`
`Contribution of Prednisone to the Effectiveness of Hexamethylmelamine
`In Multiple Myeloma‘v2
`
`'Martin M. Oken,* Raymond E. Lenhard, Jr, Anastasios A. Tsiatis, John H. Glick,
`and Murray N. $ilverstein2
`
`I The Eastern Cooperative Oncology Group evaluated hexamethylmelamine in 89 patients
`. With advanced refractory or relapsing multiple myeloma. Hexamethylmelamine was initially
`used as a single agent administered orally at 200 mg/mz/day for the first 3 weeks of each 4-
`week cycle. When this regimen proved to be ineffective. it was modified first by increasing
`~ the dose of hexamethylmelamine to 280 mg/mZ/day and subsequently by adding prednisone
`at 75 mg for the first 7 days of each 28-day cycle. None of the 39 patients receiving hexa-
`methylmelamine without prednisone had an objective response, while two patients had mini-
`mal objective improvement (25%—50% decrease in M protein with symptomatic improvement).
`Only 14% of these patients had objective or symptomatic response or both. In contrast,
`patients treated with hexamethylmelamine plus prednisone had a 22% objective response
`rate, with another 14% showing lesser degrees of objective improvement. Fifty-one percent of
`the patients treated with this regimen had either objective or symptomatic improvement or
`both. Severe (grade 3) toxicity was seen in nearly two-thirds of the patients on the higher-
`dose hexamethylmelamine regimens compared with 37% of the patients receiving low-dose
`hexamethylmelamine; however, in most instances this represented rapidly reversible cytope-
`nias. Because all but one of the patients responding to hexamethylmelamine plus prednisone
`had experienced previous treatment failure on regimens containing prednisone in similar
`dose and schedules, it is unlikely that the responses are due to prednisone alone. Instead, this
`study suggests that the activity of hexamethylmelamine in multiple myeloma is dependent on
`the concomitant administration of prednlsone and that the combination regimen appears to
`be synergistic.
`[Cancer Treat Rep 71:807-811, 1987]
`
`Only a limited number of drugs have proven effec—
`tiveness in chemotherapy for multiple myeloma. This
`represents a major obstacle to the treatment of refrac—
`tory myeloma and to the improvement of primary treat-
`ment of this disease. The Eastern Cooperative Oncology
`Group (ECOG) conducted a study of hexamethylmela-
`mine in the treatment of advanced refractory or relaps-
`ing multiple myeloma (EST-3477). This agent was se-
`
`in part. because of its demonstrated
`lected for study.
`activity in alkylating agent—resistant lymphomas (1—5).
`Although hexamethylmelamine is structurally related
`to triethylenemelamine, it does not appear to function as
`an alkylating agent (4—6). Thus,
`it represents a new
`class of drugs with potential for the treatment of multi-
`ple myeloma.
`In this study hexamethylmelamine was initially used
`
`
`dence. RI (CA-15947); Case Western Reserve University. Cleveland, OH
`IReceived Sept 19, 1986; revised May 20, 1987; accepted May 28.
`(CA—14548): Chicago Medical School, IL (CA-14144): Hahnemann Medi-
`1987.
`cal College, Philadelphia. PA (CA—13611): Harbor General Hospital,
`2This study was conducted by the Eastern Cooperative Oncology
`Torrance. CA (CA-21091): Medical College of Ohio, Toledo; New York
`Group (Paul P. Carbom'. chairman. CA‘21115) and supported by Public
`University Medical Center. New York (CA-16395): Northwestern Uni-
`Health Service grants (CA) from the National Cancer Institute. National
`versity Medical Center. Chicago. IL (CA-17145); Our Lady of Lourdes
`Institutes of Health, Department of Health and Human Services. The
`Hospital, Binghamton. NY: Pennsylvania Hospital. Philadelphia (CA-
`following members participated in the study: University of Minnesota.
`13613); University of Pittsburgh. PA (CA-18653); University of Roches-
`Minneapolis (M. M. Oken. CA-20365): The Johns Hopkins Oncology Cen»
`ter Cancer Center. NY (CA-11083); Rush-Presbyterian-St. Luke’s Medi-
`ter. Baltimore. MD (R. E. Lenhard, Jr, CA—16116): Dana-Farber Cancer
`cal Center, Chicago. IL (CA-25988): Tufts University, Walpole, MA
`Institute. Harvard School of Public Health, Boston, MA (A. A. Tsiatz's,
`(CA<07190): Natalie Warren Bryant Cancer Center. Tulsa, OK; and
`CA-23318); Hospital of the University of Pennsylvania, Philadelphia
`Wisconsin Clinical Cancer Center. Madison (CA-21076).
`(.1. H. Glick. CA-15488); and Mayo Clinic, Rochester, MN (M. N. Silver-
`*chrint requests to: Martin Oken. MD, Department of Medicine.
`stein. CA-13650). Other participating institutions include: Albany Medi-
`Veterans Administration Medical Center, 54th Street and 48th Ave S.
`cal College, NY (CA-06594): Albert Einstein College of Medicine. Bronx.
`Minneapolis. MN 55417.
`NY (CA-14958); American Oncologic Hospital, Philadelphia, PA (CA-
`18281); Brown University and Roger Williams General Hospital, Provi-
`
`Cancer Treatment Reports Vol. 71. No. 9. September 1987
`
`807
`
`ALVOGEN, Exh. 1048, p. 0001
`
`ALVOGEN, Exh. 1048, p. 0001
`
`

`

`as a single agent administered at 200 mg/mz/day for the
`first 3 weeks of each 4-week cycle. When only marginal
`activity of this regimen was demonstrated despite the
`report of convincing efficacy of another regimen which
`employed hexamethylmelamine at a higher dose with
`prednisone (7), the treatment schedule was amended,
`first by increasing the dose of hexamethylmelamine and
`subsequently by adding prednisone.
`
`Treatment was suspended for wbc count < 2000/mm3
`or platelet count < 50,000/mm3 and not resumed until
`recovery above these levels occurred. Treatment was
`reduced by 50% for moderate neurotoxicity or sustained
`nausea and vomiting and was discontinued for severe
`neurotoxicity or intractable vomiting.
`
`RESULTS
`
`METHODS
`
`Patients with an established diagnosis of multiple
`myeloma supported by the demonstration of a focal or
`generalized increase in plasma cells in the bone marrow
`and a monoclonal protein in the serum or urine, who
`were refractory to or relapsing from prior standard
`chemotherapy, were potentially eligible for this study.
`Other eligibility requirements included no antitumor
`chemotherapy for at least 4 weeks prior to study; ade
`quate bone marrow, renal, and liver functions; and wbc
`count > 2000/mm3, platelet count > 50,000/mm3, creati-
`nine < 2.0 mg/dl, and bilirubin < 1.5 mg/dl with no
`active liver disease.
`
`Response was evaluated according to both objective
`and symptomatic criteria. A 50% decrease in serum M
`protein or a 90% decrease in 24—hour urine light-chain
`excretion in patients lacking serum M protein consti-
`tuted an objective response. A 25%—49% decrease in
`serum myeloma protein or a 50%—90% decrease in
`24-hour light—chain excretion in patients lacking serum
`myeloma protein was rated as objective improvement
`only if it was associated with a sustained symptomatic
`improvement. Symptomatic response required an un-
`equivocal improvement in bone pain or improvement in
`performance status from chronically bedridden to am-
`bulatory. This improvement must persist 4 weeks and
`not be attributable to supportive care. Toxicity was
`evaluated by ECOG standardized criteria (8).
`Response rates between treatment regimens were sta-
`tistically compared using Fisher’s exact test (two-sided).
`Response curves were generated using the method of
`Kaplan and Meier and compared using the log-rank
`test.
`
`Initially, hexamethylmelamine was administered as a
`single agent at 200 mg/mz/day orally on Days 1—21 of
`each 28-day cycle (Regimen H). Subsequently, the regi-
`men was modified by increasing the dose of hexa—
`methylmelamine to 280 mg/mZ/day orally on Days 1—21
`and pyridoxine at 100 mg orally three times a day was
`added (Regimen HP). The final modification (Regimen
`HPP) consisted of Regimen HP with the addition of
`prednisone at 75 mg orally on Days 1—7 for each 28-day
`cycle. Patients were treated to relapse or disease pro—
`gression unless unacceptable toxicity or patient refusal
`caused earlier cessation of therapy. For the second and
`all subsequent treatment cycles the hexamethylmela-
`mine dose was reduced by 25% if the wbc count was <
`4000/mm3 or the platelet count was < 100,000/mm3 or
`by 50% if the who count was < 3000/mm3 or the platelet
`count was < 75,000/mm3.
`
`808
`
`Of the 89 patients entered in this study, 80 were eval-
`uable (table 1). Three patients were removed from study
`before starting therapy, while two others were ineligi-
`ble because of platelet counts < 50,000/mm3 at the time
`of entry. Four other patients were inevaluable because
`of major protocol violations. Five of the 80 evaluable
`patients could be evaluated for toxicity, survival, and
`symptomatic response but not for objective response
`because of the lack or inadequate follow-up of measur-
`able disease. Patients were evaluable for symptomatic
`response only if they entered the study with marked
`bone pain or impaired performance status (bedridden).
`Therefore, 11 asymptomatic patients were excluded
`from this analysis. Sixty-five patients were evaluable
`for both objective and symptomatic response. The three
`patients who died during the first 30 days in the study
`were considered evaluable and counted as nonrespond~
`ers. They included one patient treated with each regi-
`men.
`
`The patients treated on the three regimens are com-
`parable with regard to age, extent of disease (9), num-
`ber of prior treatment regimens, and prior response to
`therapy (table 1). Patients receiving the HP regimen
`included a greater proportion of women, whites, and
`patients with severe anemia. The severity and manifes-
`tations of skeletal disease were comparable on the three
`regimens except that no patient treated with the HP
`regimen was hypercalcemic prior to entry.
`No patient receiving hexamethylmelamine without
`prednisone had an objective response (table 2), and only
`two had objective improvement. In contrast, eight pa—
`tients who received the prednisone-containing HPP
`regimen had objective response and five additional
`patients in this group showed objective improvement.
`The overall objective response or improvement rate of
`36% for the HPP regimen is superior to the 5% response
`rates in the H and HP regimens (P = 0.001). One patient
`who responded to the HPP regimen had steroid psychosis
`and received no further prednisone after the second
`cycle of chemotherapy. He had a 5-month objective re-
`sponse and was successfully reinduced to a second objec-
`tive response on hexamethylmelamine alone. Examina-
`tion of the 13 patients responding to HPP reveals that
`12 of them had had prior treatment failure on regimens
`containing prednisone in doses and schedules similar to
`the prednisone used in this protocol: 75 mg/day on
`Days 1—7. In their treatment immediately preceding en-
`try in this study, five of the responding patients on the
`HPP regimen had received regimens containing pred-
`nisone at 60 mg X 4—7 days each cycle, four received
`prednisone at 120 mg X 4 days each cycle, one re-
`
`.
`,
`
`Cancer Treatment Reports
`
`ALVOGEN, Exh. 1048, p. 0002
`
`
`
`ALVOGEN, Exh. 1048, p. 0002
`
`

`

`
`
`TABLE 1.—Patient characteristics
`
`Regimen
`
`
`Characteristic
`H
`HP
`HPP
`Total
`
`
`33
`32
`30
`29
`
`15
`15
`13
`10
`
`41
`40
`37
`36
`
`89
`87
`80
`75
`
`64.0 (50—84)
`23“ l
`
`60.8 (45—82)
`15%
`
`63.0 (38—83)
`19%
`
`47%
`53%
`
`23%
`77%
`
`46%
`54%
`
`No. of patients—
`Entered
`Eligible
`Total evaluable
`Evaluable for objective response
`Pretreatment data“
`Average age in yrs (range)
`Patients > 70 yrs
`Sex
`
`MF
`
`Estimated tumor burden
`Low
`Intermediate
`High
`Severe anemia (Hgb < 8 g/dl)
`Moderate to severe bone pain
`Extensive skeletal disease
`Hypercalcemia
`Prior treatment
`70%
`62%
`67%
`2 2 regimens
`22%
`23%
`20%
`Primary refractory (no prior response)
`
`* 80 evaluable patients.
`
`7%
`17%
`76%
`37%
`67%
`63%
`13%
`
`8%
`23%
`69%
`62%
`54%
`62%
`0%
`
`8%
`14%
`78%
`35%
`59%
`62%
`14%
`
`ceived prednisone at 90 mg X 5 days each cycle, one
`received 75 mg X 7 days each cycle, and one received
`continuous prednisone at 30 mg/day for 3 months. These
`12 patients all had progressive disease on their pred—
`nisone-containing regimens from 1 to 4 months prior to
`entry in this study (median, 2.0 months). One of the re—
`sponding patients had received no prior corticosteroid
`therapy. It is possible that this patient’s 1-month objec—
`tive improvement was due to the prednisone alone. Ten
`of the responding patients had received two or more
`prior regimens. The three other patients were unrespon-
`sive to their only prior treatment which consisted of
`high-dose intermittent melphalan and prednisone (two
`patients) or the M2 protocol (one patient).
`Symptomatic responses followed the same pattern as
`objective responses. Sixteen percent of the evaluable
`patients receiving hexamethylmelamine without pred—
`nisone had improvement of symptoms compared with
`50% of patients receiving the HPP regimen (P = 0.004).
`Clinical benefit in the form of objective response, objec-
`
`TABLE 2.—Response to therapy*
`Regimen
`
`
`H
`HP
`HPP
`
`
`Evaluable
`Objective response
`Objective improvement with
`symptomatic response
`
`28 (97) 9 (90)No response 23 (64)
`
`36
`8 (22)
`5 (14)
`
`10
`0
`l (10)
`
`
`
`29
`0
`1 (3)
`
`
`
`*Values : No. of patients (%).
`
`Vol. 71, No. 9, September 1987
`
`tive improvement, or symptomatic response was ob-
`tained in 13% of the patients treated with Regimen H,
`15% of the patients treated with Regimen HP, and 51%
`of the patients treated with Regimen HPP. The median
`duration of objective response is 5 months, including
`three response durations of 15, 17, and 30+ months. The
`median duration of objective response and objective
`improvement is 4 months (range, 1—34). Symptomatic
`improvement lasted > 1 year in seven patients, of whom
`five were receiving Regimen HPP.
`The median survival of all evaluable patients was
`9.6 months. The survival of the 80 patients by regi-
`men is shown in figure 1. There are no significant dif-
`ferences when these curves are analyzed by log-rank
`test (P : 0.32). Furthermore, these data do not suggest
`that the addition of prednisone enhanced survival. The
`1-year survival rate of the 25 patients with objective or
`symptomatic response was 76%. Their median survival
`was 19.5 months. The median survival of the eight
`patients with objective response was 17.9 months.
`Severe toxicity (grade 3 or more) was seen in 37% of
`the patients with Regimen H compared with 69% and
`62%, respectively, on patients treated with Regimens
`HP and HPP (table 3). The latter two regimens contain
`hexamethylmelamine at a 40% higher dose. Severe de-
`pression of the leukocyte or platelet count was two to
`three times more likely to occur on the high-dose hexa-
`methylmelamine regimens as on the lower dose. A
`somewhat higher incidence of infection was seen on the
`HPP regimen; however, only 11% of patients had severe
`infections. Severe hemorrhage occurred in two patients,
`both receiving HPP. Nausea and vomiting was seen in
`809
`
`ALVOGEN, Exh. 1048, p. 0003
`
`
`
`ALVOGEN, Exh. 1048, p. 0003
`
`

`

`
`
`Length of Survival
`
`
`
`10
`
`20
`
`30
`
`4O
`
`50
`
`Months
`
`3‘
`Ea!
`
`DOhn
`
`.
`
`
`Treatment
`H
`------ HP
`
`HPP
`
`Allve
`0
`0
`4
`
`Deed Total Median
`30
`30
`5.4
`13
`13
`1 1.3
`33
`37
`1 1.9
`
`FIGURE 1.—0verail survival probability for all evaluable patients from start of chemo-
`therapy.
`
`about one-half of the patients and was severe in about
`10%. Severe peripheral neuropathy was rarely encoun-
`tered, but mild peripheral neuropathy was seen, par-
`ticularly in patients receiving Regimen HPP, perhaps
`because this regimen has more responders who there-
`fore received the treatment for a longer period of time.
`Nearly 25% of the patients experienced some CNS symp-
`toms in the form of dizziness, tremor, or depression.
`There was no suggestion of decreased neurotoxicity in
`the two pyridoxine-containing regimens.
`
`DISCUSSION
`
`This study demonstrates that hexamethylmelamine
`has minimal activity in the treatment of multiple mye-
`loma when used as a single agent. However, when hexa-
`methylmelamine is combined with prednisone in an
`intermittent dose schedule, objective response or im-
`provement may be obtained in one-third of the patients
`and symptomatic responses obtained in one-half. This
`finding confirms the report of Cohen and Bartolucci (10)
`
`TABLE 3.—Toxicity*
`
`Regimen
`
`
`
`H (n z 30)
`HP (11, : 13)
`HPP (n : 37)
`
`Grades
`Grades
`Grades
`Grades
`Grades
`Grades
`Toxic effect
`1—2
`3—5
`1—2
`3—5
`1—2
`3—5
`
`
`50%
`30%
`27%
`7%
`37%
`
`37%
`10%
`10%
`7%
`10%
`
`31%
`31%
`23%
`0%
`38%
`
`Maximum toxicity
`Leukopenia
`Thrombocytopenia
`Infection
`Nausea and vomiting
`Neurotoxicity
`0%
`32%
`0%
`15%
`3%
`3%
`Peripheral neuropathy
`11%
`16%
`0%
`23%
`3%
`17%
`CNS
`
`
`
`
`
`
`0% 0% 0% 0% 11%Corticosteroids 3%
`
`69%
`31%
`23%
`15%
`15%
`
`32%
`57%
`30%
`14%
`46%
`
`62%
`30%
`24%
`11%
`11%
`
`*n : No. of patients. Toxicity grade: 0 : none; 1 : mild; 2 2 moderate; 3 2 severe; 4
`life-threatening; and 5 = lethal. Myelotoxicity: wbc count (cells/mmfl—O = 2 4500,
`1
`3000—4499. 2 : 2000—2999, 3 = 1000—1999. and 4 : < 1000; platelet count (cells/mm3)—O
`2 130.000. 1 : 90000—129999, 3 = 50000—89399. and 4 : < 50,000.
`
`810
`
`Ca ncer Treatment Reports
`
`ALVOGEN, Exh. 1048, p. 0004
`
`ALVOGEN, Exh. 1048, p. 0004
`
`

`

`
`
`appears to be dependent on the concomitant administra-
`tion of corticosteroids.
`
`REFERENCES
`1.
`
`(1, combined with their experience, represents the
`ults of > 100 patients treated with essentially the
`me hexamethylmelamine plus prednisone regimen.
`Before one can consider this as evidence of a synergis—
`antitumor effect of prednisone with hexamethylmela-
`ine, the alternate proposition that some of the re-
`nses could have been caused by prednisone alone
`ust be considered. Objective and symptomatic re-
`ponses have been reported with higher and more fre-
`uent doses of prednisone in patients with no prior cor-
`‘icosteroid therapy (11) and in patients who had received
`rior corticosteroids in standard dosage (12). Frequent
`ourses of highvdose dexamethasone can also produce
`responses in refractory myeloma (13). In each of these
`regimens, unlike the present study, corticosteroids were
`given to patients either for the first time or in regimens
`'with marked intensification of dosage and frequency of
`‘drug administration. In the present series all but one of
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`Therefore,
`it
`is unlikely that the responses to hexa—
`methylmelamine plus prednisone are due to prednisone
`alone. These data suggest that prednisone augments the
`‘ effectiveness of hexamethylmelamine in multiple my-
`eloma. There is precedence for this apparent synergy of
`corticosteroids with other agents in the treatment of
`multiple myeloma. A randomized study demonstrated
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`melphalan therapy doubled the response rate in pre-
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`is important to recognize that drugs such as doxorubi-
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`Vol, 71, No. 9. September 1987
`
`811
`
`ALVOGEN, Exh. 1048, p. 0005
`
`
`
`ALVOGEN, Exh. 1048, p. 0005
`
`