily). Patients with fever (>38.3"C) or any sign of serious infection were hospitalized and were administered broad-spectrum i.v. antibiotics. Patients received a second course of hyperCVAD provided there had been a 50% reduction of myeloma protein. Responding patients were maintained on oral cyclophosphamide (125 mg/m' every 12 hr) and dexamethasone (20 mg/m2 each morning) for 5 days every 5 weeks. Eight patients received subsequent myeloablative treatment with autologous blood stem cell transplantation either for persistent resistant disease (seven patients) or to consolidate remission (one patient) [6]. Response and Survival Response was defined as a 75% or greater reduction of serum myeloma protein production, a 95% or greater reduction of Bence Jones proteinuria and decrease of bone marrow plasmacytosis to less than 5% for at least 2 months [7]. The life table method was used to calculate survival from the onset of therapy, and to assess remission time from the onset of remission to the earliest sign of relapse. Chi-square tests were used to compare response rates and Wilcoxon tests to compare remission and survival data. RESULTS Response Twenty-three of the 58 patients responded to treatment (40%, 95% confidence interval 27-53%), including one patient for whom immunofixation studies showed disappearance of serum myeloma protein. The median tumor halving time for responders was 0.6 month (range = 0.2-2.0 months), and a remission was recognized in all but 3 patients within 2 months. In all responding patients, soft tissue masses disappeared, hypercalcemia reversed, and anemia improved. Toxicity HyperCVAD was well tolerated and only one patient died of a treatment-related complication (2%) (Table 11). Granulocytes fell to less than 5001~1in a11 patients and then recovered to this level after a median of 4 days (range 1-15 days), and on a median day 15 after the start of treatment (range 12-22 days). Platelet levels fell to less than 20,OOO/pl in 35% of patients, with recovery to 50,0OO/pl after a median of 5 days. HyperCVAD for VAD-Resistant Myeloma TABLE II. Outcome and Complications Following Chemotherapy HyperCVAD Cyclophosphamide-etoposide Disease Outcome Response rate (%) Median remission (months) Median survival (months) Major toxicities Early death (%) Hospitalization (%) Median days granulocytes <50O/p,l 40 8 15 2 34 5 35 10 11 6 93 9 *n.s., not significant. P n.s.* ns. n.s. n.s. <.01 <.01 79 Thirty-four percent of patients required hospitalization who received hyperCVAD or cyclophosphamide-etopo- for a median of 7 days for treatment of documented side. Among 53 patients with both low LDH and B2M, or presumed infection (17 patients), hyponatremia (two resistant relapse was associated with significantly shorter patients), or severe ileus (one patient). Among the 17 remission and survival times (Table 111, Fig. 3). patients admitted with fever, 13 had no apparent cause and four had pneumonia; a pathogenic organism was cultured from blood or sputum in two patients (Esche- DISCUSSION richia coli, S. auueus). All but one responded to intrave- This paper describes an effective regimen of acceptable nous broad-spectrum antibiotics concurrent with granulo- toxicity for patients who have VAD-resistant multiple cyte recovery. Alopecia occurred in 83% of patients and myeloma. The program was designed for outpatients and 22% developed symptoms of mild neuropathy attributed G-CSF was preferred to GM-CSF to reduce the duration to vincristine. Mild mucositis developed in five patients of granulocytopenia with a cytokine that has been associ- and no side effects were attributed to G-CSF. With a ated with fewer side effects [8]. Cyclophosphamide was previous cyclophosphamide-etoposidecombination given given twice daily because this schedule appeared to in- to a similar cohort of patients, the treatment-related mor- crease the response rate for acute lymphocytic leukemia tality rate was 6%, granulocyte levels fell below 5 0 0 / ~ 1 and Burkitt's lymphoma, possibly because of a greater for a median of 9 days, and hospitalization was required effect of fractionated treatment against dividing cells for 93% of patients (Table 11) [5]. [9,10]. Cyclophosphamide given daily for 4 days also Survival and Prognostic Factors appeared superior to a single injection for multiple myeloma [11,121.Our program of twice-daily cyclophospha- The median survival was 15 months for all patients, mide with VAD induced responses in 40% of patients 10 months for those with resistant relapse, and projected who had multiple myeloma that was resistant to prior at 22 months for patients with primary resistance. After therapies that usually included VAD, a frequency similar major prognostic factors were found to be similar for to that induced by high-dose cyclophosphamide-etopo- the 58 patients who received hyperCVAD and the 72 side [5].These treatments were dissimilar and were given comparable patients treated previously with cyclophos- to consecutive patients during different time periods. phamide-etoposide (Tables I, II), both groups were com- While the results were similar, any meaningful compari- bined for further analysis of these factors. son of the 2 treatments is not justified and would require Twenty-two percent of the 130 patients showed a high a concurrent, controlled trial. Yet, the consistent results serum LDH level (>300 U/l) with normal liver function were supported by the cross-resistance observed in eight and no other clinical explanation for the elevation than of nine patients with resistant disease excluded from the myeloma. This feature was associated with resistance to study who were treated sequentially with cyclophospha- treatment and very short survival (Table 111,Fig. 1).There mide-etoposide and then hyperCVAD. The activity of were no significant differences in survival for patients hyperCVAD against disease resistant to VAD suggests with high or low LDH who received hyperCVAD or that high-dose fractionated cyclophosphamide accounts cyclophosphamide-etoposide. for most of the antitumor effect and justifies current trials Among 101 patients with lower LDH levels (<300 U/ of higher doses of fractionated cyclophosphamide alone. l), no features were associated with resistance to treat- Despite the inclusion of more older patients, the hyper- ment. However, an elevated B2M(>4.0 mg/l) was associ- CVAD regimen was reasonably well tolerated; only one ated with significantly shorter remission and survival patient died as a result of treatment, and hospitalization times (Table 111, Fig. 2); there were no significant differ- for complications was required less than one-half as fre- ences in survival for patients with high or normal B2M quently as after cyclophosphamide-etoposide.The re- 80 Dimopoulos et al. TABLE 111. Maior Prognostic Factors Affecting Outcome Remission Survival No. Response (%) P (median months) P (median months) P All patients LDH (U/1) <300 >300 130 36 101 29 43 14 <.01 9 lo <.01 3 12 18 5 <.01 LDH <300 UA BZM(mg/l) <4.0 >4.0 4583 4450 n.s.* 2y7 <.01 2151 <.01 LDH <300 U/1 + B2M <4.0 mg/l Primary resistant Resistant relapse 33 20 46 45 ns. 36 C.01 42 <.01 6 14 *n F., not significant. 100 Survival Remission 100 c Survival .o$l 50 3 c 0 !! a LDH<3OO U/L LDH> 300 UIL E n 20 10 20 30 40 50 Months of Treatment .p>- 50 3 c 0 2 a 20 1B,M >4.0mg/L .y , , 10 20 30 40 50 `"7B,M>4.0 mgit ..... 10 20 30 40 50 Months of Treatment Fig. 1. Survival and remission times for 130 patients ac- cording to LDH level. The median survival was 5 months with LDH >300 UII and 18 months with LDH <300 UII. Fig. 2. Survival and remission times for 101 patients with LDH <300 UIl according to B,M level. The median survival was 11 months with B2M>4.0 mg/l and 25 months with B2M <4.0 mgk duced toxicity was attributed mainly to the shorter duration of severe granulocytopenia and the less frequent thrombocytopenia, so that most patients were treated as outpatients. Possible benefits from the substitution of GCSF for GM-CSF and the administration of prophylactic antibiotics were not clear. To identify patients who were more likely to have a favorable outcome, we examined the prognostic factors of 130 consecutive and comparable patients who had myeloma resistant to VAD and who received either hyperCVAD or cyclophosphamide-etoposideP.atients who had a high LDH level rarely benefitted from therapy or qualified for myeloablative treatment, consistent with the inherent resistance to treatment and poor prognosis associated with this disease feature [131. Alternative investigative therapies are preferable for such patients. Although myeloma in resistant relapse responded frequently, remission and survival times were much shorter than those for comparable patients who had primary resistant disease. Intensive therapy for relapsing disease should be offered to selected patients after careful review of the potential risks and limited benefit for most patients. The short remission after treatment for resistant relapse was similar to that observed after myeloablative therapy [2]. One explanation for the initial sensitivity but early recurrence of disease in resistant relapse could be the evolution with time of more resistant and proliferative subclones [141. Relapsing myeloma has a higher growth fraction and more colony-forming cells on in vitro culture studies [15,161,features that could account for the short remission and rapid tumor regrowth of relapsing disease despite the more intensive therapy. Many patients who had primary resistant disease responded to hyperCVAD with a long remission time, but no further prolongation of survival resulted after additional HyperCVADfor VAD-Resistant Myeloma 81 1oc Remission REFERENCES Primary Resistance ..p>__ 5c "-1 em 2 2c I .C- L -Resistant Relapse 10 20 30 40 50 10 20 30 40 50 Months of Treatment Fig. 3. Survival and remission times for 53 patients with both LDH <300 U/I and B,M <4.0 mg/l according to disease status. myeloablative consolidation therapy [2]. Should the disease remain resistant to hyperCVAD or a similar treatment, myeloablative therapy has often been effective in reducing the myeloma, confirming the ease by which apparent tumor resistance can be overcome by progressively higher doses of alkylating agents [3,17]. Thus, hyperCVAD provides an effective treatment of acceptable toxicity that should be considered for all patients with primary resistant myeloma regardless of age or performance. This treatment also constitutes a useful priming therapy for blood stem cell harvest in support of myeloablative treatment when that procedure is indicated ~71. ACKNOWLEDGMENTS This work was supported by a grant from the Robert Hompe Myeloma Research Fund. We thank Rose Guevara for secretarial assistance. I . Jagannath S, Vesole D, Glenn L, et al: Low-risk intensive therapy for multiple myeloma with combined autologous bone marrow and blood stem cell support. Blood 80:1666-1672, 1992. 2. Alexanian R, Dimopoulos M, Smith T, et al: Limited value of myeloablative therapy for late multiple myeloma. Blood 83:5 12-5 16, 1994. 3. Selby P,McElwain T, Nandi A, et al: Multiple myeloma treated with high-dose intravenous melphalan. Br J Haemat 66:55-62, 1987. 4. Barlogie B, Jagannath S, Dixon D, et al: High dose melphalan and granulocyte-macrophage colony-stimulating factor for refractory multiple myeloma. Blood 76:677480, 1990. 5. 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