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S a lv a g e T h er a py w it h T h a lidom ide in P a t ien t s w it h Re la ps e d or Re f r a ct or y M u lt iple M y e lom a Do Yeun Kim, M.D.1, Seock- Ah Im, M.D.1, Chu- Myong Seong, M.D.1, Soon Nam Lee, M.D.1, Soo- Mee Bang, M.D.2, Jae Hoon Lee, M.D.2, Sung- Soo Yoon, M.D.3, Byoung Kook Kim, M.D.3, Seon Yang Park, M.D.3 and Myung- Ju Ahn, M.D.4 D e p ar t m e nt of I n t e rn al M e d icine 1, E w ha W om ans U niv e r s it y C olle g e of M e d icine , D e p ar t m e nt of I n t e rn al M e d icine 2, Gachon M e d ical C e nt e r , D e p art m e nt of I nt e rn al M e d icine 3, S e ou l N at ional U niv e r s it y C olle g e of M e d icin e , and D e p ar t m e n t of I nt e r nal M e d icine 4, H any an g U n iv e rs it y C olle g e of M e d icine , S e ou l, K ore a B a c k g ro un d : The re are few therape utic op-
Re s u lts : The se rum or urine levels of pa -
tions for patie nts with multiple mye loma who raprotein were reduced by a t le ast 90 pe rcent relapse after autologous or a llogeneic ste m cell in two patients , a t lea st 50 perce nt in three patients , and at lea st 25 perce nt in two pa- fractory to conventiona l chemothe rapy a nd not tients; for a total res ponse rate of 25 pe rcent.
e ligible for s alvage high- dos e the rapy. Tha lido- 13 patients had sta ble dis eas e and 8 patients mide, a potent antiangiogenic agent, has bee n had progres se d. At lea st ha lf of the patie nts s ugge ste d as an effective sa lva ge thera py in refra ctory multiple myeloma. The aim of this tigue . More severe advers e effects were in- Co nc lus io n : This study confirms that tha-
lidomide is an effective and safe agent in pa- Me t h o d : From February 2001 to September
tients with relapsed or refractory multiple mye- loma. (Korean J Hematol 2002;38:259 included. At sta rt of treatment, all patie nts ha d Ke y Words : Thalidomide, Multiple myeloma
a ctive dise as e and 17 (61%) had received at le as t one autologous trans pla ntation.
r elaps e r ate r emains hig h in all patient s , s o the dis eas e Recently, it has been r eport ed t hat ang iog enes is is v as cular endothelial g row t h fact or (VEGF ) and bas ic chem other apy to hig h- dos e chemotherapy follow ed by peripheral s tem cell or bone m arrow t rans plantation.1) ant i- ang iog enic dr ug plays the treat ment for my eloma.
T halidom ide is a glutam ic acid deriva tive that dis appoint ing . M elphalan bas ed high dos e chemot herapy s how s a potent a ntiangiogenic activity.7,8) Als o, this drug has been found as im munom odulatory proper- ties and an effective inhibitor of T NF - alpha.9) Re- cognition of its a nti- a ngiog enic effect led to its evalua tion in the treatm ent of various m alignancies , Correspondence : Soon Nam Lee M.D., Department of Interna w here angiogenes is has been s how n to play an Do Ye un Kim : Thalidomide in Multiple Mye loma In 1999, Singhal et al. reported the overall respons e lines). T he previous therapy included either single (N= rate of 32% of thalidomide in 84 heavily pre- treated 15) or double (N=2) autologous trans plantation. T here w as 1 patient who received autologous transplant and after then allogeneic trans plant due to diseas e progres- confirmed by numerous studies.11 13) We report the sion. Disease status at study entry w as evaluated w ith res ults of a retrospective study of the 28 Korean res pect to the last line of treatment the patient had patients from 4 centers with refractory or relaps ed received before thalidomide therapy; 23 patients (82%) w ere class ified as relapsed and 5 patients (8%) as re- Complete respons e was defined as lack of detectabl M- component in serum and/ or urine. Partial and minor Between February 2001 and September 2002, 28 res ponses w ere defined as 50% and 25% M- component patients from 4 centers w ere enrolled. Patients' charac reduction in serum and/or urine, respectively. Patients teristics at the onset of thalidomide treatment ar w ith a reduction of les s than 25 percent without ev presented in table 1. T he median age was 54 years dence of additional myeloma- related complications w er considered to no res ponse. Patients w ere cons idered in 93% w ere s tage III. T he median time from diagnosis to thalidomide therapy w as 31 months. Prior to thalido res ponse or stable disease. In patients with a res ponse, mide therapy, 10 patients had been treated with con- an increase in serum or urine paraprotein levels b ventional chemotherapy alone (1 4 lines, median 2 more than 25 percent above the nadir value w as con Participating centers were asked to provide detaile information about the occurrence of side effect, their onset date, duration and intensity and about the tha lidomide dose modifications which w ere due to thes side effect. We confirmed these contents by telephone Overall survival (OS) w as defined as the time elapse form onset of thalidomide to death whatever the caus Dis ea se s tatus at the ons et of thalidomide of death. Event free survival (EFS) was defined as th time elaps ed from the onset of thalidomide to pro gres sion, s top medication of thalidomide for any rea son, death from any cause, or the last follow - up visit, w hichever occurred first. Dis tributions over time w er estimated by Kaplan- Meier analysis.
months (range; 3.6 15.4). T hirteen patients had sta- ble disease. Eight patients progressed.
Distribution of the maximum tolerated dose of tha summarized in T able 2. T w o patients(7%) achieved a lidomide is show n in Fig. 1. T hree patients w ho stop- complete response. Partial response was observed in 3 ped thalidomide medication due to WHO grade patients (11%) and there w as minimal response in 2 toxic effects w ere not cons idered. T hirteen patient patients (7%). T hus, the overall response rate was (52%) took the 200mg dose. No patients did not take 25%. T he hemoglobin levels and platelet count were dose of thalidomide up to 800mg. WHO grade improved in 2 patients among responders.
effects such as skin ras h, paresthes ia and constipation One patient of complete responder w as relapsed afte prompted dose reduction in 3 patients. As shown in w ithdraw al of thalidomide due to grade 3 skin rash T able 3, constipation (68%) and lethargy (54%) w ere One patient who show ed minimal response w as relapse the most frequent adverse events . No thalidomide- after self w ithdraw al of thalidomide. T he median inter related mortality w as noted and most of toxicities we val betw een ons et of thalidomide and the firs t decreas grade 1 or 2. Neurologic toxicity such as dizziness, of M- protein by at least 25% w as 1.7 months (range; tingling sensation was obs erved in 4 patients . Nin 1.9). T he median response duration w as 7.7 patients experienced skin rash, in three cases treatmen 3. Event free survival and overall survival T he median follow- up duration from the start o thalidomide treatment w as 5.8 months . T w enty tw patients are still alive and followed up as outpatien T he median EFS was 4 months (Fig. 2). T he median time to OS had not been reached. After 12 months follow- up, 58 percent of patients w ere alive (Fig. 3).
Fig. 1. Dis tribution of the ma ximum tole ra te d dose of tha-
Do Ye un Kim : Thalidomide in Multiple Mye loma anti- multiple myeloma cells effect. T he median time to res ponse w as rapid similar to other study. Even though we did not observe bone marrow angiogenesis after thalidomide, there were no statistically significant in pos ttreatment microvessel dens ity.10) From these tw o points of observations, possible other mechanis ms of thalidomide except angiogenesis are immunomodulary agents such as potent inhibitor of T - cell proliferation15) and secretion of interferon- In addition, it may modulates the expression of cell surface adhesion molecules16) that allow myeloma cells Fig. 2. Kaplan- Meier es timate of event fre e s urviva l.
to interact with the bone marrow microenvironment.
So it may be action of mechanis m to myeloma cells w hich complex effects on tumor angiogenesis, the immune system, and various cytokines and adhesion molecules. By searching the more detailed mechanis ms of action of thalidomide to plas ma cells , it w ill contribute to new insight into tumor biology and T he optimal dose of thalidomide remains to be determined. Barlogie et al. concluded that there is a dose- response relationship betw een tumor cell reduc tion and a cumulative dose of thalidomide.17) In con- trast, other studies achieved comparable results using much low er dose of the drug.18,19) Also, in our study, median dos e betw een responder and nonresponder w as not different. T his means for some subset of patients Fig. 3. Kaplan- Meier es timate of overall survival.
dose de- es calation may be necessary w ithout sufferin toxicities. T his iss ue must be solved w ith the detaile mechanis m of action of thalidomide to myeloma.
T he overall response rate in most studies so fa While conventional therapies have become inef reported averages approximately 30%.11 13) T he re- fective in patients w ith refractory myeloma, thalidomid sponse rate with 25% of this s tudy is s lightly belo given substantial respons e. We observed tha compared to other studies. We can' t assure that rel- angiogenesis is increased in myeloma.6) Antiangiogenic atively low dose of thalidomide in our patients ma therapy represents a novel and pos sibly less tox contribute, though the dose- response relation is not T his study confirms an antitumor activity of thalid T he predictive factors which indicators are associate mide to advanced multiple myeloma. Since almost al response of thalidomide to myeloma patient available therapy for relapse had failed in most of thes remains to be unsolved. Barlogie et al have reported patients, the respons es observed are impres sive.
that normal cytogenetic, low plasma cell labeling index thalidomide.17) Dose res ponse effect w as apparent in labeling index. Meanwhile, intergroupe francophone du myeloma (IFM) defined poor risk features s uch as IgA level < 3g/ dL for myeloma patients with treatment of thalidomide.20) We had limitation for analyze about this As many other reports, constipation was the mos common side effect. Almost of the toxicities were mil and eas ily manageable w ithout drug- related mortality T he incidence of skin rash w as slightly more commo compared to other study. T he s ide effect was dos e dependent. Reducing the dose of thalidomide alleviated the effects in 3 patients. One patient, who developed grade 3 skin rash during dose up to 600mg, stopped taking thalidomide for 1 month, and then restarted 1) Alex anian R, Dim opoulos M : T he tre at m e nt of m ul- w ithout skin rash. Side effect such as deep vein tiple m y elom a. N E ng l J M ed 330:484- 489, 1994 thrombosis w as not noted. Hematologic toxicity w as no 2) Bar log ie B : A d vances in the rapy of m ultiple m ye - remarkable. Recent report about the adverse effect o thalidomide in advanced myeloma concluded that safet of higher dose (800 mg/ day) of thalidomide given over F uzibet JG, Ros s i JF , Cas as s us P, Mais onneuve H, a long period(> 15 months).21) All the adverse effects s pectiv e , random iz e d trial of autolog ous bone m ar- did not warrant decreas e or termination of therapy, and row t rans plantation and che m othe rapy in m ult iple then tolerance developed to sedation, cons tipation, and m y elom a. N E ng l J M e d 335:91- 99, 1996 skin les ion later. But the patients in our study tolerated 4) Vacca A, Ribatti D, Roncali L, S erio G, S ilves t ris poorly to dose escalation schedule. We ass ume that prog re ss ion in m ultiple m ye lom a. B r J H ae m atol there are possible pharmacodynamic differencies o Overally thalidomide w as an effective and s afe drug Recently, thalidomide in combination with other drugs is investigated actively.22,23) Also the role as remission 6) P ark SY, Im S A, Nam EM, Kim DY, Choi YA, Lee induction or maintenance therapy still need to be deter and inte rle uk in- 6 in m ultiple m ye lom a. K orean J 7) D' Amato RJ, Loughnan MS , F ly nn E, F olkaman J : T halidom ide is an inhibitor of ang iog enes is . P roc N atl A cad S ci U S A 91:4082- 4085, 1994 8) Bauer KS, Dix on S C, F ig g W D : I nhibitor of ang io- g e ne sis by thalidom ide re quires m e tabolic act iva- Do Ye un Kim : Thalidomide in Multiple Mye loma s pe cie s - de pend ent . B ioche m nopharm acolog y 31:213- 221, 1996 17) Bar log ie B, Des ikan R, Eddlem on P , Spencer T , Zeldis J, Muns hi N, Badr os A, Zang ari M, Anais s ie E, Eps tein J, Shaug hnes s y J, Ayer s D, S poon D, phocyt e, prefere ntially inducing proliferation, cy to- T ricot G : E xte nde d s urv ival in advance d and re - fractory m ultiple m ye lom a afte r sing le- ag e nt tha- subs e t. J E xp M e d 187:1885- 1892, 1998 lidom ide : I de ntificat ion of prog nos tic factors in a 10) S ing hal S , Mehta J, Des ikan R, Ayer s D, Robers on phas e 2 st udy of 169 patie nts . B lood 98:492- 494, P , Eddlemon P, Muns hi N, Anais s ie E, W ils on C, Dhodapkar M, Zeddis J, Bar log ie B : A ntit um or acti- 18) P ini M, Baraldi A, Pietr as anta D, Allione B, Depaoli v ity of thalidom ide in re fractory m ultiple m y elom a L, S alvi F : L ow dos e t halidom ide in the tre at m e nt N E ng l J M e d 341:1565- 1571, 1999 of re fractory m ye lom a. H em at olog ica 85: 1111- 1112, lidom ide in m ult iple m ye lom a. Cancer T re at R ev e ffe ct ive in m ultiple m ye lom a. L ance t 354:925, 1999 20) Yakoub- Ag ha I, Attal M, Dumontet C, Delannoy V, 12) Rajkumar S V, F ons eca R, Dis penzier e A, Lacy MQ, Berthou C, Lam y T , Durv aus V, Monconduit M, Lus t JA, W itzig T E, Kyle RA, Gert z MA, Gr eipp Dug uet C, Duhamel A, F acon T : T halidom ide in P R : T halidom ide in the tre at m e nt of re lapse d m ul- patie nts with advanced m ultiple m ye lom a: A s tudy t iple m ye lom a. M ayo Clin P roc 75:897- 902, 2000 of 83 patie nts - report of the inte rg roupe francophone 13) Julius s on G, Cels ing F , T ur es s on I : F re quent g ood du m ye lom a (I F M ) . H e m atolog y J 3:185- 192, 2002 partial re m is sions from thalidom id e includ ing be st 21) Grov er JK, Uppal G, Raina V: T he adv ers e e ffe ct of re spons e ev er in patie nts with adv ance d re fractory t halidom ide in re lapse d and refractory patie nts of and re lapse d m ye lom a. B r J H em at ol 109:89- 96, m ultiple m ye lom a. A nn Oncol 13:1636- 1640, 2002 22) Rajkumar S V, Hayman S, Ger tz MA, Dis penzier i A, 14) S am paio EP, S arno EN, Galilly R, Cohn ZA, Kaplan Lacy MQ, Gr eipp PR, Geyer S , It ur ria N, F ons eca G : T halid om ide se le ctive ly inhibits tum or ne cros is fact or alpha product ion by st im ulate d hum an m ono- cyt es . J E xp M e d 173:699- 670, 1991 ne wly diag nose d m ye lom a. J Clin Oncol 20:4319- 15) McHug h S M, Rifkin IR, Deig hton J, W ils on AB, Lopez C, Gonzalez M, S an Mig uel JF : T he com - he lpe r ce ll t ype 2 ( T h2) and concom it ant ly inhibit s bination of t halidom ide , cyclophos pham ide and de - T h1 cyt ok ine production in m itog e n- and antig en- xam e thasone (T haCyD e x) is fe asible and can be an s tim ulat ed hum an pe riphe ral blood m ononuclear cell culture s. Clin E xp I m m unol 99:160- 167, 1995 16) Geit z H, Handt S, Zw ing enberg er K : T halidom ide m olecule s inv olve d in the adhe sion cas cad e. I m m u-

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