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High-Dose Melphalan With Autotransplantation for Refractory Multiple Myeloma: Results of a Southwest Oncology Group Phase II Trial

From the University of Arkansas for Medical Science, Little Rock, AR; Southwest Oncology Group Statistical Center, Seattle, WA; Michael Reese Hospital and Medical Center, Chicago, and Loyola University Stritch School of Medicine, Maywood, IL; Wichita Community Clinical Oncology Program, Wichita, KS; and the University of Arizona Cancer Center, Tucson, AZ.

Address reprint requests to Southwest Oncology Group (SWOG-8993), Operations Office, 14980 Omicron Drive, San Antonio, TX 78245-3217.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate high-dose melphalan followed by autologous stem-cell transplantation in patients with refractory multiple myeloma.

PATIENTS AND METHODS: Multiple myeloma patients with alkylating agent or vincristine/doxorubicin/dexamethasone–refractory disease were eligible for the phase II multi-institutional Southwest Oncology Group trial S8993. Patients up to age 70 years were enrolled between April 15, 1991, and May 1, 1996. Patients without prior stem-cell collection were primed with high-dose cyclophosphamide (HD-CTX; 6 g/m²) and granulocyte-macrophage colony-stimulating factor. After stem-cell procurement, patients received melphalan 200 mg/m² with autologous transplantation. Upon recovery from melphalan, patients were to receive interferon alfa-2b until relapse.

RESULTS: Seventy-two patients were enrolled onto S8993; five were ineligible and one received no therapy. Of the 66 assessable patients, 56 patients underwent the transplant procedure; 54 were assessable for response and 56 for toxicity. The response to HD-CTX (n = 37) included three complete remissions (CRs; 8%) and five partial remissions (PR; 14%); response to melphalan (n = 54) included 16 CRs (30%) and 19 PRs (35%), for an overall CR and PR (n = 66; intent-to-treat) of 27% and 58%, respectively. Toxicities included six treatment-related deaths: two during HD-CTX and four during transplantation. The median progression-free survival (PFS) and overall survival (OS) durations on an intent-to-treat basis from transplant registration was 11 months and 19 months (95% confidence interval, 14 to 29 months), respectively. The 3-year actuarial PFS and OS rates were 25% and 31%, respectively.

CONCLUSION: High-dose therapy with melphalan 200 mg/m² is feasible with high response rates (58% overall) and an OS of 19 months in patients with refractory multiple myeloma.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MULTIPLE MYELOMA (MM) remains an incurable malignancy as a result of innate drug resistance present at diagnosis.¹ Initial treatment with alkylating agents or vincristine/doxorubicin/dexamethasone (VAD) chemotherapy effects response rates of 40% to 60% with a median remission duration of 18 months and median survival duration of approximately 30 to 36 months.^2,3 Once resistance to standard regimens has been established, salvage therapy results in responses of 20% to 40% but usually provides only short-term palliation with median survival of 3 to 12 months.^4-6 Therefore, novel approaches to salvage therapy are essential for the nearly half of newly diagnosed patients who fail to achieve remission (primary unresponsive) and for those who relapse despite re-treatment with myelosuppressive therapy (resistant relapse).

Evidence that increased dose-intensity of melphalan could overcome drug resistance was demonstrated by McElwain and Powles.⁷ Because of encouraging results, further dose escalation was attempted, initially requiring hematopoietic stem-cell support with bone marrow and subsequently with peripheral-blood stem cells.^8-12 The considerable treatment-related mortality and morbidity observed in early studies was significantly reduced with the use of hematopoietic stem cells and hematopoietic growth factors because of marked shortening of the duration of marrow aplasia.¹³ Over the past 15 years, a number of clinical trials have been devoted to evaluating high-dose myeloablative chemoradiotherapy requiring hematopoietic stem-cell support.^8-13 These single-institution trials were initially piloted in patients with refractory myeloma and more recently applied to newly diagnosed patients.^14-18 This approach was subsequently extended to tandem transplants and demonstrated improved response rates, event-free survival (EFS), and overall survival (OS).^17,18 The Southwest Oncology Group (SWOG) initiated a phase II trial of high-dose therapy with autologous hematopoietic stem-cell transplant to evaluate the feasibility and efficacy of conducting a multi-institutional trial in patients with MM resistant to VAD and alkylating agents as a prelude to future trials for patients earlier in the disease course.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Between April 1991 and May 1996, 72 patients were enrolled onto the SWOG 8993 phase II trial of high-dose melphalan with hematopoietic stem-cell support in refractory MM, and results are reported as of August 1998. All patients were alkylating agent, dexamethasone, or VAD refractory, defined as persistent or progressive disease while receiving myelosuppressive doses of such therapy, or had primary drug resistance for at least 4 months. At least 1 month had elapsed since the last chemotherapy treatment. Eligible patients had measurable myeloma paraprotein in the blood and/or urine, age less than 70 years, SWOG performance status of 0 to 2, and adequate renal, hepatic, pulmonary, and cardiac function for first and second registration. Patients with overt infection, unexplained fever, or who had a previous high-dose therapy with autologous transplantation were not eligible. The study protocol was approved by the institutional review board at each participating site, and written informed consent was obtained from all patients.

Treatment Schema
After initial registration, patients without previous or inadequate stem-cell collections were treated with high-dose cyclophosphamide (HD-CTX; 6 g/m²) administered at a dose of 1.2 g/m² in 100 mL of 5% dextrose and water (D5W) intravenously over 1 hour every 3 hours for five doses. Uroprotection was provided by intravenous hydration with normal saline with 30 mEq/L KCl at 150 mL/h starting 12 hours before administration of HD-CTX and continuing for a total of 48 hours. In addition, mesna 3.6 g/m² in 1 L of D5W was administered by continuous infusion over a 24-hour period starting with the first dose of cyclophosphamide. Starting on day +2, granulocyte-macrophage colony-stimulating factor (GM-CSF; 0.25 mg/m²) was administered subcutaneously daily until completion of peripheral-blood stem-cell collections (or until WBC count reached > 30 x 10⁹/L). Apheresis was initiated when the WBC count was greater than 1 x 10⁹/L and the platelet count was greater than 7 x 10¹⁰/L. Apheresis duration and blood volumes were measured according to institutional guidelines. A minimum of 7 x 10⁸ mononuclear cells/kg was required to proceed to transplantation. Patients without adequate stem-cell collection after apheresis could undergo additional hematopoietic stem-cell collection by bone marrow harvest if the bone marrow plasmacytosis was less than 30%. Patients with previous adequate stem-cell collection (either autologous bone marrow and/or peripheral-blood stem cells) proceeded to second registration.

Criteria to define adequate autograft(s) included less than 30% bone marrow plasmacytosis with (1) a bone marrow transplant 1.5 x 10⁸ mononuclear marrow cells/kg; (2) a peripheral-blood stem-cell transplant 7 x 10⁸ mononuclear peripheral-blood stem cells/kg; (3) a bone marrow and peripheral-blood stem-cell transplant 1.5 x 10⁸ mononuclear marrow cells/kg and 5 x 10⁸ mononuclear peripheral- blood stem cells/kg. Patients with 30% bone marrow plasmacytosis could only receive peripheral-blood stem-cell transplant 7 x 10⁸ mononuclear peripheral-blood stem cells/kg. All autografts required less than 30% tumor cell contamination. The choice of autologous bone marrow and/or peripheral-blood stem cells was at the discretion of the attending physician.

At the time of second registration, patients were required to meet the autograft stem-cell requirements as defined in the first registration. After hydration with 1 L of D5W/normal saline over 3 hours and premedication with dexamethasone 50 mg and antiemetics (per institutional guidelines), patients received melphalan 100 mg/m² in 100 mL of D5W infused over 20 minutes on day –4; hydration with D5W/ normal saline with 30 mEq/L KCl at 75 mL/h continued for 7 days. A second dose of melphalan 100 mg/m² was administered on day –3. Autologous peripheral-blood stem cells or bone marrow were infused on day 0 after premedication with 50 mg of diphenhydramine hydrochloride and 500 mg of methylprednisolone. Patients with both marrow and blood stem-cell infusion were administered marrow on day 0 followed by blood stem cells on day +1. Within 24 hours of transplantation, GM-CSF 0.25 mg/m² was administered subcutaneously daily until the absolute neutrophil count was more than 2 x 10⁹/L for 3 consecutive days. Patients received prophylactic antibiotics according to institutional guidelines. Intravenous immunoglobulins (15 g/m²) were to be administered twice weekly until hematologic recovery.

Upon recovery of performance status and hematologic parameters from autologous transplantation, patients were intended to receive interferon alfa-2b (Intron-A; Schering Plough, Kenilworth, NJ) 3 MU/m² three times weekly (SWOG performance status of 0 to 2, platelet count > 10 x 10¹⁰/L, and neutrophil count > 1.5 x 10⁹/L) no later than 3 months after transplantation. Interferon was continued until relapse. Interferon dosage modifications were initiated if grade 2 interferon-related toxicity occurred.

Patient Flow
Of the 72 patients registered, 67 were eligible, 66 were assessable, and 56 completed the planned transplantation. The reasons patients were either not assessable or did not undergo transplantation are listed in Table 1. Peripheral-blood stem-cell mobilization with HD-CTX and GM-CSF was used for hematopoietic stem-cell support in 37 patients; 29 patients had previous hematopoietic stem-cell collection from peripheral blood (n = 21), bone marrow (n = 6), or peripheral blood and bone marrow (n = 2) before second registration.

Patient Characteristics
Characteristics of patients who underwent transplantation are listed in Table 2. All patients had VAD- and/or alkylator-refractory disease; 80% had refractory relapse, and 20% had primary refractory disease. The patients with advanced-stage disease were heavily pretreated (84% with two prior treatment regimens); approximately one half of the patients had Durie-Salmon stage III disease at diagnosis and a pretransplant beta-2 microglobulin level greater than 3 mg/dL. The median age was 55 years.

Response Criteria and Statistical Methods
Clinical end points included transplant-related mortality within 100 days of transplantation. Standard SWOG response criteria were used: a partial remission (PR) was defined as more than 50% reduction in production rate (synthetic index) of the monoclonal serum protein and reduction in Bence Jones protein to less than 0.2 g/d. Complete remission (CR) was defined as 75% reduction in production rate (synthetic index) of the monoclonal serum protein and 90% reduction and decrease to less than 0.2 g/d in urine paraprotein. With both PR and CR, these findings had to be present on at least two occasions with a minimum interval of 3 weeks. Improved status was defined as a reduction of serum paraprotein of 25% to less than 50% and decrease in Bence Jones protein to less than 0.2 g/d. Stable disease included patients who failed to satisfy the criteria for response or improvement. Relapse or progressive disease was defined as an increase by 100% from the lowest level of serum paraprotein, increase by more than 25% above any remission level of paraprotein peak, reappearance of myeloma peaks that had disappeared with treatment, increase in size or number of lytic lesions (but not compression fractures), hypercalcemia, or other new manifestations of disease constituted relapse. Progression-free survival (PFS) and OS were both calculated from the time of first registration. An event included disease recurrence and death from any cause; in case of survival projections, deaths from disease or other causes were considered events.

Patients were stratified at the time of treatment by percent bone marrow plasmacytosis (< 30% v 30%), adequate bone marrow cells (yes v no or not applicable), and adequate peripheral-blood stem cells (yes v no or not applicable). The descriptive factors for treatment were performance status (0 to 1 v 2), prior chemotherapy (1 v 2), and disease status (resistant v primary refractory). All analyses were performed on an intention-to-treat basis. The results are reported as of August 7, 1998. The rates of PFS and OS were estimated by the Kaplan-Meier method¹⁹ and compared by the log-rank test.²⁰

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Response
HD-CTX. Thirty-seven patients received protocol HD-CTX for peripheral-blood stem-cell mobilization. Overall response to HD-CTX was 22%, including three CRs and eight PRs (Table 3). Two patients had unconfirmed responses; 20 had stable disease; seven were not assessable because of inadequate assessment of disease (n = 3), early death (n = 1), or disease progression (n = 3).

Transplantation. Fifty-six patients received high-dose melphalan chemotherapy and autologous transplantation (Table 3). Fifty-four patients were assessable; two were not assessable at the time of the data analysis. Overall response to transplantation was 65%, including 16 CRs and 35 PRs. One patient had an unconfirmed response, 13 had stable disease, two had progressive disease, and three had inadequate disease assessment.

Overall response. Overall response on an intention-to-treat basis for all 66 eligible patients was 58%, including 19 CRs (29%) and 38 PRs.

Survival
The median PFS and OS durations from initial registration for the 66 assessable patients were 11 months and 19 months, respectively (Fig 1A and 1B). Of the 37 patients who required priming and collection, the median time from registration to transplant was 2 months (range, 1 to 3 months). The actuarial 3-year PFS and OS rates were 25% and 31%, respectively.

View larger version (20K): [in this window] [in a new window]   Fig 1. Kaplan-Meier curves of (A) PFS and (B) OS for 66 patients from initial registration on the S8993 trial. Analysis showed (A) a median PFS of 11 months and (B) a median OS of 19 months.

Prognostic Factors
Evaluation of prognostic factors by univariate analysis was limited by small patient numbers. No significant differences were observed based on percent bone marrow plasmacytosis at the time of stem-cell collection, disease status at transplantation, beta-2 microglobulin, Durie-Salmon stage, immunoglobulin isotype, performance status, or prior chemotherapy (Table 4).

Toxicities
HD-CTX. Thirty-three of 37 patients who completed HD-CTX on protocol experienced grade 4 hematologic toxicity and/or infection associated with the priming chemotherapy. Treatment-related deaths occurred in two patients, both from infectious complications.

Transplantation. All 56 patients were assessable for toxicity. Four patients died from infectious complications; 51 of the remaining 52 patients experienced grade 4 toxicities. Grade 3 nonhematologic toxicities occurring in more than 10% of the patients included diarrhea, nausea/vomiting, stomatitis, hypertension, and fatigue.

Interferon Maintenance
Thirty patients received posttransplant interferon; 26 patients did not receive interferon, which constituted a major late protocol deviation. Because interferon was initiated in only 53% of the patients on this trial because of incomplete hematopoietic recovery by 3 months and the marked variation in dose and duration of therapy, no analysis of interferon efficacy could be performed.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Over the past 30 years, there has been minimal improvement in the median survival of newly diagnosed patients with MM treated with conventional chemotherapy. The median survival duration has remained constant at 30 to 36 months. Once resistance to standard regimens has been established, salvage therapy results in responses of 20% to 40% but usually provides only short-term palliation with median survival of 3 to 12 months.^4-6 Primary refractory MM has a more favorable outcome than resistant relapse, with median survival duration ranging from 15 to 36 months.^21-23

Because of patient heterogeneity, it is difficult to compare directly the results observed in this trial of patients with refractory MM with other trials of conventional or high-dose therapy. However, the SWOG has completed a number of prior single-agent phase II trials in patients with refractory disease, including trials of alcacinomycin, prednisone, amonafide, diaziquone, bisantrene, pentostatin, VAD and VAD/verapamil, and carboplatin.^24-30 The median survival duration in these trials have ranged from 6 to 12 months. A recent phase II trial of topotecan in patients with primary resistant disease or relapse after a single prior chemotherapy regimen demonstrated a 16% response rate, with median PFS and OS durations of 13 months and 28 months, respectively.³¹

We report a multi-institutional cooperative group trial (SWOG) of high-dose therapy with autologous transplantation for refractory MM. Although this was a heavily pretreated group of patients with MM (84% underwent two prior chemotherapy regimens), 85% of the eligible patients completed transplantation. Although the majority of the patients had received extensive prior alkylating agents, only 3% of patients had inadequate hematopoietic stem-cell collections to preclude transplantation, substantiating the feasibility of this approach in this group of patients. For the 37 patients who received the HD-CTX on protocol, overall response and CR (22% and 8%, respectively) were similar to those reported by other investigators using similar HD-CTX regimens.^12,13,18 In contrast to published reports of salvage therapy responses in patients with refractory MM (eg, 20% to 40%), we observed an overall response of 65% to high-dose melphalan, including 16 CRs (30% of assessable patients); CRs with conventional salvage therapy are infrequently observed. Furthermore, the actuarial PFS and OS rates at 3 years were 25% and 31%, respectively, which is higher than anticipated in heavily pretreated, patients with refractory MM treated with conventional therapy. Nonhematologic toxicities were similar to those reported in other transplant trials.^12,13 Recent reports indicate that sufficient hematopoietic stem cells to support high-dose therapy can be generated with hematopoietic growth factors alone, thus eliminating the toxicity associated with HD-CTX.³² Therefore, in extensively pretreated patients, stem-cell mobilization with hematopoietic growth factors alone should be strongly considered.

The randomized French Myeloma Intergroup trial comparing high-dose therapy supported by autologous transplantation with conventional chemotherapy has demonstrated the superiority of high-dose therapy in newly diagnosed MM patients.¹⁴ A number of single-institution phase II trials have shown the feasibility, safety, and efficacy of high-dose therapy in heterogeneous populations of previously treated patients with MM: the majority of these clinical trials included small numbers of patients with primary refractory and/or resistant relapse, substantiating the concept that high-dose therapy can overcome innate (primary refractory disease) and acquired (relapsing disease) resistance.^{8-13,17,21-23} The largest single-institution trial of high-dose therapy with autologous hematopoietic stem-cell transplantation in refractory MM was reported by investigators at the University of Arkansas.¹² They reported on 135 patients with refractory disease who received intensive therapy. Melphalan 200 mg/m² with autologous transplantation markedly prolonged EFS and OS, especially among patients with resistant relapse compared with historical controls and patients treated with melphalan 100 mg/m². Longer EFS and OS durations were observed in patients with primary refractory MM compared with those with resistant relapse. They also demonstrated that further dose intensification to the point of tandem transplantation effected additional tumor cytoreduction and, hence, extended remission and survival duration. In contrast to the Arkansas study, in the current trial, no specific prognostic feature was identified as predictive of a favorable outcome.

A more recent analysis of 496 consecutive patients with MM enrolled onto tandem transplantation trials at the University of Arkansas included a group of patients with refractory disease. The 109 with primary refractory disease had superior EFS (23 v 14 months; P = .002) and OS (39 v 25 months; P = .008) compared with 69 patients with resistant relapse.¹⁷ This compared with a similar EFS (P = .2) but longer OS (52 v 39 months; P = .05) in 296 patients with sensitive MM than those with primary refractory disease. Using more stringent response criteria, the complete response rate in patients with primary refractory disease and refractory relapse were similar at 11% and 14%, respectively (compared with 48% with chemotherapy-sensitive disease). In a smaller study, the M.D. Anderson Cancer Center group's experience in refractory myeloma demonstrated that 70% of primary refractory patients (n = 27) who underwent autologous transplant within the first year from diagnosis responded to high-dose therapy (8% CR), with prolongation of OS from 37 to 83 months compared with primary refractory patients treated with conventional therapy (n = 60).²¹ However, primary refractory patients treated after 1 year had fewer responses (50% for 13 to 24 months; 25% for > 24 months) and shorter duration of PFS (60 months for < 1 year of resistance v < 6 months for > 1 year of resistance). A second study by the M.D. Anderson Cancer Center group that used triple–alkylating agent therapy included 23 patients with refractory myeloma.²³ Forty-eight percent responded; however, the PFS and OS duration was only 4 months after transplantation in the resistant-relapse group, similar to their previous observations with regimens of melphalan and total-body irradiation. Although direct comparison of these trials is not possible, the SWOG 8993 trial demonstrated superior response rate, PFS, and OS compared with these earlier trials. This may be a result of improved supportive care (peripheral-blood stem-cell transplants and hematopoietic growth factors) and a less toxic preparative regimen (melphalan 200 mg/m² v total-body irradiation– or triple alkylator–based regimens).

Despite high response rates with high-dose therapy supported with hematopoietic stem-cell transplantation in the current trial, median PFS and OS (11 months and 19 months, respectively, from first registration on an intent-to-treat basis) were relatively brief. These results are commensurate to the Arkansas data for tandem transplant. These short-lived responses probably reflect the inherent resistance in this heavily pretreated group of patients with refractory MM that can only transiently be controlled with one or two courses of high-dose therapy. Alternatively, because patients were eligible for peripheral stem-cell collection with 30% bone marrow plasmacytosis and for bone marrow collection for less than 30% bone marrow plasmacytosis, high tumor cell contamination may have contributed to disease relapse. Technologic advances with CD34⁺ cell selection techniques can produce a two- to four-log tumor cytoreduction in the autograft product, which may result in improved PFS and OS.^33-35

This is the first study of high-dose therapy with autologous transplantation in refractory MM to prove the feasibility of this approach in the cooperative group setting. This lead to the current S9321 trial in patients with newly diagnosed MM. This trial was initially designed as a randomized trial to compare standard therapy to high-dose therapy. However, once the French Myeloma Intergroup trial demonstrated the superiority of high-dose therapy over standard therapy, the S9321 trial was modified to randomize patients to early or late transplant. Although the response rates observed in the S8993 refractory MM trial seem to be an improvement compared with historical controls treated with conventional therapy, a randomized trial is necessary to determine if salvage treatment with high-dose therapy is indeed superior to conventional therapy. On the basis of the promising results observed in the present trial of patients with refractory MM, additional transplant trials in previously treated patients are in development within the cooperative groups. Future trials are anticipated to focus on tandem transplantation to optimize tumor cytoreduction, stem-cell selection techniques to reduce tumor cell contamination in autografts, and posttransplant immunotherapy to eradicate minimal residual disease.

	ACKNOWLEDGMENTS

 
Supported in part by Public Health Service Cooperative Agreement grants no. CA38926, CA32102, CA37981, CA58686, CA46282, CA35431, CA13612, CA35117, CA04919, CA22433, CA45377, CA32734, CA58416, CA46441, CA58658, CA04920, and CA58861 from the National Cancer Institute, Department of Health and Human Services.

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Submitted October 30, 1998; accepted February 26, 1999.

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