Investigational New Drugs 20: 117–121, 2002.
`© 2002 Kluwer Academic Publishers. Printed in the Netherlands.
`
`117
`
`The evaluation of gemcitabine in resistant or relapsing multiple myeloma,
`phase II: a Southwest Oncology Group study
`
`James K. Weick1, John J. Crowley2, Mohamed A. Hussein3, Dennis F. Moore4 and Bart
`Barlogie5
`1Hematology Oncology Associates, Lake Worth, FL; 2Southwest Oncology Group Statistical Center, Seattle, WA;
`3Cleveland Clinic Foundation, Cleveland, OH; 4Wichita Community Clinical Oncology Program, Wichita, KS;
`5University of Arkansas for Medical Science, Little Rock, AR, USA
`
`Key words: gemcitabine, multiple myeloma, phase II
`
`Summary
`
`Gemcitabine is a cytosine arabinoside (Ara-C) analog with activity in many human tumor systems. We evaluated
`the drug’s activity in resistant or relapsing multiple myeloma. Gemcitabine 1000 mg/m2 was administered as a 30
`minute infusion on days 1, 8, and 15 of a 28-day cycle. No dose escalations were permitted and dose reductions
`were scheduled for hematologic toxicity. Twenty-nine eligible patients were entered into Southwest Oncology
`Group (SWOG)-9803. One patient received no treatment and 5 patients had inadequate response assessments. The
`major toxicity was hematologic with grade 3/4 neutropenia in 9 and grade 3/4 thrombocytopenia in 15 patients. No
`responses were seen. Stable disease was confirmed in sixteen patients (57%). Median survival was eight months.
`Gemcitabine as utilized in this trial has shown little activity and is not to be strongly considered for future multiple
`myeloma trials.
`
`Introduction
`
`Multiple myeloma accounts for approximately 10 per-
`cent of all hematologic malignancies and 1 percent
`of all malignancies [1–3]. Despite the emergence of
`data supporting aggressive therapies of multiple my-
`eloma with chemotherapy including high-dose treat-
`ments with stem cell support, most patients ultimately
`become resistant to this therapy and/or relapse after
`treatments [4]. Response rates to second and sub-
`sequent chemotherapy regimens have been reported,
`but new drugs are certainly needed [5–7].
`Gemcitabine is a fluorine-substituted Ara-C ana-
`log, which requires intracellular phosphorylation to
`the active form of the drug. Nucleoside kinases meta-
`bolize gemcitabine intracellularly to active diphos-
`phate and triphosphate nucleosides. The resultant di-
`phosphate inhibits ribonucleoside reductase which is
`responsible for generating deoxynucleoside triphos-
`phates for DNA synthesis. Further, a reduced concen-
`
`tration of dCTP enhances the incorporation of gem-
`citabine triphosphate into DNA (self potentiation) and
`DNA polymerase is unable to repair growing DNA
`strands (masked chain termination) [8]. It is likely that
`gemcitabine also induces apoptosis in certain tumor
`targets [9]. In experimental antitumor models,
`this
`agent has a much broader spectrum of activity against
`solid tumors than does Ara-C, encouraging further
`drug development [10–11]. Phase I trials found a max-
`imum tolerated dose (MTD) to be between 790 and
`1,370 mg/m2 per week with bone marrow suppression
`being the dose-limiting toxicity [12]. Antitumor activ-
`ity was found in a variety of solid tumors, including
`pancreas, lung, ovary, bladder, breast, head and neck,
`Hodgkin’s, and cutaneous T-cell lymphoma [13–20].
`In these early Phase II trials, there was minimal
`toxicity when the starting dose was between 800 and
`1,250 mg/m2 [21–22]. Grade 4 neutropenia occurred
`in only 6 percent of patients and grade 3 neutropenia
`in 19 percent of patients.
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`118
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`Similarly, thrombocytopenia was noted only occa-
`sionally. Mild liver abnormalities and nausea/vomiting
`occurred in two-thirds of patients, but was never a
`reason for discontinuation of therapies. Mild protein-
`uria and hematuria developed in approximately 50
`percent of patients, but was clinically insignificant. A
`few cases of renal failure of undetermined etiology
`were reported as were 4 cases of hemolytic-uremic
`syndrome. Less often seen were flu-like symptoms,
`peripheral edema, and dyspnea as well as alopecia,
`diarrhea, constipation, somnolence, and oral toxicit-
`ies. When tried in multiple myeloma, small trials
`of gemcitabine utilized doses of 800 mg/m2 over 30
`minutes and revealed little activity [M. Voi, personal
`communication]. Conversely, the suggested Phase II
`doses of 1,250 mg/m2 are probably excessive for
`multiple myeloma patients with prior chemotherapy
`regimens and thus the lower starting dose for the fol-
`lowing study, 1000 mg/m2 days 1, 8, and 15, every 28
`days. Despite the demonstrated activity in a number of
`solid tumors and because lower doses were ineffective
`in multiple myeloma, the Southwest Oncology Group
`undertook the study #S9803 in an attempt to reevaluate
`the activity of this agent at an increased dose. Patients
`were accrued on this study between August 1998 and
`March 2000. Patient accrual ceased in April of 1999,
`for review of the data and the study was permanently
`closed in March 2000.
`
`Patients and methods
`
`Patients with all stages of proven multiple myeloma
`(stages I, II, and III at the time of diagnosis) were eli-
`gible. Protein criteria were present and patients with
`no quantifiable monoclonal proteins were ineligible.
`Patients must have received at least one prior regi-
`men for multiple myeloma including chemotherapy,
`bone marrow transplant, biologic therapy, and/or ra-
`diation therapy. Patients must have shown indicators
`of disease progression.
`Additional eligibility requirements included a pre-
`treatment granulocyte count of equal to or greater than
`1500/microliter, normal platelet count, and creatinine
`and bilirubin levels within institutional normal lim-
`its. If prior radiation therapy were delivered, at least
`21 days must have elapsed since completion of this
`treatment. Performance status of SWOG 0–2 criteria
`were required. No concomitant radiation therapy, hor-
`monal therapy, or other chemotherapy was permitted
`and patients with prior malignancy, except adequately
`
`treated skin cancer or any other cancer from which
`the patient had been disease-free for five years were
`excluded. Pregnant or nursing women were ineligible
`and persons of reproductive potential may not have
`participated unless an effective contraceptive method
`was approved.
`The objective of the trial was to evaluate the con-
`firmed response rates in patients with myeloma as well
`as to evaluate quantitative and qualitative toxicities of
`gemcitabine in a Phase II Study. Pretreatment determ-
`inations and laboratory determinations included CBC,
`serum chemistries, total serum protein electrophoresis
`as well as urine protein and electrophoresis, a bone
`marrow specimen, and a skeletal survey.
`Gemcitabine was administered at a starting dose
`of 1,000 mg/m2 intravenously over 30 minutes on
`days 1, 8, and 15 of a 28-day cycle. Complete blood
`counts and toxicity notations were performed weekly
`and doses were adjusted for subsequent treatments.
`No dose escalations were permitted and dose re-
`ductions were accomplished for hematologic toxicity
`as follows: For an absolute neutrophil count (ANC)
`greater than 1 × 109/L and platelets over 100 × 109/L,
`100 percent of the dose was given; for an ANC of
`0.5–1.0 × 109/L and/or platelets of 50–100 × 109/L,
`a 75 percent dose was permitted, and for values under
`these minimums, the drug was omitted. Similarly, full-
`dose chemotherapy was given for non-hematologic
`toxicities of NCI grade 0–2, whereas 50 percent of
`the dose was given for grade 3 toxicities, and the
`drug was omitted for grade 4 toxicities. Courses were
`repeated every four weeks for an ANC greater than
`1.5 × 109/L, platelets greater than 100 × 109/L and
`non-hematologic toxicity improved to grade 0–1. If
`these parameters were not met and if treatment were
`delayed more than three weeks from the planned date
`of re-treatment,
`the patient was removed from the
`study.
`Responses were determined after 3 courses (12
`weeks) of therapy. The Southwest Oncology Group
`(SWOG) follows one set of criteria for both Phase II
`and Phase III myeloma studies: Remission is defined
`as a 50% or greater reduction in serum myeloma pro-
`duction for Phase II studies and further characterized
`as complete and partial remissions for Phase III stud-
`ies. Stable disease is anything less than a 50 percent
`reduction in the protein determination. Progressive
`disease is defined by an increase of more than 100
`percent of the lowest level of protein production seen.
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`Table 1. Patient characteristics
`
`Characteristic
`
`Median
`
`Minimum
`
`Maximum
`
`Age
`Hemoglobin
`Platelets × 109/L
`B2M (17 patients)
`% plasma cells
`M-component
`
`68.0
`9.6
`1.59
`13.6
`41
`3.1
`
`45.0
`6.0
`1.05
`0.5
`13
`1.6
`
`81.0
`12.0
`3.09
`29.8
`95
`7.1
`
`Table 2. Toxicity
`
`Toxicity
`
`Anemia
`Granulocytopenia
`Thrombocytopenia
`Fatigue/malaise
`
`0
`
`5
`14
`7
`7
`
`1
`
`3
`1
`0
`8
`
`2
`
`7
`4
`6
`8
`
`3
`
`10
`6
`14
`5
`
`4
`
`3
`3
`1
`0
`
`5
`
`0
`0
`0
`0
`
`Results
`
`A total of 30 patients from 22 institutions were re-
`gistered to SWOG-9803 between August 15, 1998
`and March 27, 2000. Twenty-nine patients were eli-
`gible and one patient received no treatment. All 28
`patients are evaluable for toxicity, although 5 patients
`had inadequate response assessment (considered to be
`nonresponders). Patient characteristics are listed in
`Table 1: The median age of registrants was 68 years
`(range 45 to 81). 16 males and 12 females are rep-
`resented with 22 white non-Hispanics and 4 black
`non-Hispanics, 1 Hispanic, and 1 Asian or Pacific
`Islander. At the time of this report, no patients are
`receiving protocol treatments and are off protocol for
`the following reasons: Toxicity was responsible in 5
`patients, refusals unrelated to toxicity in 3 patients,
`progression in 11 patients, death in 3 patients, and
`not specified in 6 patients. No major protocol de-
`viations were discovered. Hematologic toxicity was
`dose-limiting. Table 2 lists toxicities and shows grade
`3 and 4 neutropenia in 9 cases, grade 3 and 4 throm-
`bocytopenia in 15 patients, and anemia of grade 3 or
`4 severity in 13 patients. Fatal toxicity was seen in
`1 patient with grade 3–4 neutropenia, 1 patient with
`renal failure, and in a third patient with respiratory
`infection with grade 3–4 neutropenia. The only recur-
`ring non-hematologic toxicity was that of fatigue or
`malaise seen in 21 patients (grade 1–3).
`
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`
`No responses of greater than 50% reduction were
`seen in the study. Stable disease was determined in 16
`patients (57 percent), increasing disease in 6 patients
`(21 percent), early death in 1 patient (4 percent), and
`inadequate assessment in 5 other patients (18 percent),
`for a total of 28 patients. Patients considered to have
`stable disease were treated from a minimum of 1 dose
`of gemcitabine to a maximum of 14 doses before ther-
`apies were discontinued. In this “stable” population, 4
`persons had reductions in myeloma proteins of 10%,
`17%, 21%, and 31 percent. Twelve patients had an
`increase in protein of less than 100% required to fulfill
`the criteria of progression; these increases average 25
`percent (range 3–75%).
`Figure 1 details the survival patterns, showing me-
`dian of 8 months; to date 18 deaths have occurred in
`the 28-patient population.
`
`Discussion
`
`That the patients entered into this chemotherapy trial
`had received an average number of prior therapies with
`2.5 different regimens (range 1–9) speaks to the de-
`sirability and necessity of new treatment programs.
`Comparisons of combination chemotherapy programs
`for initial and re-treatment therapies have consistently
`demonstrated response rates of 50 to 60 percent with
`no significant differences in overall survival ascribed
`to one best schema [23]. Studies continue to show
`excellent response of myeloma patients treated with
`either autografting or allografting, but neither of these
`modalities are curative. Obstacles to better results have
`included toxicities to grafting procedures (allograft)
`contaminating tumor cells (autograft), and persistent
`residual disease (allografting and autografting). Major
`efforts are being undertaken by laboratories to date to
`improve the outcome using immune-based strategies.
`New agents are continually being investigated for
`the treatment of resistant or recurrent myeloma. Topo-
`tecan was the most recent candidate drug investigated
`by SWOG and the first reported instance of topoi-
`somerase activity in multiple myeloma [7]. Our cur-
`rent attempts using conventional doses of chemother-
`apy as salvage therapy utilize DCEP (dexamethasone,
`cyclophosphamide, etoposide, and cisplatin) with or
`without thalidomide in a Phase III trial.
`The observation that anti-angiogenesis may be
`seen in human tumors and that anti-angiogenesis
`therapy is effective therapy in both murine models
`and human tumors has been well-demonstrated [24].
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`120
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`Figure 1. Overall survival
`
`Thalidomide responses were seen in 32% of patients
`with advanced refractory myeloma [25].
`Additional treatment options being investigated
`today include Phase II trials of arsenic trioxide,
`suramin, tyrosine kinase inhibitors, and farnesyl trans-
`ferase inhibitors [26,27]. The initial reports of tri-
`als with these biologic response modifiers are en-
`couraging and results of Phase II trials are eagerly
`anticipated.
`The reports of efficacy of gemcitabine, an analog
`of cytarabine, in solid tumors and hematologic malig-
`nancies was the impetus for the current clinical trial
`in plasmacytic myeloma. Recent reports of response
`in refractory Hodgkin’s disease (39%) and cutaneous
`T-cell lymphoma (69%) contribute to the anticipated
`benefits. Unfortunately,
`the results of single agent
`gemcitabine from this SWOG trial are disappointing.
`It is possible that the dose of 1000 mg/m2/wk was
`insufficient to achieve the desired biological effect.
`Higher doses of 1250 mg/m2 are common in solid
`tumor studies, but the heavy pre-treatment and the in-
`trinsic marrow abnormalities suggested that the lesser
`dose be chosen. Minor responses in four evaluable
`patients confirm the activity of this agent in myel-
`oma, but the data does not support the inclusion of
`gemcitabine in future myeloma trials.
`
`Acknowledgements
`
`This investigation was supported in part by the fol-
`lowing PHS Cooperative Agreement grant numbers
`awarded by the National Cancer Institute, DHHS:
`
`CA38926, CA32102, CA04919, CA35431, CA37981,
`CA13612, CA45450, CA35178, CA58416, CA35176,
`CA52386, CA58861, CA14028, CA42777, CA68183,
`CA35261, CA35262, CA12644, CA27057, CA35281,
`CA46113, CA35128, CA58415, and supported in part
`by Eli Lilly and Company.
`
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`Address for offprints: Southwest Oncology Group (SWOG-9803),
`Operations Office, 14980 Omicron Drive, San Antonio, TX 78245-
`3217, USA
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