Intravenous melphalan, thalidomideand prednisone in refractory and relapsedmultiple myeloma

Recent progress in the treatment of multiplemyeloma (MM) has stemmed from the introduct-ion of agents that hit multiple pathways of themalignant plasma cells and their cross talk with themarrow microenvironment (l). Several clinical trialsare currently investigating the use of these drugs incombination, rather than as single agents, toidentify and take advantage of their best molecularsynergism.Single agent thalidomide initially showed po-

tent activity in refractory myeloma with responsesup to 30% (2, 3). Thalidomide was shown to actin synergy with dexamethasone in preclinicalstudies (4) and their combination induced partial

responses (PRs) up to 41% and 55% with medianprogression free survival (PFS) of 1 yr inadvanced MM patients (5, 6). Thalidomide com-bined with chemotherapy including doxorubicininduced PRs in 32% of refractory patients eventhough significant cardiac toxicity was reported(7). The combination of thalidomide with cyclo-phosphamide induced a response rate of 68%,including a complete remission (CR) rate of 4%,with median event free survival of 11 months (8).The promising results obtained with thalidomide,alone or in combination, as salvage therapyformed the rational for its use in untreated MM(9–12).

Palumbo A, Avonto I, Bruno B, Ambrosini MT, Bringhen S, Cavallo F,Falco P, Boccadoro M. Intravenous melphalan, thalidomide andprednisone in refractory and relapsed multiple myeloma.

Abstract: Objectives: Thalidomide combined with conventional chem-otherapies including oral melphalan shows significant anti-myelomaactivity. To address this issue, feasibility and efficacy of a three drugcombination consisting of intravenous (i.v.) melphalan, thalidomide andprednisone [M(i.v.)PT] was evaluated in advanced myeloma patients.Patients and methods: Twenty-four advanced myeloma patients weretreated with multiple cycles of a regimen consisting of low dose i.v.melphalan (20 mg/m2) at d 1, thalidomide at the dose of 50–100 mg/dgiven continuously and oral prednisone at the planned dose of 50 mg/devery other day. Intravenous melphalan was administered every fourthmonth. Median time from diagnosis was 40 months (range: 8–144 months). Fifteen patients (66%) had previously been treated with acombination of thalidomide and dexamethasone or with thalidomidealone. Results: Overall, on an intent-to treat basis, 14 patientsresponded: three achieved near complete remission (nCR), sevenachieved partial response (PR), four minimal response (MR). Six pa-tients showed stable disease (SD) and four-disease progression. Inter-estingly, of five patients who had previously progressed while onthalidomide and prednisone, one reached nCR, two PR and one MR.After a median follow up of 14 months, median progression free sur-vival was 9 months. Response duration was longer than that induced bythe previous line of treatment in eight patients (33%). Thalidomide-associated toxicity mainly consisted of constipation, tingling and seda-tion. Conclusions: M(i.v.)PT is an effective regimen, which can over-come resistance to thalidomide plus prednisone in advanced myelomawith acceptable toxicity.

Antonio Palumbo, Ilaria Avonto,Benedetto Bruno, Maria TeresaAmbrosini, Sara Bringhen, FedericaCavallo, Patrizia Falco, MarioBoccadoroDivisione di Ematologia dell'Universit� di Torino,Azienda Ospedaliera S. Giovanni Battista, OspedaleMolinette, Torino, Italy

Key words: intravenous melphalan; thalidomide;prednisone; advanced myeloma

Correspondence: Mario Boccadoro, Divisione diEmatologia dell'Universit� di Torino, AziendaOspedaliera S. Giovanni Battista, Ospedale Molinette,Torino, ItalyTel: +0039-011-6635814Fax: +0039-011-6963737e-mail: mario.boccadoro@unito.it

Accepted for publication 4 November 2005

Eur J Haematol 2006: 76: 273–277doi:10.1111/j.1600-0609.2005.00610.xAll rights reserved

� 2006 The AuthorsJournal compilation � 2006 Blackwell Munksgaard

EUROPEAN JOURNAL OF HAEMATOLOGY

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The combination of thalidomide with melphalanis currently being explored. Continuous adminis-tration of oral melphalan is common and practical.However, the gastrointestinal absorption is variableand thrombocytopenia is inevitable with prolongedadministration. The combination of intravenous(i.v.) melphalan with thalidomide and corticoster-oids allows for a less frequent administration, thusreducing its haematologic toxicities. Moreover thiscombination may exert additive or synergisticeffects. We recently implemented a three drugregimen with oral thalidomide and prednisonecombined with single infusions of low dose mel-phalan every four month [M(i.v.)PT]. This regimenwas effective and well tolerated in heavily pretreat-ed patients.

Materials and methods

Patients

Between April 2002 and January 2005, 24 consecu-tive patients with refractory or relapsed MM wereenrolled on the study. The Durie and Salmonstaging system was used (13). Patient characteristicsare illustrated in Table 1. At diagnosis, 16 patients(66%) were treated with i.v. melphalan and autol-ogous haematopoietic cell transplantation. Sevenpatients were conditioned to transplant with highdose melphalan (140–200 mg/m2), nine withreduced doses (60–100 mg/m2) because of ageand/or medical conditions. The remaining eightpatients (34%) were treated with conventional oralmelphalan and prednisone. At study entry, median

time from diagnosis was 40 months (range: 8–144 months) and median number of prior therapylines was three (range: 2–6). Pretreatment work upincluded routine complete blood counts, renal andliver function tests, serum and urine myelomaparaproteins, and bone marrow aspirates. Inclusioncriteria included relapsed or refractory myeloma,measurable disease, Karnofsky performance status‡60, platelet count ‡75 000/lL before enrolment,creatinine clearence ‡20 mL/min. Patients with‡grade 2 peripheral neuropathy were not eligible.

Treatment plan

Low dose thalidomide was administered at dailydoses of 50–100 mg. Oral prednisone was admin-istered orally every other day with doses rangingfrom 12.5 to 50 mg as tolerated by patients.Intravenous melphalan was administered at thedose of 20 mg/m2 every forth month. No antico-agulant prophylaxis was used.

Response criteria

Response to therapy was evaluated according toEBMT criteria by Blade et al. (14). Briefly, CR wasdefined as the disappearance of the monoclonalparaprotein from blood and urine by immunofix-ation, less than 5% marrow plasma cells and noincrease in size or number of osteolytic lesions.Near complete remission (nCR) required the dis-appearance of the monoclonal paraprotein bystandard electrophoresis with positive immunofix-ation studies. Partial response was defined as ‡50%reduction in the level of serum paraprotein, reduc-tion in 24 h Bence Jones protein excretion of atleast 90%, no increase in size or number of ostelyticlesions. Minimal response required all of thefollowing criteria: ‡25% or <50% reduction inserum paraprotein, if present, a 50–89% reductionin Bence Jones protein excretion, no increase in sizeor number of bone lesions. Progressive disease (PD)was defined as reappearance of any detectableparaprotein by immunofixation, by standard elec-trophoresis, or an increase in size or number ofbone lesions, or as >25% increases in the para-paraprotein level or Bence Jones protein, >25%increase in marrow plasma cells. Stable disease(SD) defined patients who did not meet criteria forminimal response (MR) or PD.

Statistical analysis

The Kaplan–Meier method was used to estimatedisease-free and overall survival (OS), which werecalculated from the beginning of treatment withM(i.v.)PT (15).

Table 1. Patient characteristics

Patients 24

Male 14 (58%)Female 10 (42%)Age (yr) 64Durie–Salmon stage at diagnosis

IIA 8 (33)IIIA 14 (60)B 2 (9)

IsotypeIgG 16 (67%)IgA 5 (21%)BJ 2 (8)Plasmacell leukemia 1 (4%)

B2 microglobulin at diagnosis£ 3 mg/L 6 (25%)>3 £ 5 mg/L 4 (17%)>5 mg/L 11 (46%)n.v. 3 (12)

Resistant relapse 4 (17)Untreated relapse 20 (83)Median number of prior therapy lines 3 (2–6)Median time from diagnosis to M(i.v.)PT (months) 40 (range: 8–144)Prior high therapy with PBSC rescue 16 (66)

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Results

Treatment and response

As of June 30, 2005, a total of 50 M(i.v.)PT courseswere administered. Five patients received fourcourses each, four patients three courses, threepatients two courses and 12 patients one course ofM(i.v.)PT.All patients were evaluable for response. Disease

response is illustrated in Table 2. Briefly, threepatients (12%) obtained nCR, seven patients (29%)PR, four patients (17%) MR. Four patients (17%)showed NC in disease status, and six patients(25%) showed PD. Maximal response was achievedafter a median of one M(i.v.)PT course (range: 1–4). In eight responsive patients (34%) responseduration was almost 4 months longer than thatobtained with the previous line of treatment. Nocorrelation between response duration and max-imal response after M(i.v.)PT was observed. In the16 patients who previously underwent autologoustransplantation, 3 (19%) reached nCR, 4 (24%) RPand 3 (19%) MR. Interestingly, of five patients whohad previously progressed while on thalidomideand prednisone, one reached nCR, two PR and oneMR. Median PFS and median OS from the start ofM(i.v.)PT was 9 months (Fig. 1) and 14 months(Fig. 2), respectively. After a median of 14 months(range: 3–41), four patients (17%) were alive inremission, nine patients (37%) relapsed and 11patients (46%) died from disease progression.

Toxicity

Adverse events were graded according to thecommon toxicity criteria (16). Toxicity in term ofbone marrow is illustrated in Table 3. Medianduration of neutropenia was 4 d, median durationof trombocytopenia (<75 000/ll) was 6 d. Patientsrequired a median of one platelet transfusion andtwo blood transfusions.Constipation was relatively frequent (26%

grades 1–2, 4% grade 3), but well controlled with

laxative. Grades 1–2 tingling and numbness werereported in 21% of patients, and 17% complainedof grades 1–2 sedation. Grade 3 neuralgia wasexperienced in 8% of patients, grades 2 and 3vertigo was observed in 8% and 4% of patients,respectively. One patient experienced cardiac fail-ure and another one deep-venous thrombosis thatrequired M(i.v.)PT discontinuation.

Infectious toxicity consisted of pneumonia in twopatients who discontinued treatment. Three addi-tional patients (13%) showed grades 1–2 infectioustoxicity which did not require dose reduction and/or discontinuation.

Overall, thalidomide was discontinued in eightpatients (33%) mainly for tingling and numbness,vertigo, sedation and neuralgia. Thalidomide dosereduction was required in five patients (20%)because of neurologic toxicity.

Table 2. Disease response after M(i.v.)PT

No No

Patients 24nCR 3 (12%)PR 7 (29%) ‡PR ¼ 10 (41%)‡75 paraprotein reduction 1 ‡PR ¼ 10 (41%)‡50 paraprotein reduction 6MR 4 (17%) ‡MR ¼ 14 (58%)SD 6 (25%)PD 4 (17%)

NCR, near complete response; PR, partial response; MR, minimum response; SD,stable disease; PD, progression disease.

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 5 10 15 20 25 30 35 40 45 50 55

Previous line MivPT

Previous lineMivPT

Fig. 1. Progression free-survivals from the start ofM(i.v.)PT treatment (solid line) and from the start of thepreceding therapy (dot line).

10.90.80.70.60.50.40.30.20.1

00 5 10 15 20 25 30 35 40

0 20 14 11 4 5 1 1 1

45Months

MivPT

MivPT

Patients

Fig. 2. Overall survival from the start of M(i.v.)PT treat-ment.

Table 3. Haematologic toxicity observed in patients treated with M(i.v.)PT

Toxicity Grades 1–2 n (%) Grade 3 n (%) Grade 4 n (%)

Anemia 16 (64) 7 (32) 1 (4)Thrombocitopenia 19 (81) 3 (12) 2 (7)Neutropenia 15 (63) 8 (33) 1 (4)

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Discussion

Agents capable of extending disease control with aminimum impact on quality-of-life are needed forheavily pretreated MM patients for whom highdose treatments are contraindicated on medicalgrounds or on account of their age. Thalidomide,as single agent or in combination, has extensivelybeen used in advanced and in newly diagnosedMM. Overall, thalidomide-related severe haemato-logical toxicity has rarely been reported. Venousthromboembolism has emerged as the most severeside-effect when thalidomide was used in combina-tion with other drugs in newly diagnosed MM,whereas its incidence was low when employed assingle agent in advanced MM (17). Neurologicalcomplications appear to be dose-related. The anti-MM effects of thalidomide include inhibition ofangiogenesis and of several MM cell interactionswith extracellular matrix proteins and bone marrowstromal cells; down-regulation of cytokines in-volved in MM cell survival and drug resistance;and enhanced host anti-MM immunity (1). Import-antly, thalidomide has been shown to act in synergywith dexamethasone (4). This observation formedthe rationale for their combined use in patientsrefractory to both drugs administered previously assingle agents or with chemotherapy (6–8, 18). Theuse of thalidomide was later extended to untreatedMM (9–12, 19). Weber et al employed it as singleagent in asymptomatic MM and in combinationwith dexamethasone in symptomatic untreatedMM (11). Overall, several studies have reportedthe clinical efficacy of thalidomide and dexameta-sone used alone or in combination in differentdisease stages. However, the optimal treatmentmodality when combined with melphalan has notbeen determined yet.

In one study, Offidani et al. reported on the useof thalidomide combined with oral melphalan in 27advanced MM patients (20). The starting dose ofthalidomide was 100 mg/d, escalated by 100 mg/wkas per patient tolerance up to a maximum dose of600 mg. Melphalan was administered monthly at0.20 mg/kg/d for four consecutive days. Regimenrelated toxicities included constipation (82%),somnolence (41%), fatigue (22%), sensory neurop-athy (56%) and grade 3 leukopenia. Reductions ofthe monoclonal paraprotein ‡50% and ‡75% wereobtained in 59% and 15% of the patients, respect-ively. Both the 2 yr OS and progression freesurvival were 61%. In the M(i.v.)PT study, similarresponse rates were reported. However, thalido-mide-related toxicity was less frequent probablydue to the low doses employed. Recently, Palumboet al. reported 18% CR and 6% nCR in newlydiagnosed elderly patients treated with monthly

cycles of oral melphalan and prednisone for 7 d,and low dose thalidomide until progression orrelapse (21).

In another study, 21 heavily pretreated MMpatients were treated with cycles of i.v. melphalan(50 mg) combined with thalidomide, up to 400 mg/d, and oral dexamethasone, 40 mg/d on d 1through 4, every 4–6 wk (22). Maintenance treat-ment consisted of daily thalidomide and monthlydexamethasone until disease progression. Overall,reduction ‡25% of the monoclonal paraproteinoccurred in 14 (70%) of 20 evaluable patients.Median progression free survival was 270 d (range:73–87 d) and median OS was 382 d. However, thisregimen was associated with grade 4 neutropenia,fatal in two patients, and thrombocytopenia in52% and 38% of patients, respectively. Grade 3non-haematologic toxicities included fatigue, neuro-pathy and nausea. In the M(i.v.)PT regimen, thereduction of melphalan from 50 to 20 mg/m2

drastically decreased the haematological toxicitywhich was similar to that reported with oralmelphalan and no treatment related mortality wasobserved.

Interestingly, in the M(i.v.)PT study, in four outof five patients who showed disease progressionwhile on thalidomide plus dexamethasone theaddition of i.v. melphalan was highly effectiveand induced one nCR, two PR and one MR. Thisfinding suggests that i.v. melphalan may overcomeMM drug resistance to thalidomide plus dexa-methasone thus determining disease control.Furthermore, in 33% of the M(i.v.)PT patients,the duration of response was longer that obtainedwith the previous line of salvage treatment,whereas remission duration is usually progres-sively reduced as the number of salvage therapylines increases.

In summary, our findings show that the additionof low doses of i.v. melphalan to the combinationof thalidomide and prednisone may produceresponses and durable remissions in heavily pre-treated MM patients, thus prolonging OS. More-over, M(i.v.)PT had a minimum impact on qualityof life because of its good toxicity profile, thussuggesting its use also in elderly MM patients whomay not tolerate high dose regimens.

Acknowledgements

This work was supported in part by Associazione ItalianaLeucemie (AIL), Ministero Universita e Ricerca Scientifica eTecnologica (MURST), Consiglio Nazionale Ricerca (CNR),Compagnia di S. Paolo, Associazione per lo Studio e la Curadelle Malattie del Sangue. We thank Miss Federica Leotta andMiss Tiziana Marangon for their technical assistance in thepreparation of the manuscript. We are grateful to the nursesand the physicians of all participating centres.

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