Leukemia (2008), 1–8& 2008 Macmillan Publishers Limited All rights reserved 0887-6924/08 $32.00 1Divisione di Ematologia dell’Universita` di Torino, Azienda Ospedaliera S. Giovanni Battista, Ospedale Molinette, Turin, Italy and 2Division of Haematology, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, MN, USA The introduction of thalidomide, bortezomib and lenalidomide were noted in patients with de novo myeloma or in those with a has dramatically changed the treatment paradigm of multiple preceding diagnosis of plasma cell disorder such as MGUS or myeloma (MM). In patients eligible for autologous stem cell smoldering myeloma.5 To avoid the risk of an undue therapy in transplant (ASCT), combinations including thalidomide/dexa-methasone (Thal/Dex) or bortezomib/dexamethasone (Bort/Dex) asymptomatic myeloma, the start of treatment requires the or lenalidomide/dexamethasone (Rev/Dex) have been intro- presence of at least one organ damage defined by hypercalce- duced as induction regimens in patients eligible for ASCT.
mia, anemia, renal insufficiency or bone lesions (CRAB criteria), New induction regimens have significantly increased complete which clearly define the occurrence of symptomatic myeloma.
response rate before and after ASCT with a positive impact on Recently, agents with novel mechanisms of action, such as progression-free survival. Maintenance therapy with thalido- thalidomide, bortezomib and lenalidomide, have shown sig- mide, under investigation with lenalidomide, may further pro-long remission duration. In patients not eligible for ASCT, nificant activity in MM. Thalidomide and lenalidomide have randomized studies have shown that melphalan, prednisone, antiangiogenesis properties, stimulate T- and natural killer cells thalidomide (MPT) and melphalan, prednisone and bortezomib and interfere with cytokines. They suppress growth factors such (MPV) are both superior to melphalan and prednisone (MP), and as interleukin-6, tumor necrosis factor-a, inhibit myeloma cell are now considered standard of care. Ongoing trials will soon adhesion and blood vessel growth cytokines such as vascular assess if MP plus lenalidomide may be considered an attractive endothelial growth factor.6,7 Bortezomib, a first in class option. More complex regimens combining thalidomide orbortezomib or lenalidomide with cyclophosphamide or doxo- proteasome inhibitor, specifically interferes with the 26S rubicin have been also tested. In small cohorts of patients proteasome, which is responsible for degrading protein that bortezomib or lenalidomide may overcome the poor prognosis control transcription, the cell-proliferation cycle and metabo- induced by deletion 13 or translocation t(4;14) or deletion lism.8 Combinations of these agents with steroids, alkylating 17p13. If these data will be confirmed, a cytogenetically risk- agents or anthracyclines have significantly improved response adapted strategy might become the most appropriate strategy.
rate and progression-free survival (PFS). In a large group of Leukemia advance online publication, 13 November 2008;doi:10.1038/leu.2008.325 newly diagnosed myeloma patients, no difference in overall Keywords: new drugs; therapy; diagnosis; myeloma survival was reported during a 24-year period from 1971 to1994, there was a trend toward improvement during the period1995–2000 and a statistically significant benefit in overallsurvival was shown during the last 6 years (2001–2006).9 Thesedata suggest that autologous stem cell transplant (ASCT) was responsible for the trends seen during 1994–2000, while novelagents contributed to the improvement observed since 2001.
Multiple myeloma (MM) accounts for approximately 10% of In newly diagnosed myeloma patients younger than 65 years, hematological malignancies, the frequency is constantly induction regimens including dexamethasone plus thalidomide increasing due to aging of the general population.1,2 At present, or bortezomib or lenalidomide followed by high-dose melpha- about 35% of myeloma patients are younger than 65 years, 28% lan and ASCT have significantly increased response rate. In are 65–74 years and 37% are older than 75 years.3 The current elderly patients, usually older than 65 years, oral melphalan and SPOTLIGHT
changes of the demographic curves will probably increase the prednisone (MP) has been combined with thalidomide or incidence of elderly patients in the near future. In some patients, bortezomib significantly improving response rate and PFS.
symptomatic myeloma evolves from an asymptomatic benign The future challenge is to define the optimal sequence and stage termed MGUS. In others, an intermediate asymptomatic combination of these drugs to significantly impact the natural premalignant stage referred to as smoldering MM can be history of the disease. This paper will focus on the role of new recognized. The overall risk of progression from smoldering to drugs for frontline treatment of MM.
symptomatic myeloma is 10% per year for the first 5 years,approximately 3% per year for the next 5 years and 1% for thenext 10 years. The significant risk factors for progression included the amount of monoclonal protein and the extend ofbone marrow involvement.4 No differences in overall survival A monoclonal protein can be detected by serum proteinelectrophoresis alone in 82% of patients and by serum Correspondence: Dr A Palumbo, Divisione di Ematologia dell’Uni- immunofixation in 93%; a combination of serum and urine versita` di Torino, Department of Hematology, Azienda Ospedaliera S.
protein immunofixation studies improve the sensitivity to Giovanni Battista, Ospedale Molinette, Via Genova 3, Torino 10126, 97%.10 Less than 3% of patients have no evidence of monoclonal paraproteins (non-secretory myeloma). The serum E-mail: [email protected] 13 August 2008; revised 8 October 2008; accepted 14 immunoglobulin-free light-chain assay negates the need of immunofixation and 24-h urine electrophoresis for purposes of diagnosis; the assay also allows the quantitative monitoring of progression of smoldering myeloma. Treatment choices are patients with oligo-secretory or non-secretory myeloma. In mainly based on age and presence of comorbidities. Preliminary addition, the baseline-free light-chain measurement represents a data show that new drugs may overcome the poor prognosis prognostic factor for myeloma.11 The diagnosis of MM requires induced by chromosomal aberrations such as deletion 13, 10% or more monoclonal plasma cells in the bone marrow and/ or a presence of biopsy proven plasmacytoma, monoclonalprotein in the serum and/or urine (except in patient with truenon-secretory myeloma) and presence of end-organ damage felt Treatment of myeloma in patients eligible for transplantation related to the underlying plasma cell proliferative disorder:hypercalcemia (serum calcium 410 mg/l), renal insufficiency Initial therapy for patients is dependent on eligibility for ASCT, (serum creatinine 42 mg per 100 ml), anemia (hemoglobin mainly determined by age, performance status and coexisting o10 g per 100 ml), bone lytic lesions detected by skeletal comorbidities. Protracted melphalan-based therapy should be avoided in patients with newly diagnosed myeloma who areconsidered eligible for ASCT, as it can interfere with adequatestem cell mobilization. Typically, patients are treated with approximately 2–4 cycles of induction therapy before stem cellharvest. This includes patients who are transplant candidates but The clinical course of MM is quite heterogeneous: some patients who wish to reserve ASCT as a delayed option for relapsed SPOTLIGHT
die from disease evolution within few weeks, whereas others refractory disease. Such patients can resume induction therapy live for more than 10 years. Although very useful, it must be following stem cell collection until a plateau phase is reached, noted that most of the following parameters were studied before the advent of new active agents, and hence we need additional The present choices for initial therapy are thalidomide/ studies in the present era of novel therapy.
dexamethasone (Thal/Dex), bortezomib/dexamethasone (Bort/ The International Staging System (ISS) provides a simple, Dex) and related bortezomib-based combination regimens, and powerful and reproducible three-stage classification: stage I is lenalidomide/dexamethasone (Rev/Dex). These regimens act characterized by b2-microglobulin less than 3.5 mg/l plus serum rapidly and are associated with high-response rates; Thal/Dex albumin X3.5 g per 100 ml and showed a median survival of 62 and Rev/Dex have the added advantage of being orally months; stage II is represented by neither stage I nor III and administered. Thal/Dex and Rev/Dex are associated with an exhibited a median survival of 44 months; and stage III is increased risk of deep vein thrombosis (DVT), necessitating defined by b2-microglobulin X5.5 mg/l with a median survival routine thromboprophylaxis. New combinations including of 29 months.13 Acquired chromosomal abnormalities have thalidomide, bortezomib or lenalidomide with chemotherapy shown to significantly impact survival in myeloma patients. Poor agents, such as doxorubicin or cyclophosphamide, are currently prognosis has been associated with the presence of immuno- globulin heavy chain translocations t(4;14), t(14;16), t(14;20),deletion 17p13 or deletion 13. By contrast a favorable prognosishas been observed in the presence of t(11;14), t(6;14) or hyperdiploidy.14–16 In a large study, the prognostic value of Thalidomide and dexamethasone combination has increasingly deletion 13 was almost entirely dependent on the association been used instead of VAD. In 2005, a case-matched control with t(4;14) and deletion 17p13. On a multivariate analysis, analysis showed that response rates with Thal/Dex were superior patients lacking t(4;14) and deletion 17p13 with a low b2- to those achieved with VAD (76 vs 52%).20 Randomized trials microglobulin value had an excellent prognosis with a 4-year confirmed these findings.21–23 The Eastern Cooperative Oncol- overall survival at 83%; patients presenting a single alteration ogy Group (ECOG) compared Thal/Dex to high-dose dexa- either t(4;14) or deletion 17p13 or high b2-microglobulin value methasone alone in 470 newly diagnosed myeloma patients.
had an intermediate prognosis; while patients showing the The overall response rate was significantly higher with Thal/Dex cumulative alterations t(4;14) plus deletion 17p13 plus high b2- compared with dexamethasone (63 vs 46%; Po0.001). Time to microglobulin had a very poor prognosis with a median survival progression was significantly longer with Thal/Dex compared of only 19 months.16 It must be noted that the adverse impact of with dexamethasone (median, 22.6 vs 6.5 months, Po0.001).
these cytogenetic abnormalities is firmly established in the DVT was more frequent with Thal/Dex (18.8 vs 5.6%). Overall, context of conventional therapies but not with novel treatments.
grades 3–4 non-hematologic toxicities were seen in 79.5% of Bortezomib was shown to overcome the poor prognosis induced patients with Thal/Dex and 64.2% with dexamethasone alone by deletion 13 and t(4;14) and deletion 17p13, whereas there is (Po0.001).24 In another trial, 204 patients were randomly currently only preliminary data on efficacy with lenalido- assigned to receive induction treatment with Thal/Dex or with a mide.17,18 It is now strongly recommended that all newly VAD-like regimen followed by high-dose therapy and ASCT.
diagnosed myeloma patients be tested at minimum for t(4;14), The very good partial response (VGPR) rate was 34.7% in the t(14;16) and deletion 17p13 by fluorescence in situ hydridiza- Thal/Dex group and 12.6% in the VAD group (P ¼ 0.002) before tion together with measurements of serum b2-microglobulin and ASCT. At 6 months post-transplant, the benefit of Thal/Dex was not further observed with VGPR rates of 44.4% in the Thal/Dexarm and 41.7% in the VAD arm (P ¼ 0.87).23 When thalidomidewas incorporated into the high-dose therapy followed by ASCT, a higher complete response (CR) rate (62 vs 43%) and improved5-year event-free survival (56 vs 44%) was observed compared There is little evidence that early treatment of patients with with high-dose therapy without thalidomide.25 Unfortunately, asymptomatic MM prolongs survival compared with therapy the 5-year overall survival was similar in both groups (P ¼ 0.9).
delivered at the time of symptoms or end-organ damage.
In the thalidomide group, a higher rate of thromboembolism Clinical trials are ongoing to determine if new agents can delay (30 vs 17%) and peripheral neuropathy (27 vs 17%) were Treatment of newly diagnosed myelomaA Palumbo and SV Rajkumar reported.25 In the Medical Research Council (MRC) Myeloma IX patients who subsequently received ASCT and those who did trial, which has recruited 900 patients, cyclophosphamide- not receive any ASCT, and instead received continued BiRD thalidomide-dexamethasone (CTD) was compared with cyclo- treatment. Cyclophosphamide plus growth factor was used to phosphamide-VAD as induction regimen before ASCT. In a mobilize stem cells, resulting in a successful harvest in all preliminary analysis, the CR rate was 20.3% after CTD and patients. The number of CD34 cells collected ranged from 4 to 11.7% after cyclophosphamide-VAD; this difference was main- 21.5 CD34 Â 106/kg.31 These studies confirm the high efficacy tained at 100 days post-ASCT, the CR rate was 58.2% after CTD of lenalidomide in the upfront treatment of younger myeloma plus ASCT and 41% after cyclophosphamide-VAD plus ASCT.26 patients with a better safety profile compared with the parent compound thalidomide. In particular, the combination of response when used as induction therapy in comparison with lenalidomide with low-dose dexamethasone appears to be the standard treatment. Further studies are needed to assess if this more suitable option in this setting. The incidence of DVT is low advantage is maintained after ASCT. The efficacy of this with single-agent lenalidomide or Rev/low-dose Dex, but rises combination must be balanced against the greater toxicity and markedly when the agent is combined with high-dose dex- the need for antithrombotic prophylaxis. Patients receiving amethasone. Recommendations for thromboprophylaxis are thalidomide in combination with high-dose steroids or similar to those discussed above with Thal/Dex; aspirin alone chemotherapy need routine thromboprophylaxis. The presence is probably sufficient for patients receiving Rev/low-dose Dex.27 of a central venous catheter, comorbidities, immobilization aswell as the administration of high-dose dexamethasone, multi-agent chemotherapy may significantly increase the risk of thromboembolic events. In these conditions, coumadin (target Bortezomib is a novel proteasome inhibitor approved by the INR 2–3) or low-molecular weight heparin (equivalent of FDA for the treatment of myeloma in patients who have failed enoxaparin 40 mg once daily) are suggested for the first 4–6 one prior therapy. In newly diagnosed myeloma patients, the months of therapy. In patients lacking these risk factors aspirin combination Bort/Dex showed an overall response rate of 66%, including 21% CR/near CR (nCR) and 10% VGPR.32 The mostcommon side effects were gastrointestinal symptoms, peripheralneuropathy and fatigue. Peripheral neuropathy was grades 2–3 in 14% of patients. No DVTs and no hematologic toxicity The Rev/Dex combination has shown significant activity in a greater than grade 2 were observed. Grade 3 infections were phase II trial conducted at the Mayo Clinic. Thirty-one of 34 recorded in five patients including three who had herpes zoster newly diagnosed patients (91%) achieved a partial response infections.29 To decrease toxicity and to assess efficacy Bort/Dex (PR), including 2 (6%) achieving CR, and 11 (32%) meeting has been administered in an alternating schedule (bortezomib at criteria for VGPR.28 With a longer follow-up, 56% of patients 1.3 mg/mq bi-weekly, cycles 1, 3, 5 only) as induction therapy achieved VGPR or better. In the subset of 21 patients receiving followed by ASCT. This alternating schedule induced a PR rate Rev/Dex as primary therapy without ASCT, 67% achieved VGPR of 65%, including a CR rate of 12.5% and a VGPR rate of 10%.
or better.29 The 2-year time to progression was 71% for the Toxicity was low with no grades 3–4 peripheral neuropathy or entire cohort, including 66% of patients who received Rev/Dex grades 2–4 thrombocytopenia. Chromosome 13 deletion, t(4;14) without ASCT and 83% of those who received Rev/Dex with and t(14;16) did not have a negative impact on response.33 In a ASCT. Approximately, half of the patients experienced grade 3 randomized trial, Bort/Dex has been compared with VAD as or higher non-hematologic toxicity.29 In a recent study, 198 induction therapy before ASCT.32 Response to induction patients were randomly assigned to receive Rev/Dex or showed a significant higher CR plus nCR rate for Bort/Dex dexamethasone alone. The CR rate was significantly higher in (21.3 vs 8.3%), the superiority of Bort/Dex was maintained after the Rev/Dex group (22.4%). The superior response rate ASCT: the CR plus nCR rates were 38 vs 28%. At the interim translated in a prolonged remission duration: the 1-year PFS analysis, the 1-year PFS was 93% for Bort/Dex and 90% for was 77% in the Rev/Dex group and 55% in the dexamethasone VAD.34 The combination bortezomib–dexamethasone–thalido- group (P ¼ 0.002). ECOG tested Rev/Dex as administered in the mide has been compared with Thal/Dex in a randomized trial as Mayo Phase II trial (and in the regulatory relapsed/refractory induction treatment before double ASCT. The CR plus nCR rate SPOTLIGHT
myeloma studies) vs Rev/low-dose Dex (40 mg dexamethasone was 36% with bortezomib–dexamethasone–thalidomide and once weekly).30 Results show that toxicity rates are significantly 9% with Thal/Dex, and 57% with bortezomib–dexamethasone– higher with Rev/high-dose Dex compared with Rev/low-dose thalidomide plus ASCT and 28% with Thal/Dex plus ASCT.
Dex. Early (first 4 month) mortality rates were low in both Response to bortezomib–dexamethasone–thalidomide was not groups, 5 and 0.5%, respectively. The early mortality rate in the adversely affected by chromosome 13 deletion or t(4;14).35 In a Rev/low-dose Dex group is probably the lowest reported in any phase II study, 100 patients received bortezomib, pegylated– large phase III trial, in which enrollment was not restricted by liposomal–doxorubicin and dexamethasone before reduced age or eligibility for stem cell transplantation. The DVT rates intensity ASCT (melphalan 100 mg/m2). After induction with observed in this study were also low, making Rev/low-dose Dex pegylated–liposomal–doxorubicin and dexamethasone, the CR one of the safest pretransplant induction regimens for myeloma.
plus nCR rate was 23% and increased to 60% with pegylated– Although combinations including low-dose Dex are more liposomal–doxorubicin and dexamethasone plus reduced appropriate, higher doses of dexamethasone should be con- intensity ASCT.36 A novel combination including bortezomib, sidered in the presence of a very aggressive disease, in very lenalidomide and dexamethasone has been investigated, it young patients, or in the relapse setting. In a phase II trial, Rev/ produced high quality responses and was well tolerated in Dex was combined with clarithromycin (Biaxin), with this BiRD newly diagnosed patients. In 42 patients, this combination regimen the CR rate was particularly high (38.9%) including a induced a PR rate of 98% including 52% VGPRs.37 The risk of 30.6% of stringent CR (immunofixation negative plus normal DVT is low with bortezomib (o5%), while peripheral neuro- free light-chain ratio, plus a negative marrow biopsy by pathy can be higher, but alternating regimens significantly immunohistochemistry).31 The 2-year PFS was 75.2% both in reduced this risk. Bortezomib-based regimens may be of value in patients with renal failure, and in those with adverse intermediate-dose melphalan appears a suitable option. In a cytogenetic features such as t(4;14) or deletion 17p13.
randomized study, patients, aged 65–70 years, receivedmelphalan 100 mg/m2 or MP, and the reduced intensity ASCTprogram was superior to MP.42 In another study, patients, aged 65–75 years, received melphalan 100 mg/m2 or MP, ASCT wassuperior to MP in terms of response rate, but not in terms of PFS The concept of maintenance therapy may open new avenues for and overall survival.43 In the first study, 22% of patients did not new treatment approaches in myeloma. In a large study, patients complete the assigned treatment; in the second trial, 37% of younger than 65 years were randomly assigned to receive no patients did not complete it. According to these data, the age of maintenance, pamidronate, or pamidronate plus thalidomide.38 70 years should be considered as the age limit for intermediate- The 3-year post-randomization probability of event-free survival dose melphalan. Once again, the balance between efficacy and (Po0.009) and the 4-year overall survival (Po0.04) were toxicities is extremely important to improve outcome. The significantly prolonged in patients who received thalidomide.
discovery of novel therapies, targeting myeloma cells and the The incidence of thromboembolic events was not significantly bone marrow microenvironment, has changed the treatment different in the three groups. In another study, thalidomide– paradigm of myeloma therapy, especially for the elderly prednisone was compared with prednisone alone as mainte- nance therapy after ASCT: the 1-year PFS was 91 vs 69%, andthe 2-year overall survival was 90 vs 81%, respectively.39 In SPOTLIGHT
both studies grades 3–4 peripheral neuropathy was significantly more prominent in the thalidomide group than in the controls.
In younger patients Thal/Dex significantly improves PFS in More recently, newly diagnosed patients received Thal/Dex as comparison with high-dose dexamethasone alone.24 In elderly induction, they were then randomly assigned to tandem ASCT or patients, Thal/Dex was compared with MP in a randomized single ASCT followed by thalidomide maintenance.40 The 3- study. An interim analysis showed a significantly higher year PFS was 57% in the double ASCT group and 85% in the response rate in the Thal/Dex group but failed to show any single ASCT group, followed by thalidomide maintenance advantage in PFS, while overall survival was superior in the MP (P ¼ 0.02). This study is of particular interest because it shows group (P ¼ 0.02).44 Patients on Thal/Dex experienced more the advantage of a maintenance approach, even in patients grades 2–3 neuropathy (25%) and skin toxicity (12%) compared previously treated with Thal/Dex as induction therapy. Borte- with those on MP (8 vs 3%, respectively). Thromboembolic zomib also showed promising results as a maintenance therapy, complications were seen in 8% of patients receiving Thal/Dex suggesting that bortezomib maintenance may favorably impact and in 3% of patients receiving MP. The higher toxicity rate of time to recurrence.41 Additional studies are needed to determine Thal/Dex regimen can explain the lower efficacy of Thal/Dex in the role of routine maintenance in myeloma, especially the use the elderly population. This study raises the question if an of lenalidomide, which has a better safety profile than alkylating agent is an essential component of drug combinations thalidomide for long-term maintenance.
to improve treatment efficacy. Recently, MP has been combined Patients who are candidates for ASCT should follow a with thalidomide (MPT) in four different randomized studies. In treatment strategy that includes ASCT. However, ASCT can be the first trial, oral MPT was compared with MP in patients aged delayed until relapse if facilities are available to harvest and 60–85 years.45 The PR rates were 76% in the MPT group and cryopreserve stem cells early in the disease course. Bortezomib- 47.6% in the MP group, nCR or CR rates were 27.9 and 7.2%, or lenalidomide-based regimens should be introduced as respectively. The 2-year event-free survival rates were 54% for induction therapy before ASCT, as they significantly increase MPT and 27% for MP (P ¼ 0.0006), with similar 3-year survival the VGPR and CR rates before transplantation. Thalidomide rates (P ¼ 0.19). In the second study, MPT was compared should be considered as maintenance after ASCT, specifically in with MP and with intermediate-dose melphalan (100 mg/m2) patients who did not reach at least VGPR after single or tandem followed by ASCT in patients aged 65–75 years. A higher PR rate transplantation. The incorporation of new drugs as induction was seen in the MPT and in the melphalan 100 mg/m2 groups, and maintenance therapy along with ASCT appears to produce compared with MP (81 vs 76 vs 35%, respectively).43 Similarly, VGPR rates slightly superior to those achieved by conventional the CR rates were significantly higher with MPT and inter- chemotherapy with new drugs. Randomized trials are needed to mediate-dose melphalan compared with MP. Median PFS was directly compare the present best chemotherapeutic approach 27.5 months in the MPT patients and 17.8 months in the MP with best ASCT strategies and guide clinical practice for patients group (Po0.0001), and median overall survival were 51.6 and 32.2 months, respectively (P ¼ 0.001). In the third study, patientsaged 75 years and older were randomly assigned to receive MPTor MP plus placebo. The PR rate was 62% in the MPT group and Treatment of myeloma in patients not eligible for ASCT 31% in the MP group, median PFS was 24.1 months for MPTand 19.0 months for MP (P ¼ 0.001), and median overall Patients who are not candidates for transplant have been treated survival was 45.3 months for MPT and 27.7 months for MP for years with standard alkylating agent therapy. In elderly (P ¼ 0.03).46 In the fourth study, 362 patients with a mean age of patients, biological age may be quite different from chronolo- 75 years (range, 49–92) received MPT or MP plus placebo.
gical age, for this reason it is difficult to clearly define who is a Results of an interim analysis showed better response rates and candidate for ASCT and who is not. The inclusion in an ASCT time to progression in the MPT group than in the MP group program should always be considered in the absence of any (Po0.03), but did not show any improvement in overall serious heart, lung, renal and liver dysfunction, while an age survival.47 Results from these four randomized studies consis- limit should be considered and balanced with the biological tently showed better response rates and remission duration age. With these limitations it is generally accepted that patients in patients assigned to MPT than in those receiving MP, but an older than 65 years should not receive melphalan 200 mg/m2 overall survival benefit was only reported in the two French followed by ASCT. In the age group between 65 and 70 years, studies. Comparisons between different studies are difficult to Treatment of newly diagnosed myelomaA Palumbo and SV Rajkumar make because of differences in patient populations, duration of presence of severe neutropenia despite granulocyte-colony treatment and use of maintenance regimens. Despite these differences, data strongly support the MPT as the new standardof care for elderly myeloma patients. In all studies, the MPTpatients showed a higher incidence of grades 3–4 extra-hematological toxicities compared with the MP regimen, especially neurological adverse events, infections, cardiac The Spanish cooperative group conducted a large phase I/II trial toxicity and thromboembolism. Antithrombotic prophylaxis is of bortezomib, melphalan and prednisone (MPV).49 The recommended when using MPT. Recommendations for throm- association showed encouraging results: PR rate was 89%, boprophylaxis are similar to those previously discussed with including 32% immunofixation-negative CR, half of them Thal/Dex.27 The higher toxicity rate significantly reduced the achieved immunophenotypic remission (no detectable plasma efficacy of the MPT combination. Randomized studies that used cells at 10À4 to 10À5 sensitivity). PFS at 16 months for VMP more strict inclusion criteria showed better outcome. In theFrench studies, a higher incidence of grades 3–4 hematologicaltoxicity (neutropenia and thrombocytopenia) was also observed, due to a higher number of MP cycles administered (12 cycles)and a higher dose of thalidomide (median dose 200 mg). The duration of MP treatment should be reduced from 12 cycles to 6cycles, as prolonged melphalan exposure induces thrombo- Oral thalidomide 100–200 mg on days 1–28 cytopenia that hampers the delivery of subsequent effective Oral dexamethasone 40 mg on days 1, 8, 15, and In the Medical Research Council (MRC) Myeloma IX trial, Repeated every 4 weeks for four cycles aspretransplant induction therapy; or continued for up CTD has been compared with MP in 900 patients. In the CTD group, the PR rate (82 vs 49%) and the CR rates (23 vs 6%) were Oral lenalidomide 25 mg on days 1–21, every 28 significantly superior in the CTD group.26 Unfortunately, data daysOral dexamethasone 40 mg on days 1, 8, 15, and on remission durations are not available; if they also are superior to MP, the CTD regimen should be added as an alternative standard frontline approach for elderly patients.
pretransplant induction therapy; or continued untilprogression if used as primary therapy Intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11Oral dexamethasone 40 mg on days 1–4, 9–12 Reduce dexamethasone to days 1–4 only after firsttwo cycles The Italian group evaluated in a phase I/II trial, dosing, safety Repeated every 3 weeks for 2–4 cycles as and efficacy of melphalan plus prednisone and lenalidomide in newly diagnosed elderly myeloma patients.48 The maximum Intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, tolerated dose was considered to be melphalan at 0.18 mg/kg on days 1–4, prednisone at a 2-mg/kg dose on days 1–4 and Dexamethasone 20 mg on the day of and the day lenalidomide at 10 mg on days 1–21, every 28 days for nine after bortezomibRepeated every 3 weeks for three cycles as cycles. Aspirin was given as a prophylaxis for thrombosis.
Eighty-five percent of patients achieved at least a PR, and 23.8% Intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8, achieved immunofixation-negative CR. The 1-year event-free Pegylated liposomal doxorubicin 30 mg/m2 on day 4 and overall survival was 92 and 100%, respectively. Grades 3–4 Dexamethasone 40 mg on days 1–11, and 15–18 adverse events were mainly related to hematologic toxicities for cycle 1 and days 1–4 for cycles 2–4 (neutropenia 66%). Severe non-hematologic side effects were Cyclophosphamide 500 mg post-operative on days less frequent and included febrile neutropenia (8%), cutaneous rash (10%) and thromboembolism (6%). Preliminary results Dexamethasone 40 mg/day post-operative on days1–4, 12–15 every 3 weeks SPOTLIGHT
showed that the event-free survival of patients with deletion ofchromosome 13 or chromosomal translocation (4;14) was notsignificantly different from those who did not have such abnormalities. This study formed the basis for the ongoing international phase III study comparing MP vs melphalan plus Oral thalidomide 100–200 mg on days 1–28Repeated every 6 weeks for 12 cycles prednisone and lenalidomide. In the near future, the MPT combinations will be challenged by the recent results reported with Len/Dex, using low-dose dexamethasone (40 mg on days 1, Intravenous bortezomib 1.3 mg/m2 on days 1, 4, 8,11, 22, 25, 29 and 32 8, 15 and 22, every 4 weeks). Neutropenia and DVT are the Repeat every 42 days for four cycles followed by major complications with lenalidomide, although the addition of aspirin markedly reduced the risk of thromboembolic events Oral melphalan 9 mg/m2 on days 1–4Oral prednisone 60 mg/m2 on days 1–4 in newly diagnosed patients treated with lenalidomide in Intravenous bortezomib 1.3 mg/m2 on days 1, 8, 15 association with dexamethasone or chemotherapy. Recommen- dations for thromboprophylaxis have already been discussed, Oral melphalan from 0.18 mg/kg on days 1–4 with lenalidomide aspirin seems to be the preferred choice in the absence of additional risks of thromboembolism.27 The Oral lenalidomide from 10 mg on days 1–21 addition of granulocyte-colony stimulating factor is recom- Repeated every 28 days for 9 monthly cycles mended in case of neutropenia, and melphalan dose reduction aDexamethasone dose listed is lower than used in trial.
(from 0.18 to 0.13 mg/kg) should always be applied in the bThalidomide dose listed is lower than used in trial.
Efficacy of regimens used as frontline treatment in multiple myeloma SPOTLIGHT
Abbreviations: ASCT-T, autologous stem cell transplantation+thalidomide; BiRD, biaxin+lenalidomide+dexamethasone; Bort/Dex, bortezomib+-dexamethasone; MPR, melphalan+prednisone+lenalidomide; MPT, melphalan+prednisone+thalidomide; MPV, melphalan+prednisone+bortezo-mib; bortezomib+pegylated-lyposomal-doxorubicin+dexamethasone; lenalidomide+dexamethasone; Thal/Dex, thalidomide+dexamethasone; VGPR, very good partial response; VTD, bortezomib+thalidomide+dex-amethasone.
Safety of regimens used as frontline treatment in multiple myeloma Abbreviations: ASCT-T, autologous stem cell transplantation+thalidomide; BiRD, biaxin+lenalidomide+dexamethasone; Bort/Dex, bortezomib+dexamethasone; MPR, melphalan+prednisone+lenalidomide; MPT, melphalan+prednisone+thalidomide; MPV, melphalan+prednisone+bortezo-mib; ND, not determined; PAD, bortezomib+pegylated-lyposomal-doxorubicin+dexamethasone; Rev/Dex, lenalidomide+dexamethasone; Thal/Dex, thalidomide+dexamethasone; VTD, bortezomib+thalidomide+dexamethasone.
patients was significantly prolonged in comparison with thromboembolism, MPV could be the preferred option; in the historical controls treated with MP only (91 vs 66%), similarly presence of peripheral neuropathy, MPR should be considered; overall survival at 16 months was improved (90 vs 62%).
in patients with renal insufficiency, MPV is better tolerated; and Interestingly, response rate, PFS and overall survival were MPT should be considered if costs are a concern. Oral treatment similar among patients with or without chromosome 13 deletion should also be balanced vs intravenous treatment, as the latter is or IgH translocations. Grades 3–4 adverse events observed with MPV were mainly thrombocytopenia, neutropenia, peripheralneuropathy, infections and diarrhea. The treatment appearedmore toxic in patients older then 75 years. Bortezomib can induce transient thrombocytopenia and peripheral neuropathy.
Pre-existing neuropathy or previous neurotoxic therapy in- Bone lytic disease is the most frequent complication of creases the risk of peripheral neuropathy, which can be reduced myeloma. Pamidronate and zoledronic acid are the cornerstone or resolved by prompt dose reduction of the drug. Bortezomib for the treatment of lytic disease in myeloma. Concerns have may enhance the incidence of infections, in particular, herpes risen during the last years about their renal side effects and zoster reactivation, and prophylactic antiviral medications are osteonecrosis of the jaw, a complication which is related to highly recommended. These data have recently been confirmed long-term use of potent biphosphonates.51 The discovery of in a large randomized trial comparing MPV with MP and have novel agents with a beneficial effect on abnormal bone provided the basis for MPV as an alternative standard of care for remodeling of myeloma is highly expected. Bortezomib has special effects on myeloma bone metabolism. Bortezomib The efficacy of these new regimens should be balanced increased the number of osteoblastic cells/mm2 and the against their higher toxicities: in the presence of high risk of Runx2/Cbfa1-positive osteoblasts in bone biopsies of responding Treatment of newly diagnosed myelomaA Palumbo and SV Rajkumar myeloma patients, but not in those who did not respond.52 In (asymptomatic) multiple myeloma. N Engl J Med 2007; 356: addition to promoting bone formation, bortezomib has been reported to affect osteoclast differentiation and function.
5 Kumar SK, Dingli D, Lacy MQ, Dispenzieri A, Hayman SR, Buadi Bortezomib was shown to inhibit osteoclast differentiation in a FK et al. Outcome after autologous stem cell transplantation formultiple myeloma in patients with preceding plasma cell dose- and time-dependent manner, as well as inhibit the bone disorders. Br J Haematol 2008; 141: 205–211.
resorption activity of osteoclasts.53 The results of these studies 6 Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ indicate that bortezomib may be the first agent that combines et al. Differential cytokine modulation and T cell activation by two potent antimyeloma activity with potential beneficial effects on distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999; 163: 380–386.
7 Dredge K, Marriott JB, Macdonald CD, Man HW, Chen R, Muller GW et al. Novel thalidomide analogues display anti-angiogenic activity independently of immunomodulatory effects. Br J Cancer2002; 87: 1166–1172.
8 Mitra-Kaushik S, Harding JC, Hess JL, Ratner L. Effects of the High-dose melphalan followed by ASCT in younger patients and proteasome inhibitor PS-341 on tumor growth in HTLV-1 tax oral MPT or MPV in elderly patients are the standard of care for transgenic mice and tax tumor transplants. Blood 2004; 104: 802–809.
the frontline therapy of myeloma. Survival after transplant 9 Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, appears to be related to the achievement of CR or VGPR.
Buadi FK et al. Improved survival in multiple myeloma and the Improved response rate after induction treatment, before impact of novel therapies. Blood 2008; 111: 2516–2520.
10 Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A transplant, could translate to better results after high-dose et al. Review of 1027 patients with newly diagnosed multiple therapy with prolonged survival. In younger patients, combina- myeloma. Mayo Clin Proc 2003; 78: 21–33.
tions incorporating thalidomide or lenalidomide or bortezomib 11 Van Rhee F, Bolejack V, Hollmig K, Pineda-Roman M, Anaissie E, significantly increase the pretransplant CR plus VGPR rate Epstein J et al. High serum-free light chain levels and their rapid before high-dose melphalan and autologous transplantation.
reduction in response to therapy define an aggressive multiple These combinations may further improve the CR plus VGPR rate myeloma subtype with poor prognosis. Blood 2007; 110: achieved after transplant. A reasonable alternative approach is 12 Durie BG, Kyle RA, Belch A, Bensinger W, Blade J, Boccadoro M to collect stem cell at diagnosis and leave the ASCT option for et al. Myeloma management guidelines: a consensus report from relapse. Both approaches need the evidence of efficacy from the the Scientific Advisors of the International Myeloma Foundation.
ongoing prospective randomized studies. These evidences should always include at least data on PFS advantage. If survival 13 Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade´ J improvement represents the ultimate goal, response advantage et al. International staging system for multiple myeloma. J Clin is not adequate, by itself, to define treatment efficacy.
14 Gertz MA, Lacy MQ, Dispensieri A, Greipp PR, Litzow MR, Cytogenetic abnormalities, such as chromosome 13 deletion Henderson KJ et al. Clinical implications of t(11;14)(q13;q32), or t(4;14), are considered negative prognostic factors. Unfortu- t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with nately, most of the studies reported to date have not high-dose therapy. Blood 2005; 106: 2837–2840.
prospectively stratified patients based on cytogenetic abnorm- 15 Zhan F, Huang Y, Colla S, Stewart JP, Hanamura I, Gupta S et al.
alities, making a firm conclusion difficult. In a small cohort of The molecular classification of multiple myeloma. Blood 2006; patients receiving bortezomib or lenalidomide, the PFS of patients with deletion of chromosome 13 or chromosomal 16 Avet-Loiseau H, Attal M, Moreau P, Charbonnel C, Garban F, Hulin C et al. Genetic abnormalities and survival in multiple translocation (4;14) was not significantly different from those myeloma: the experience of the Intergroupe Francophone du who did not show such abnormalities. It must however, be Mye´lome. Blood 2007; 109: 3489–3495.
mentioned that irrespective of cytogenetic ‘risk profile,’ MM 17 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, remains incurable. To determine the optimal regimen for each Shpilberg O, Kropff M et al. Bortezomib plus melphalan and individual patient based on a cytogenetically adapted strategy, prednisone for initial treatment of multiple myeloma. N Engl J Med comprehensive study and long-term follow-up is required.
18 Bahlis NJ, Song K, Trieu Y, Roland B, Masih-Khan E, Chang H et al.
Lenalidomide overcomes poor prognosis conferred by del13q and t(4;14) but Not del17p13 in multiple myeloma: results of the SVR has received research support to cover cost of clinical trials Canadian MM016 trial. Blood 2007; 110: (Abstract 3597).
at Mayo Clinic from Celgene Corporation. AP has received 19 Stewart AK, Bergsagel PL, Greipp PR, Dispenzieri A, Gertz MA, scientific advisory-board and lecture fees from Pharmion, Hayman SR et al. A practical guide to defining high-risk myeloma Celgene and Janssen-Cilag. Also supported by CA 62242, for clinical trials, patient counseling and choice of therapy.
CA107476, CA 100080 and CA 93842 to SVR; Universita` degli 20 Cavo M, Zamagni E, Tosi P, Tacchetti P, Cellini C, Cangini D et al.
Studi di Torino; Compagnia di S Paolo, MIUR and CNR to AP.
Superiority of thalidomide and dexamethasone over vincristine-doxorubicin-dexamethasone (VAD) as primary therapy in prepara-tion for autologous transplantation for multiple myeloma. Blood2005; 106: 35–39.
21 Rajkumar SV, Blood E, Vesole DH, Fonseca R, Greipp PR, Eastern Cooperative Oncology Group. Phase III Clinical Trial of Thalido- 1 Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med 2004; mide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Co- 2 Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and ordinated by the Eastern Cooperative Oncology Group. J Clin treatment. Mayo Clin Proc 2005; 80: 1371–1382.
3 Ries LAG, Eisner MP, Kosary CL, Linet M, Tamra T, Young JL et al.
22 Fermand J-P, Jaccard A, Macro M, Uzunhan Y, Allard C, Castaigne (eds). SEER cancer statistics review, 1975–2000. National Cancer S et al. A randomized comparison of dexamethasone+thalidomide http//seer.cancer.gov//csr/1975_2001.
(Dex/Thal) vs Dex+Placebo (Dex/P) in patients (pts) with relapsing multiple myeloma (MM). Blood 2006; 108: (Abstract 3563).
4 Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, 23 Macro M, Divine M, Uzunhan Y, Jaccard A, Bouscary D, Leblond V Hodnefield JM et al. Clinical course and prognosis of smoldering et al. Dexamethasone+thalidomide (Dex/Thal) compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma (ALLG) trial of thalidomide and alternate day prednisolone (MM): a randomized trial. Blood 2006; 108: (Abstract 57).
following autologous stem cell transplantation (ASCT) for 24 Rajkumar SV, Rosin˜ol L, Hussein M, Catalano J, Jedrzejczak W, patients with multiple myeloma (ALLG MM6). Blood 2006; 108: Lucy L et al. Multicenter, randomized, double-blind, placebo- controlled study of thalidomide plus dexamethasone compared 40 Abdelkefi A, Ladeb S, Torjman L, Othman TB, Lakhal A, with dexamethasone as initial therapy for newly diagnosed Romdhane NB et al. Single autologous stem-cell transplantation multiple myeloma. J Clin Oncol 2008; 26: 2171–2177.
followed by maintenance therapy with thalidomide is superior to 25 Barlogie B, Tricot G, Anaissie E, Shaughnessy J, Rasmussen E, van double autologous transplantation in multiple myeloma: results Rhee F et al. Thalidomide and hematopoietic-cell transplantation of a multicenter randomized clinical trial. Blood 2008; 111: for multiple myeloma. N Engl J Med 2006; 354: 1021–1030.
26 Morgan G, Davies FE, Owen RG, Rawstron AC, Bell S, Cocks K 41 Schillera GJ, Liaoa M, Sohna JP, Malonea R, Bartonia K, et al. Thalidomide combinations improve response rates; results Habtemariam B et al. Phase I/II trial of bortezomib maintenance from the MRC IX study. Blood 2007; 110: (Abstract 3593).
following autologous peripheral blood progenitor cell transplanta- 27 Palumbo A, Rajkumar SV, Dimopoulos MA, Richardson PG, San tion as treatment for intermediate- and advanced-stage multiple Miguel J, Barlogie B et al. Prevention of thalidomide-associated myeloma. Biol Blood Marrow Transplant 2008; 14 (2 Suppl 1): thrombosis in myeloma. Leukemia 2008; 22: 414–423.
28 Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, 42 Palumbo A, Bringhen S, Petrucci MT, Musto P, Rossini F, Nunzi M Kabat B et al. Combination therapy with lenalidomide plus et al. Intermediate-dose melphalan improves survival of myeloma dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood patients aged 50–70: results of a randomized controlled trial.
29 Lacy MQ, Gertz MA, Dispenzieri A, Hayman SR, Geyer S, Kabat B 43 Facon T, Mary JY, Hulin C, Benboubker L, Attal M, Pegourie B SPOTLIGHT
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stem cell transplantation in elderly patients with multiple 30 Rajkumar SV, Jacobus S, Callander N, Fonseca R, Vesole D, myeloma (IFM 99-06): a randomised trial. Lancet 2007; 370: Greipp P. A randomized phase III trial of lenalidomide plus high- dose dexamethasone versus lenalidomide plus low-dose dexa- 44 Ludwig H, Tothova E, Hajek R, Drach J, Labar B, Egyed M et al.
methasone in newly diagnosed multiple myeloma (E4A03): a trial coordinated by the Eastern Cooperative Oncology Group. Blood as first line treatment in elderly patients with multiple myeloma: second interim analysis. Haematologica 2007; 92 (S1): 31 Niesvizky R, Jayabalan DS, Christos PJ, Furst JR, Naib T, Ely S et al.
45 Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea methasone) combination therapy results in high complete- and V et al. Oral melphalan and prednisone chemotherapy plus overall-response rates in treatment-naive symptomatic multiple thalidomide compared with melphalan and prednisone alone in myeloma. Blood 2008; 111: 1101–1109.
elderly patients with multiple myeloma: randomised controlled 32 Harousseau J, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM et al. Bortezomib plus dexamethasone as induction treatment prior 46 Hulin C, Facon T, Rodon P, Pegourie B, Benboubker L, Doyen C to autologous stem cell transplantation in patients with newly et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates a diagnosed multiple myeloma: results of an IFM phase II study.
significant survival advantage in elderly patients 75 years with Haematologica 2006; 91: 1498–1505.
multiple myeloma compared with melphalan-prednisone (MP) in a 33 Rosinol L, Oriol A, Mateos MV, Sureda A, Garcı´a-Sa´nchez P, randomized, double-blind, placebo-controlled trial, IFM 01/01.
Gutie´rrez N et al. Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before 47 Waage A, Gimsing P, Juliusson G, Turesson I, Fayers P.
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34 Harousseau JL, Mathiot C, Attal M, Marit G, Caillot D, Mohty 48 Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, MMM et al. VELCADE/Dexamethasone (Vel/D) versus VAD as Giuliani N et al. Melphalan, Prednisone, and Lenalidomide induction treatment prior to autologous stem cell transplantation Treatment for newly diagnosed myeloma: a report from the (ASCT) in newly diagnosed multiple myeloma (MM): updated GIMEMA-Italian Multiple Myeloma Network. J Clin Oncol 2007; results of the IFM 2005/01 trial. Blood 2007; 110: (Abstract 450).
35 Cavo M, Patriarca F, Tacchetti P, Galli M, Perrone G, Petrucci MT 49 Mateos MV, Hernandez JM, Hernandez MT, Gutie´rrez NC, et al. Bortezomib (VELCADE)-thalidomide-dexamethasone (VTD) Palomera L, Fuertes M et al. Bortezomib plus melphalan and vs thalidomide-dexamethasone (TD) in preparation for autologous prednisone in elderly untreated patients with multiple myeloma: stem-cell (SC) transplantation (ASCT) in newly diagnosed multiple results of a multicenter phase I/II study. Blood 2006; 108: myeloma (MM). Blood 2007; 110: (Abstract 73a).
36 Palumbo A, Avonto I, Patriarca F, Crippa C, Petrucci MT, Rossini F 50 San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, et al. Bortezomib, pegylated-liposomal-doxorubicin and dexametha- Shpilberg O, Kropff M et al. Bortezomib plus melphalan and sone followed by melphalan 100 mg/m2 in elderly newly diagnosed prednisone for initial treatment of multiple myeloma. N Engl J Med patients: an interim analysis. Blood 2007; 110: (Abstract 448a).
37 Richardson P, Jagannath S, Raje N, Jakubowiak A, Lonial S, Avigan 51 Terpos E, Dimopoulos MA, Sezer O. The effect of novel anti- D et al. Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/ myeloma agents on bone metabolism of patients with multiple Dex) as front-line therapy for patients with multiple myeloma myeloma. Leukemia 2007; 21: 1875–1884.
(MM): preliminary results of a phase 1/2 study. Blood 2007; 110: 52 Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M et al. The proteasome inhibitor bortezomib affects 38 Attal M, Harousseau JL, Leyvraz S, Doyen C, Hulin C, Benboubker osteoblast differentiation in vitro and in vivo in multiple myeloma L et al. Maintenance therapy with thalidomide improves survival in patients. Blood 2007; 110: 334–338.
patients with multiple myeloma. Blood 2006; 108: 3289–3294.
53 von Metzler I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth 39 Spencer A, Prince M, Roberts AW, Bradstock KF, Prosse IW. First M et al. Bortezomib inhibits human osteoclastogenesis. Leukemia analysis of the Australasian Leukaemia and Lymphoma Group

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