Leukemia (1997) 11, Suppl 5, S22-S26
`© 1997 Stockton Press All rights reserved 0887-6924/97 $12.00
`
`Oral idarubicin, dexamethasone and vincristine (VID) m the treatment of multiple
`myeloma
`A G lasmacher1, T H aferl ach2·3, M Gorsc h1Uter1, J M ezger 1·4
`R Klein schmidt1 and F G iese ler8
`
`, C Ma in tz5, M R Clemens6, Y Ko7, C Hahn1, R Obelacker8
`
`,
`
`'Medizinische Universitatsklinik und Poliklin ik, A llgemeine lnnere Medizin, University of Bonn; 2Abteilung fur Hamatologie und Onkologie,
`Zentrum fur /nnere Medizin, University of C6ttingen; 3Medizinische Universitats- und Poliklinik, University of Kiel; 4 Med1Z1n1sche Abtet!ung
`II St Vincentius-Kranken haus, Karlsruhe; 5Abteilung fur Hamatologie und Onkologie, St Antonius-Krankenhaus, Eschwet!er; 6Med1Z1n1sche
`Abteilung /, Mutterhaus der Borromaerinnen, Trier; 7 Medizin ische Universitatspoliklinik, Un iversity of Bonn; "Medizin ische
`Universitatspoliklinik, University of Wurzburg, Germany
`
`In order to replace the central venous line necessary for con(cid:173)
`tinuous infusion of vincristine and doxorubicin with high-dose
`dexamethasone (VAD) and to avoid hospitalization, we evalu(cid:173)
`ated the efficacy and toxicity of oral idarubicin, vincristine and
`dexamethasone (VID) in patients with multiple myeloma. Vincri(cid:173)
`stine (1 .6 mg/m2, max 2 mg) was given as a bolus injection on
`day 1. ldarubicin was given in capsules 1 O mg/m2/day for days
`1-4 with an intraindividual dose escalation, 40 mg dexame(cid:173)
`thasone were given on days 1-4, 9-12, 17-20. Treatment cycles
`were repeated every 28 days. At this interim analysis, 53
`patients have been entered into the ongoing trial ; 46 patients
`are evaluable for toxicity. The median age was 60 years
`(interquartile range, 52-65). 46% were primary or secondary
`refractory, 20% had previously been treated with VAD and 30%
`had previously untreated disease, 4% had two or more
`relapses. Four patients died within 2 months from entry and
`were considered as early deaths (8.7%). 45% of the 42 patients
`evaluable for efficacy achieved a partial remission and 26% a
`minor remission. The median reduction of the M-component
`was 43% (interquartile range, 25-64%). VID is an effective and
`convenient alternative to VAD even in relapsed or refractory
`patients.
`Keywords: multiple myeloma; idarubicin; oral application; VAD;
`VID ; therapeutic trial
`
`Introduction
`
`infusion of vi ncri stine and doxorubici n
`The co ntinuo us
`(ad ri amyc in) over 96 h combined w ith hi gh-dose oral
`dexameth asone (VA D) is an estab lished therapy fo r patients
`w ith re lapsed o r refracto ry multiple myeloma and may also
`be ad mini stered in hi gh risk patients as fi rst- line treatment. 1
`Th e rati ona le fo r the protracted ad mi nistration is based o n the
`lo ng generati o n time and the low growth frac ti o n of myeloma
`cell s in most patients. 2·3 As trea tment w ith melphalan severely
`im pa irs the mob ilizatio n of auto logous pe ri pheral stem cell s,4
`many pati ents are trea ted w ith VAD before high-dose chemo(cid:173)
`therapy. 5 The ad mini stratio n of VA D, howeve r, necess itates a
`ce ntral veno us catheter, w hi ch is complicated by in fecti on,
`th rom bosis and other prob lems in up to 24% of the cases. 6
`Therefore a cytotox ic agent w ith ora l ad mini stratio n
`is
`needed.
`ldarubi cin (4-demethoxy-daunorub icin) is an anthracycl ine
`w ith severa l properti es not seen in other substances of thi s
`gro up. 7
`8 Being highl y lipophilic it is the o nl y ora ll y absorbed
`•
`anthracycl ine. 9 Its main metabolite, idarubic inol, shows cyto(cid:173)
`tox icity co mpa rab le w ith the mother compou nd. 10 The ter(cid:173)
`minal half- li fe of idaru b icin is about 33 h and about 66 h for
`id arub icino l. 11 After o ral admi nistration of idarub icin the com-
`
`Correspondence: A Glasmacher, Med izinische Kl inik und Po liklini k,
`53 105 Bonn, Germany; Fax: 49 228 287 4466
`
`bi ned bioavai labi lity of idarubici n and idarubicinol is about
`4 1% .11 Furthermo re, it has been show n that the cytotox icity
`of idaru bicin is less infl uenced by P-glycoprote in-associated
`mu lti pl e drug res istance,12 it has a 20% higher DNA-binding
`than dauno ru bicin 13 and it is clearly less card iotoxic than
`doxoru bicin .14·15 Therefore, it seems feas ible and much more
`conven ien t for the pati ent to replace the continuous infusion
`of doxorubi cin through a centra l venous line by the oral
`admini stratio n of ida ru bicin .16 Such a new regimen wou ld be
`attractive even if its therapeutic efficacy is not superior to
`VA D.
`In thi s interim analys is we report on 46 patients w ith d iffer(cid:173)
`ent stages of mu ltip le myeloma treated with ora l idarubicin,
`dexamethasone and a bo lu s injection of vincri stine (VID).
`
`Patients and methods
`
`The study was des igned as a ph ase II stud y and approved by
`the appropri ate ethica l com mittees. Patients were included
`from 1 O participati ng centers when w ri tten informed consent
`was obtained. Fo r incl usio n of a pati ent the diagnosis of mul(cid:173)
`tip le myeloma had to be confirmed according to the British
`Co lu mbia Cancer Agency cri teria 17 and one of the criteria
`shown in Tab le 1 had to be ful fill ed . Patient accrua l is con(cid:173)
`tinued.
`Vincristine was adm inistered as an intravenous bolus injec(cid:173)
`tion on day 1 (1 .6 mg/m2, max 2 mg). ldarubici n (Zavedos;
`Pharmacia and Upjohn, Erl angen, Germany) was given as
`capsul e, 10 mg/m 2/day p.o., on days 1-4
`(tota l dose
`40 mg/m 2/course). If the leukocyte co unt at nad ir was above
`2.0 g/I and the p latelet count at nad ir above 75 g/I, the idarub(cid:173)
`icin dose cou ld be augmented by 1 mg/m 2/day each cycle to
`a maximum of 1 3 mg/m 2/day on days 1-4 (total dose
`52 mg/m2/course) after three courses of dose esca lati on. When
`leukocytes fe ll below 1 g/I or platelets below 50 g/I the last
`dose escalati on was reversed and no further dose esca lation
`was undertaken. Patients experi encing neutropeni a in the first
`course of therapy rece ived 8 mg/m 2/day on days 1-4 (total
`dose 36 mg/m 2/course). If neutropenia occurred at this dose
`level, the pati ent had
`to be w ithdrawn from the study.
`Dexamethasone was given 40 mg da il y p.o. on days 1-4, 9-
`12, 17-20. Cou rses were repea ted on day 29 for up to eight
`courses.
`Patients rece ived radiation to bone les ions if necessary.
`Pam idronate (90 mg) was given every 4 weeks and ranitidine
`(in some centers other Hrb locke rs) was admini stered together
`w ith dexamethasone. A complete blood count, paraprotein
`concentrations, creatinine and serum ca lciu m leve ls were
`assessed befo re each treatment course, bone lesions were
`exami ned every three courses o r immediately if there were
`signs of progression.
`
`DR. REDDY’S LABS., INC. EX. 1055 PAGE 1
`
`

`

`Table 1
`
`Inclusion criteria
`
`S23
`
`VID therapy in multiple myeloma
`A Glasmacher et al
`
`Previously untreated patients
`1 Patients with high-risk multiple myeloma in Durie- Salmon stage II or Ill (A/B) (eg with advanced osteolytic lesions or very high levels
`of M-component) who should be treated with VAD according to the institutions treatment guidelines.
`2 Patients with multiple myeloma in any stage scheduled to receive high-dose chemotherapy with stem cell reinfusion.
`
`Patients with relapsed or refractory disease.
`3 Patients with multiple myeloma in Durie-Salmon stage II or Ill (A/B) not responding to melphalan and prednisone standard-dose
`induction therapy (primary refractory)
`4 Patients with multiple myeloma in Durie- Salmon stage II or Il l (A/B) not responding to chemotherapy (either a repeated induction
`therapy or a different regimen) at relapse
`5 Patients with multiple myeloma in Durie-Salmon stage II or Ill (A/B) with two or more relapses
`6 Patients with multiple myeloma in Durie- Salmon stage II or Ill (A/B) previously treated with VAD
`
`The d isease stage was determined accord ing to Durie and
`Salmo n. 18 A compl ete remi ss ion w as defin ed as a respo nse to
`treatment w ith undetectabl e paraprotein by immun electro(cid:173)
`phores is w ithout hyperca lcemi a or progress io n of bo ne
`les ions. A parti al rem ission was assumed w hen the M-compo(cid:173)
`nent concentration was reduced to less th an 50% of the base
`line va lue in serum or to less than 10% of th e base lin e va lue
`in urine, in the case of li ght chain exc retio n onl y, w ith no
`evidence of progress ion of bo ne les ions (±25%) o r hyperca lce(cid:173)
`mi a. A min or remi ss io n w as assumed when the M-component
`co ncentration was reduced to 76-5 0% of the base line value
`in serum o r 10-5 1 % in urine and if there was no progression
`of bone les ions or hyperca lcemi a. A stab le di sease (no
`change) w as assumed wh en the M-component change w as
`±25% in serum or ±50% in urine with no change in bone
`les ions and no hyperca lcemi a. Progress ive di sease w as
`defined as an increase of more than 25% in M-component
`co ncentration in serum and mo re th an 50% urine o r a pro(cid:173)
`gress io n (> 25%) of bo ne les io ns. Response in no nsecreto ry
`myeloma was class ified according to the reductio n of bone
`marrow infi ltratio n by atypi ca l plasm a cell s (<5 0%: parti al
`remi ss io n, 26-5 0% mino r remission etc).
`M edi an and interquartile ranges o r 95 % co nfid ence inter(cid:173)
`va ls (95 % Cl) are given w here appropri ate. The survi va l analy(cid:173)
`sis was ca lcul ated accordin g to the method described by
`Kap lan and M eier.19 All computatio ns w ere performed w ith
`for the Soc ial Sciences
`(S PSS
`fur
`the Statisti ca l Package
`Windows, Rel 6. 1.2; Munich, Germany).
`
`Results
`
`Fifty-three pati ents have been entered into the stud y until June
`1997. Two pati ents were exc luded after registration: on e
`pati ent, w ho had already been treated with idarubi cin and
`dexamethasone; another pati ent was excluded sin ce she di ed
`after 2 days of chemotherapy in the first course fro m pneu(cid:173)
`the start of chemoth erapy. Fi ve
`moni a acquired before
`patients are not yet eva luabl e. Fo rty-si x patients are currentl y
`eva luable w ith respect to response and tox icity. Base line
`characteri sti cs of these pati ents are shown in Tabl e 2. Four
`pati ents (8.7%) di ed w ithin 2 months from entry into the
`study. Fo rty-two pati ents w ere eva luabl e for response. At this
`interim analys is, data of 206 treatment courses w ere eva luabl e
`(med ian four courses per patient, range 1-8).
`The overa ll rate of pa rti al remi ss io n w as 19/42 (45 .2%; 95%
`Cl 30-61 %) (Table 3). Patients achi eved maximal response
`after a medi an of fou r (3-6) courses. The medi an reductio n of
`M-co mponent con centration s w as 42 .8% (25-64%). Table 3
`
`Table 2
`entry
`
`Base line characteristi cs of eva luable patients at study
`
`Number of patients
`Male/female
`Age (years)
`Months from diagnosis to entry into study
`Disease status
`Primary refractory
`Secondary refractory
`More than one relapse
`Previous treatment with VAD
`Previously untreated
`High-risk myeloma
`Preparation for ASCT
`Highest Durie-Salmon stage at or prior
`to entry into the study
`IA
`llA
`ll lA
`1118
`M-component isotype
`lgG
`lg A
`Light chain
`Non-secretory
`
`46
`26/20
`60 (52- 65)
`17 (2-4 1)
`
`9
`12
`2
`9
`
`10
`4
`
`1
`9
`30
`6
`
`30
`13
`2
`1
`
`ASCT, autologous peripheral stem cell transplantation.
`
`the median M -compon ent
`
`shows the respo nse rates and
`reductio n rates for subgrou ps.
`Two patients di ed due to hematol og ica l compli cations . One
`pati ent (age 60 yea rs) succumbed to neutropeni c sepsis in the
`th erapy-related. He had
`first course whi ch w as clea rl y
`received intensive pre-treatment with 15 courses of melphalan
`before and had experi enced several neutropeni a episodes
`after th e admini stration of melphalan . Another pati ent (age 70
`years), also intensive ly pretreated with three lin es of therapy
`and severely th ro mbocytopeni c at entry into the study, died
`fro m intracerebral hemorrh age after the second course of VID
`whil e still thrombocytopeni c.
`The id arubi cin dose was esca lated in 15 pati ents. Two of
`the 27 oth er patients had a WHO grade IV leukocytopeni a
`(WBC < 1.0 g/I) and four patients a WH O grade Ill leukocyto(cid:173)
`peni a (WBC 1 .0-2 .0 g/I) after the first course and were there(cid:173)
`fore not eligibl e for dose esca lation . In th e other 21 patients
`a dose esca lati on w as not performed. O f the 1 5 pati ents with
`dose escalation, 11 have had at least four courses at thi s
`interim analysis and three (2 7%) of those pati ents did not
`reached th e hi ghest dose level due to hemato logica l toxicity,
`whereas eight pati ents escalated to the highest dose leve l
`(52 mg/m 2 per course) w ithout any hematologica l tox icity. No
`
`DR. REDDY’S LABS., INC. EX. 1055 PAGE 2
`
`

`

`S24
`
`Table 3
`
`Response rates and M-component reduction rates according to patient subgroups
`
`VID therapy in multiple myeloma
`A Glasmacher et al
`
`Subgroup
`(evaluable patients)
`
`All patients (n = 42)
`Primary refractory (n = 8)
`Secondary refractory (n = 11)
`Previous VAD (n = 9)
`;;.2 relapse (n = 2)
`De nova disease before ASCT (n = 4)
`De nova disease high-risk (n = 8)
`
`Partial
`remission
`(%)
`
`19 (45.2)
`4 (50 0)
`2 (18.2)
`4 (444)
`1
`2 (50 .0)
`6 (75 .0)
`
`Minor
`remission
`(%)
`
`11 (26.2)
`1 (12.5)
`4 (364)
`3 (333)
`
`2 (50.0)
`1 (12.5)
`
`No change
`(%)
`
`Progressive
`disease
`(%)
`
`M-component
`reduction
`(%)
`
`6 (14 .3)
`3 (37.5)
`1 (9.1)
`1 (111)
`
`0
`1 (12.5)
`
`6 (14.3)
`0
`(0)
`4 (364)
`1 ( 11 1)
`1
`0
`0
`
`42 .8 (25- 64)
`41 .7 (15-59)
`384 (0- 49)
`46.8 (27- 63)
`
`43 .9 (34- 55)
`70.1 (31 - 83)
`
`ASCT, autologous peripheral stem cell transplantation.
`
`influence of dose esca lation on the overa ll remission rate
`could be demonstrated (data not shown).
`Comp lete data to eva lu ate th e nadir was available for 146
`co urses. In all patients the perce ntage of co urses with WHO
`grade IV leukocytopenia (WBC < 1.0 g/I) was 9.6% and WHO
`grade Ill leukocytopenia (WBC 1 .0-2.0 g/I) was 13.7%.
`Clinica ll y rel evant ca rdiotoxi city was seen in one patient
`on ly who experienced moderate left ventricular fai lure (NYHA
`grade II) after 14 courses of VAD plu s four courses of VID and
`a cumulative dose of approximately 504 mg/m 2 doxorubicin
`and 184 mg/m 2 ora l id arubi cin. Treatment w as continu ed with
`dexamethasone and vin cristine on ly and the pati ent recovered
`from clini ca l symptoms.
`Th e surviva l from entry into the study is shown in Figure 1.
`As 75% of the patients have been observed for not more than
`210 days it is expected that the platea u in the survival curve
`will not persist w ith furth er fo ll ow-up.
`
`Discussion
`
`This study demonstrates that the combination of ora l idarub(cid:173)
`icin with an intravenou s bolu s inj ection of vincristine and oral
`hi gh-dose dexamethason e (VID)
`is active
`in previously
`untreated, rel apsed or refractory patients with multiple mye(cid:173)
`loma. Even 44% of patients who had been previous ly treated
`
`1.0~
`
`O>
`c:
`·5
`- ~
`::l en
`$
`c:
`
`Q) = ro a.. -0
`c:
`0 :e
`0 a.. e
`a..
`
`.8
`
`.6
`
`.4
`
`.2
`
`0.0
`0
`
`111 11 1111111 11
`
`1111
`
`100
`
`200
`
`300
`
`400
`
`500
`
`600
`
`Time from entry into study (days)
`
`Survival of 46 eva luable patients with multipl e myeloma
`Figure 1
`from entry into the study. The median tim e of observation was 162
`days (interqu artil e range, 109- 210).
`
`with VAD ach ieved a partial remiss ion. Overall, the hemato(cid:173)
`log ica l and nonhematolog ica l toxicity was low, but patients
`with a significantly dec reased bone marrow fun ction (mostly
`after prolon ged treatment with melph alan) are at risk for sev(cid:173)
`ere hematological toxicity and related in fectious events.
`Th e introduction of the VAD regimen by Barlogie, Smith
`and A lexani an in 1984 1 was a major advance in the therapy of
`multipl e myelom a. Later, these investigators and severa l other
`gro ups have reported larger non-randomized tri als with ident(cid:173)
`therapy. 5 ·6 •20 - 22
`forms of this combination
`ica l or hyb rid
`from 41 % partial and comp lete
`Response
`rates va ri ed
`remi ss ions in prev iously untreated patients receiving three
`courses in preparation for hi gh-dose chemotherapy and auto(cid:173)
`logous stem -ce ll reinfus ion 5 to 84% after six courses in pre(cid:173)
`vious ly untreated pati ents. 6 In pati ents with refractory disease
`22 Relapsed
`respo nse rates of about 40% were reported .20
`-
`patients achieved response in about 60%. 6 However, con(cid:173)
`siderable inconvenience and a 24% complication rate is asso(cid:173)
`ciated with the centra l venous line th at is necessa ry for the
`co ntinuous infusion of vincristine and doxorubicin. 6
`In a recent study patients were asked for their cho ices of
`pal li ative chemotherapy in a scenari o-based questionnaire. 23
`N inety-two out of 103 patients cl ea rly preferred an oral app li(cid:173)
`cation of chemotherapy to an intravenous (bolus) chemo(cid:173)
`therapy if efficacy was not compromised. The eva lu ation of
`less demanding app lication s for palliative chemotherapy
`seems therefore an important goal.
`A few sma ll er studies have prev ious ly demonstrated activity
`of oral idarubicin in multipl e myeloma. 24
`- 26 The pharmaco(cid:173)
`kinetic properties of id arubi cin make it possible to devise a
`regimen that cou ld replace the continuous infu sion of doxo(cid:173)
`rubi cin by an oral administration of idarubicin for severa l
`days. The first larger study of such a comb in ation chemo(cid:173)
`therapy, the Z-Dex regimen, was reported by Cook et a/16
`from the Glasgow Roya l In firma ry. In the latest upd ate of that
`study, 32 patients received ora l idarubicin (10 mg/m 2/day for
`4 days) and dexa methasone (40 mg/day, three blocks of 4
`days in the first course and days 1-4 on ly in subsequent
`courses).27 This treatment w as repeated every 3 weeks for four
`courses. Thereafter the pati ents proceeded to mobilization of
`peripheral blood stem cells with o ne of four different regi(cid:173)
`mens. In this group of mostl y untreated pati ents an overa ll
`response rate of 75% was reached. Stem ce ll mobilization was
`satisfactory in 30 patients.2 7
`The overa ll response rate in previously untreated patients
`in the Z-Dex study was 92% (22/24; 95 % Cl : 79-99%), which
`compares favorab ly with the 62% response rate (8/13; 95 %
`Cl : 32-86%) in our VID study. This may be due to variation
`by chance but there are some remarkab le differences between
`
`DR. REDDY’S LABS., INC. EX. 1055 PAGE 3
`
`

`

`S25
`
`the two studi es that shou ld be considered. First, all patients
`in the Z-Dex study w ere selected for high-dose chemotherapy
`and autologous stem-ce ll transpl antation, whereas in our
`study on ly four patients were considered for thi s therapeutic
`intensi fication wh ich may have resulted in the se lection of
`better risk patients in the Z-Dex study. Second, the duration
`of the treatment courses was 21 days in the Z-Dex and 28
`days in the VID study, so that the dose intensity of idarubicin
`was 33% higher in the Z-Dex study. Furthermore, the admini(cid:173)
`stration of dexa methasone was different and vin cri sti ne was
`not used in the Z-Dex tri al. However, the respon se and toxi(cid:173)
`city rates in our study compa re well with those reported by
`Barlogie et al.5
`With regard to refractory patients the VID regimen resu lted
`in response rates that do not differ from those reported for
`VAD. 20
`22 Surprisingly, however, patients previously treated
`-
`w ith VAD responded to VID therapy in 44%. Simil ar results
`have been recently reported by G i /es et al, 28 who used oral
`lom ustine (CCNU),
`idarubicin and dexamethasone. This
`beneficial effect could be due to a superior cytotox ic action
`of oral idarubicin in compa rison to doxorubi cin as has been
`suggested by in vitro studies. 29 Further investigation in this
`patient subgroup seems warranted.
`On ly 14% of pati ents treated in this trial were progressive
`despite VID therapy. Four of the six patients w ere secondary
`refractory and three of six had received dexameth asone before
`VID . Four of these patients died from disease progress ion.
`The majority of patients in the VID tri al did not experience
`any major side-effects. However, co nsiderabl e hematotoxicity
`and two treatment-re lated deaths occurred in intensively pre(cid:173)
`treated patients with a reduced bone marrow function. These
`patients, especiall y when pretreated with larger doses of mel(cid:173)
`phalan, should not receive fu ll dose VID. Therapeuti c options
`for these patients are dose reductions in the first course (eg
`8 mg/m 2/day id arubi cin for 3 to 4 days) with subsequent adap(cid:173)
`in pati ents with
`tation to the hemato logica l response or -
`severe cytopeni a at entry
`-
`treatment with high-dose
`dexamethasone only shou ld be cons idered. 30
`In summary, this phase 1-11
`trial demonstrates that VID
`therapy - without the necessity for a centra l venous line -
`effectively indu ces responses in previously untreated, relapsed
`and refractory patients with multipl e mye/oma. VID therapy
`ca n easil y be administered on an outpatient basis and toxicity
`was acceptable.
`
`Acknowledgements
`
`Thi s study was supported by Leukamie-lnitiative Bonn e.V.
`Furthermore, we thank Prof Dr T Sauerbruch , Bonn, and Priv(cid:173)
`Doz Dr I Schmidt-Wolf for their review of the manuscript, as
`well as Dr R Deri chs, DUsseldorf, and Dr B Meuter, Tri er, for
`inclusion of patients and documentation of results.
`
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