Published by the C
International I
Myel
T
oma Founda
ItionNVOLG
UME IV, ISSUE III S
Q3/2007
ThalidomideandRevlimid®Issue
The International Myeloma Foundation (IMF) is pleased to present our third edition of CITINGS
for 2007. This quarterly publication features citations to the most up-to-date studies on myeloma treatment. In
this issue, we focus on thalidomide and Revlimid (lenalidomide) for the treatment of multiple myeloma. Inside
you will find references to the latest published journal articles on both thalidomide and Revlimidfrom the third
quarter of this year.
It is our hope that CITINGS will help keep you abreast of the latest developments in myeloma treatment.
As always, we welcome your feedback; you may contact the IMF at (800) 452-CURE (2873) or at our website
www.myeloma.org.
Susie Novis, President, IMF
Thalidomide/RevlimidPublications
3rdQuarter,2007
N Additionoflenalidomidetomelphalaninthetreatmentofnewlydiagnosedmultiplemyeloma:the
NationalCancerInstituteofCanadaClinicalTrialsGroupMY.11trial.
White DJ, Paul N, Macdonald DA, Meyer RM, Shepherd LE.
Curr Oncol. 2007 Apr;14(2):61-5.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors discuss an upcoming trial that uses a combination of lenalidomide with melphalan for patients with newly diagnosed
myeloma, for the purpose of establishing lenalidomide's tolerability and to gain knowledge about its efficacy.
Oral melphalan and prednisone remain an effective and tolerable treatment for patients with multiple myeloma. For approximately 40
years, this combination has been the standard of care for patients not proceeding to stem cell transplant. Within the last 10 years, new
agents have been found to be efficacious in the relapsed/refractory setting. Within the last year, two trials of added thalidomide in the newly
diagnosed setting have demonstrated outcomes superior to those achieved with melphalan and prednisone alone. This improved outcome
comes at the cost of increased toxicity. The National Cancer Institute of Canada Clinical Trials Group (ncic ctg) has recently developed a
randomized phase II trial (MY.11) that uses a combination of lenalidomide with melphalan for patients with newly diagnosed multiple
myeloma. Lenalidomide is a thalidomide analogue and, like thalidomide, is thought to work through immunomodulatory effects. It was
shown to have activity in patients with relapsed or refractory disease and, in combination with dexamethasone, is superior to dexamethasone
alone. Lenalidomide holds promise as a more effective and potentially less toxic derivative of thalidomide. Experience with lenalidomide in
combination with chemotherapy is very limited, and the purpose of MY.11 is to establish tolerability and to gain knowledge about efficacy.
The information gained from MY.11 is expected to help inform dosing levels and schedules for a large phase III trial being developed by the
Eastern Cooperative Oncology Group that will include participation by the ncic ctg.
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Funded by an educational grant from Celgene Corporation.
N Currenttreatmentstrategiesformultiplemyeloma.
Thomas S, Alexanian R.
Clin Lymphoma Myeloma. 2007 Apr;7 Suppl 4:S139-44.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This article discusses myeloma treatment strategies with novel agents and novel combinations, including thalidomide and
lenalidomide, and reports upon their response rates.
In recent years, there have been major advances in the treatment of multiple myeloma. Among previously untreated patients, different
combinations of dexamethasone, lenalidomide, thalidomide, and bortezomib have produced overall response rates of 80%-90% with
complete response rates of 10%-32%, and remissions are often achieved after only 2 cycles of initiating systemic therapy. Subsequent
intensification with high-dose chemotherapy supported by autologous stem cell transplantation has enabled younger patients to achieve
partial and complete responses with evidence of prolonged survival. Tandem autologous stem cell transplantation and reduced-intensity
allogeneic stem cell transplantation are under investigation in attempts to improve outcomes. For patients unable to pursue consolidation
therapy with stem cell transplantation, remissions obtained with induction therapy can often be extended with the use of maintenance
systemic therapy. Despite available therapies, relapse of disease is inevitable for nearly all patients, and treatment strategies with novel agents
and novel combinations of established agents are under study.
N Reversibilityofrenalfailureinnewlydiagnosedmultiplemyelomapatientstreatedwithhighdose
dexamethasone-containingregimensandtheimpactofnovelagents.
Kastritis E, Anagnostopoulos A, Roussou M, Gika D, Matsouka C, Barmparousi D, Grapsa I, Psimenou E, Bamias A,
Dimopoulos MA.
Haematologica. 2007 Apr;92(4):546-9.
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The authors conclude that renal failure is reversible in the majority of newly diagnosed myeloma patients treated with high-dose
dexamethasone containing regimens, and that the addition of novel agents, such as thalidomide, induces a more rapid reversal.
The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal
of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution.
RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide
and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were
associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who
did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose
dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.
N Bortezomib,melphalan,prednisone,andthalidomideforrelapsedmultiplemyeloma.
Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P, Bringhen
S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie Ematologicche
dell'Adulto.
Blood. 2007 Apr 1;109(7):2767-72.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This multi-center phase I/II trial assesses dosing, safety, and efficacy of the 4-drug combination of bortezomib, melphalan,
prednisone, and thalidomide.
In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly
increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination,
bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2,
1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at
60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The
maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%)
achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT
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as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-
free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5
patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is
an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.
N RandomizedPhaseIItrialofthalidomidealoneversusthalidomideplusinterferonalphainpatients
withrefractorymultiplemyeloma.
Chiou TJ, Wang TH, Chao TY, Lin SF, Tang JL, Chen TY, Chang MC, Hsueh EJ, Chen PM.
Cancer Invest. 2007 Apr-May;25(3):140-7.
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ystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors conclude that thalidomide alone was effective and tolerated in patients with relapsed or refractory myeloma, but
that the combination with interferon alpha was not well tolerated within their patient population.
The potential synergistic anti-myeloma effect for thalidomide combining with interferon alpha was not yet clear clinically. From March 2001
to January 2004, a total of 28 heavily pretreated multiple myeloma (MM) patients were enrolled in this open-labeled, randomized Phase II
study. Patients with refractory MM were randomized to receive either thalidomide alone (200 mg/day up to the maximum dose 800 mg/day,
arm B) or the combination of thalidomide and interferon alpha (3 MIU/m(2) subcutaneous injection 3 times weekly, arm A). The objective
of this study was to compare the safety and efficacy of thalidomide alone to combined regimen. The patients' characteristics were similar
between the 2 arms. However, the average treatment duration was significantly longer in the arm B than the arm A (236 days versus 101
days, p = 0.029). Serum levels of paraprotein decline >/= 25 percent were obtained in 6 of 12 patients (50.0 percent) treated with arm
B and 3 of the 16 patients (18.8 percent) treated with arm A. The estimated time to event was 7.9 months (95 percent confidence interval
[95%CI], 0.5-15.4) for arm B and 1.5 months (95%CI, 0.0-3.4) for arm A (log-rank test, p = 0.0193). The major adverse events in both
arms consisted of neutropenia, anemia, thrombocytopenia, constipation, somnolence, and skin rash. Our study showed that thalidomide
alone was effective and tolerated in patients with relapsed or refractory MM. The thalidomide combined with interferon alpha resulted in a
lower frequency of paraprotein response, shorter treatment-duration and 25 percent of patients' refusing rate. It may be concluded that the
combined regimen is not well tolerated in our patients and needed to be further evaluated in the future.
N Lenalidomide(Revlimid),incombinationwithcyclophosphamideanddexamethasone(RCD),isan
effectiveandtoleratedregimenformyelomapatients.
Morgan GJ, Schey SA, Wu P, Srikanth M, Phekoo KJ, Jenner M, Davies FE.
Br J Haematol. 2007 May;137(3):268-9.
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ystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
No abstract provided.
N Medicalmanagementupdate:multiplemyeloma.
Stoopler ET, Vogl DT, Stadtmauer EA.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 May;103(5):599-609. [Epub 2007 Feb 7.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17291793&ordinalpos=70&itool=EntrezS
ystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This medical management update reviews recent clinical and therapeutic advances in the field of myeloma and highlights issues
that are important to the oral health care provider.
Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal proliferation of immunoglobulin-secreting plasma
cells. Manifestations of MM may include anemia, osteolytic lesions, and renal dysfunction. Treatment for this disease chiefly consists of
corticosteroids, bisphosphonates, chemotherapy, and hematopoietic stem-cell transplantation. This medical management update will review
recent clinical and therapeutic advances in the field of MM and highlight issues that are important to the oral health care provider.
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N PhaseIstudyoflenalidomideinsolidtumors.
Miller AA, Case D, Harmon M, Savage P, Lesser G, Hurd D, Melin SA.
J Thorac Oncol. 2007 May;2(5):445-9.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors set out to define a tolerable dose and describe the toxicity of lenalidomide administered as a daily oral dose for 4
weeks followed by a 2-week rest period (6-week cycle) in patients with solid tumors that were refractory to standard treatment,
and conclude that the recommended dose of lenalidomide for further studies in patients with solid tumors is 25 mg/day for 4
weeks followed by a 2-week rest period.
BACKGROUND: The primary objectives of this phase I study were to define a tolerable dose and to describe the toxicity of lenalidomide
administered as a daily oral dose for 4 weeks followed by a 2-week rest period (6-week cycle) in patients with solid tumors that were
refractory to standard treatment. The secondary objective was to document any antitumor activity. METHODS: Key eligibility criteria included
a performance status of 0-2 and acceptable hematologic, hepatic, and renal function. The dose was escalated from 5 to 10 to 25 mg/day.
Nine cycles (54 weeks) were planned unless the patient developed intolerable toxicity or experienced tumor progression. Dose-limiting
toxicity was defined as nonhematologic toxicity of grade 3 or higher and hematologic toxicity of grade 4 or higher occurring in cycle 1.
RESULTS: Overall, 20 patients were enrolled. One patient was ineligible due to a thromboembolic event within the preceding 6 months, but
this was not known at enrollment and this patient was included in the analysis. Three, five, and 12 patients were treated with 5, 10, and 25
mg/day, respectively. One patient on 25 mg/day developed grade 3 motor neuropathy in cycle 1, and this was the only dose-limiting toxicity.
Moderate dose-dependent and reversible hematologic toxicity was observed. The nonhematologic toxicities were otherwise mild to moderate
over multiple cycles of lenalidomide. One patient had a partial response, and three patients had stable disease; three of these patients had
non-small cell lung cancer. CONCLUSION: The recommended dose of lenalidomide for further studies in patients with solid tumors is 25
mg/day for 4 weeks followed by a 2-week rest period.
N Newtreatmentofmultiplemyeloma[Article in French].
Hulin C.
Rev Med Interne. 2007 May 24; [Epub ahead of print].
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17559982&ordinalpos=47&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The author reviews thalidomide and lenalidomide in the treatment of myeloma.
PURPOSE: After decades of minimal progress, two new classes of drugs with novels mechanisms of action: immunomodulatory drugs
(thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) have shown great activity for the treatment of multiple myeloma.
CURRENT KNOWLEDGE AND KEY POINTS: Thalidomide acts by a variety of mechanisms; its efficacy is well known in disease relapse
especially associated with dexamethasone. Recent results prove that combination of thalidomide with melphalan and prednisone should be
considered as the first line standard of care in elderly patient. The main side effects are peripheral neuropathy and deep-vein thrombosis.
Bortezomib is the first proteasome inhibitor. It is approved for the treatment in first disease relapse. The combination with glucocorticoids
is synergistic. This combination in induction treatment before autologous stem cell transplantation is promising, as well as the combination
with melphalan and prednisone in elderly patient. The main toxicities are fatigue and peripheral neuropathy. Lenalidomide is a structural
analogue of thalidomide. Its efficacy in combination with dexamethasone has been proved in relapsing patients. The main toxicity is
hematologic. Utilisation as first line treatment is also promising. FUTURE PROSPECTS AND PROJECTS: These three drugs have toxicities
predictable and manageable and can be used successively or in combination for greater effectiveness. They have an impact on the multiple
myeloma treatment strategies and on the disease course itself.
N Bortezomibincombinationwiththalidomide-dexamethasoneforpreviouslyuntreatedmultiple
myeloma.
Wang M, Giralt S, Delasalle K, Handy B, Alexanian R.
Hematology. 2007 Jun;12(3):235-9.
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17558699&ordinalpos=31&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors find the addition of bortezomib to a thalidomide-dexamethasone regimen to be a highly effective primary treatment
for newly diagnosed myeloma patients.
In a previous trial among 137 previously untreated patients with multiple myeloma, the combination of thalidomide-dexamethasone induced
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remission in 66% of patients, including complete remission in 13%. In an attempt to induce more frequent remissions, we added bortezomib
to this program. Between 7/03 and 3/06, 38 newly diagnosed patients with multiple myeloma received at least one, but no more than 3,
courses of bortezomib in a dose of 1.3 mg/m(2) IV x 4; dexamethasone 20 mg/m(2) PO for 4 days beginning on days 1, 9, 17; thalidomide
100 mg PO daily increasing to a maximum of 200 mg. There was rapid onset of remission in 33 patients (87%) including 6 patients with
complete remission (16%). Most side effects were preventable, but otherwise were usually mild and reversible. After a median of 4 months,
25 eligible patients received intensive therapy with high-dose melphalan supported by autologous blood stem cells, so that the myeloma was
in complete remission in 14 patients (37% of all patients). The combination of bortezomib-thalidomide-dexamethasone was a highly effective
primary treatment for newly diagnosed patients with multiple myeloma.
N Maintenancetherapyinmultiplemyeloma.
Mihelic R, Kaufman JL, Lonial S.
Leukemia. 2007 Jun;21(6):1150-7. [Epub 2007 Mar 8.]
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This review summarizes the currently available data in the maintenance setting for multiple myeloma (including novel agents
thalidomide and lenalidomide), as well as potential future trials to further address this important issue.
Therapeutic advances in the treatment of multiple myeloma have significantly improved remission duration and overall survival (OS). These
strategies have included the use of immunotherapy (interferon), novel agents (bortezomib, thalidomide, and lenalidomide), corticosteroids,
and chemotherapy. While novel agents have had a major impact on response rates with initial therapy, most patients with multiple myeloma
will eventually relapse. In the setting of minimal residual disease following standard dose or high-dose therapy, a number of different
`maintenance' strategies have emerged to prolong the duration of initial or subsequent remissions. The impact of these strategies on OS and
event-free survival (EFS) is critically important, as the use of ineffective maintenance therapy adds the burden of additional cost, morbidity,
and may reduce quality of life. Truly successful maintenance therapy will be effective in the setting of minimal residual disease, and will
improve not only EFS, but also OS. This review summarizes the currently available data in the maintenance setting for multiple myeloma,
and will discuss potential future trials to further address this important issue.
N Newdrugsformyeloma.
Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K.
Oncologist. 2007 Jun;12(6):664-89.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This review focuses on the extensive clinical data available from studies of thalidomide and lenalidomide in the treatment of
newly diagnosed and advanced multiple myeloma.
Although multiple myeloma remains incurable with conventional treatments, management of the disease has recently been transformed
with the introduction of three novel agents, bortezomib, thalidomide, and lenalidomide. The proteasome inhibitor bortezomib is approved
for the treatment of patients who have received one prior therapy; there is a growing body of clinical evidence showing its effectiveness
alone and in combination in the frontline setting, with high response rates and consistently high rates of complete response. Thalidomide
plus dexamethasone is approved as frontline treatment of multiple myeloma. Other combination regimens including thalidomide have
demonstrated substantial activity in both relapsed and frontline settings. Recently, the thalidomide analogue lenalidomide has been
approved, in combination with dexamethasone, for the treatment of patients who have received one prior therapy; this regimen has
shown promising results in the frontline setting. These agents represent a new generation of treatments for multiple myeloma that affect
both specific intracellular signaling pathways and the tumor microenvironment. Other novel, targeted therapies are also being evaluated
in preclinical and clinical studies. Regimens incorporating bortezomib, thalidomide, lenalidomide, and other novel agents, together with
commonly used conventional drugs, represent a promising future direction in myeloma treatment. At present, further investigation is
required to assess the safety and activity of combinations integrating these other novel agents. However, bortezomib, thalidomide, and
lenalidomide are now in widespread clinical use. This review therefore focuses on the extensive clinical data available from studies of these
drugs in the treatment of newly diagnosed and advanced multiple myeloma. Disclosure of potential conflicts of interest is found at the end
of this article.
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N PhaseItrialofthree-weeklydocetaxel,carboplatinandorallenalidomide(Revlimid)inpatientswith
advancedsolidtumors.
Kalmadi S, Davis M, Dowlati A, O'Keefe S, Cline-Burkhardt M, Pelley RJ, Borden E, Dreicer R, Bukowski R, Mekhail T.
Invest New Drugs. 2007 Jun;25(3):211-6. [Epub 2006 Nov 11.]
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This study sets out to determine the maximum tolerated doses of docetaxel and carboplatin when combined with oral
lenalidomide in a standard phase I study design. The authors conclude that docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day
1, with lenalidomide 5 mg orally daily on Days 1-14 days of a 21 day cycle is the maximum tolerated dose without the use of
prophylactic growth factors, and that this combination is active with further evaluation in a phase II trial warranted.
INTRODUCTION: Lenalidomide is an immunomodulatory derivative of thalidomide with significantly greater in vitro activity and a different
toxicity profile. In preclinical trials it has shown synergy with chemotherapy.
PATIENTS AND METHODS: Primary objective of this study was to determine the maximum tolerated doses of docetaxel and carboplatin
when combined with oral lenalidomide in a standard phase I study design. Between September 2004 and May 2005, 14 patients with
pathologically proven solid tumors, < or =2 prior chemotherapy regimens, performance status ECOG 0/1, and adequate organ function
were enrolled. Dose limiting toxicities (DLT) were defined as > or = grade 3 non-hematological, or grade 4 hematological toxicity. No
growth factors were used during cycle 1.
RESULTS: Three of four patients treated at dose level 1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 10 mg
orally daily on Days 1-14 of a 21 day cycle experienced DLT (grade 3 electrolyte changes in two patients, and grade 4 neutropenia in one
patient). Ten patients were treated at dose level -1, docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, and lenalidomide 5 mg orally
daily on Days 1-14 of a 21 day cycle with one DLT (Grade 4 neutropenia). There were no treatment-related deaths or irreversible toxicities.
Of the 14 response-evaluable patients, five achieved a partial response (5 out of 9 patients with non-small cell lung cancer.
CONCLUSIONS: Docetaxel 60 mg/m(2) and carboplatin AUC 6 on Day 1, with lenalidomide 5 mg orally daily on Days 1-14 days of a 21 day
cycle is the maximum tolerated dose without the use of prophylactic growth factors. This combination is active and further evaluation in a
phase II trial is warranted.
N Thalidomideinnewlydiagnosedmultiplemyeloma:influenceofthalidomidetreatmentonperipheral
bloodstemcellcollectionyield.
Breitkreutz I, Lokhorst HM, Raab MS, Holt B, Cremer FW, Herrmann D, Glasmacher A, Schmidt-Wolf IG, Blau IW, Martin H,
Salwender H, Haenel A, Sonneveld P, Goldschmidt H.
Leukemia. 2007 Jun;21(6):1294-9. [Epub 2007 Mar 22.]
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This phase III study investigates the influence of thalidomide on the outcome of peripheral blood stem cell (PBSC) collection in
myeloma before peripheral autologous blood stem cell transplantation, and concludes that thalidomide as part of an induction
regiment is associated with better response rates but significantly affects the yield of PBSC collection.
In a phase III randomized, multicenter study, the German-speaking Myeloma-Multicenter Group (GMMG) and the Dutch-Belgian Hemato-
Oncology Cooperative Group (HOVON) group investigated the influence of thalidomide (Thal) on the outcome of peripheral blood stem cell
(PBSC) collection in multiple myeloma (MM) before peripheral autologous blood stem cell transplantation (ABSCT). We analyzed the data
of 398 myeloma patients after induction with Thal, doxorubicin and dexamethasone (TAD) in comparison with vincristine, doxorubicin and
dexamethasone (VAD) followed by mobilization with cyclophosphamide, doxorubicin, dexamethasone (CAD) and PBSC collection. Within
both the study groups, patients treated with TAD showed to collect significantly fewer CD34(+) cells compared with VAD (GMMG, TAD:
median 9.8 x 10(6)/kg; range 2.0-33.6; VAD: median 10.9 x 10(6)/kg range 3.0-36.0; P=0.02) (HOVON, TAD: median 7.4 x 10(6)/kg; range
2.0-33.0; VAD: median 9.4 x 10(6)/kg; range 0.0-48.7; P=0.009). However, engraftment after peripheral autologous stem cell transplantation
showed no difference between Thal and VAD groups. We conclude that Thal as a part of induction regimen is associated with better response
rates (GMMG-HD3: CR/PR 79%, VAD: CR/PR 58%; HOVON-50: TAD: CR/PR 81%, VAD: CR/PR 61%), but significantly affects the yield of PBSC
collection. Nevertheless, the number of total CD34(+) cells collected was sufficient for double autologous transplantation in 82% of the Thal
patients, with at least 2.5 x 10(6)/kg CD34(+) cells.
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N Multiplemyeloma[Article in Spanish].
García-Sanz R, Mateos MV, San Miguel JF.
Med Clin (Barc). 2007 Jun 16;129(3):104-15.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors review myeloma's current standards of care, including the emergence of thalidomide and lenalidomide.
Multiple myeloma is the second most common hematological malignancy. It is defined by the presence of monoclonal plasma cells capable
to produce a monoclonal paraprotein causing clinical abnormalities such as anemia, renal insufficiency, hypercalcemia, or bone lesions. New
chromosomal or molecular abnormalities have been identified allowing a better management. Multiple myeloma is treatable and, although it
remains incurable, the patient prognosis and quality of life has notably improved, so it is not rare to see series with a median survival longer
than 5 years. Even more, it is possible by now to expect improvements respect to the standard autologous stem cell transplantation. This
must be attributed to the emergence of a number of new therapies entering clinical practice over the last 6 years: thalidomide (Thalomid®
Pharmion, Boulder, CO, USA), lenalidomide (Revlimid®, Celgene Corporation, Summit, NJ, USA) and bortezomib (Velcade®, Janssen
Pharmaceutica N.V., Belgium). Finally, we also will review the current clinical experience in supportive therapy, which has also contributed
to the patient outcome improvement with approaches such as: new indications for dialysis, use of erythropoietin receptor stimulating agents
and bisphosphonates, and new surgical therapies such as vertebroplasty and balloon kyphoplasty.
N Timetofirstdiseaseprogression,butnotbeta2-microglobulin,predictsoutcomeinmyelomapatientswho
receivethalidomideassalvagetherapy.
Palumbo A, Bringhen S, Falco P, Cavallo F, Ambrosini MT, Avonto I, Gay F, Caravita T, Bruno B, Boccadoro M.
Cancer. 2007 Jun 26; [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17594696&ordinalpos=13&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors investigate baseline parameters that may be predictive of outcome after thalidomide treatment to identify the
myeloma patient subgroups will most benefit from this drug. They find time to first disease progression > 12 months is the best
indicator of overall survival and that elevated serum beta2-microglobulin, generally considered to be a poor prognostic factor, is
not predictive of outcome.
BACKGROUND.: Baseline parameters that may be predictive of outcome after thalidomide treatment have been investigated to identify
which myeloma patient subgroups will most benefit from this drug. METHODS.: Thalidomide has been used as a salvage regimen at the
study institution since 1999. A total of 102 myeloma patients who were diagnosed between January 1999 and February 2005 were evaluable
for intention-to-treat analysis; 78 patients received thalidomide (at a dose of 100 mg/day continuously) and dexamethasone (at a dose of 40
mg/day on Days 1-4 each month) (TD) as salvage treatment whereas 24 patients died or were lost to follow-up before the initiation of TD.
Several parameters such as serum beta2-microglobulin, serum C-reactive protein, immunoglobulin A isotype, hemoglobin, stage of disease,
bone marrow plasmacytosis, age, serum creatinine, gender, stem cell transplantation at the time of diagnosis, and time to first disease
progression were analyzed in association with overall survival (OS).
RESULTS.: The OS from the time of diagnosis was 43.8 months. Using univariate analysis, factors found to be associated with a shorter OS
were a creatinine level >/=2 mg/dL (P = .05), stage III (P = .04), and time to first disease progression </=12 months (P < .0001). The
only factor that remained significantly associated with a shorter OS in multivariate models was time to first disease progression </=12
months (P = .0006). Elevated serum beta2-microglobulin was not found to be predictive of poor OS.
CONCLUSIONS.: Time to first disease progression >12 months was found to be the best indicator of OS. Elevated serum beta2-
microglobulin, generally considered to be a poor prognostic factor, was not found to be predictive of outcome.
N Deepveinthrombosisoccurringontreatmentofpatientsreceivingthalidomidewitherythropoietin.
Chennuru S, Baumann MA.
Intern Med J. 2007 Jul;37(7):506-7.
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17547733&ordinalpos=59&itool=EntrezSy
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No abstract available.
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N Doesmaintenancetherapywiththalidomidebenefitpatientswithmultiplemyeloma?
Munshi NC, Mitsiades CS, Richardson PG, Anderson KC.
Nat Clin Pract Oncol. 2007 Jul;4(7):394-5. [Epub 2007 May 29.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17534287&ordinalpos=10&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
No abstract available.
N Melphalananditsroleinthemanagementofpatientswithmultiplemyeloma.
Falco P, Bringhen S, Avonto I, Gay F, Morabito F, Boccadoro M, Palumbo A.
Expert Rev Anticancer Ther. 2007 Jul;7(7):945-57.
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The authors discuss thalidomide, lenalidomide and bortezomib, in combination with oral melphalan in the elderly and with
intravenous melphalan in younger patients, as changing the traditional treatment paradigm of multiple myeloma.
Melphalan is an alkylating agent approved for the treatment of multiple myeloma and ovarian cancer. The combination of oral melphalan
and prednisone was first introduced in the 1960s and remains the standard therapy for elderly multiple myeloma patients. High-dose
melphalan followed by autologous stem cell support became the standard treatment for younger patients since the 1990s. The occurrence
of drug resistance is the major limiting factor for the long-term success of this therapy, and relapse always occurs. In recent years, advances
in the understanding of the pathogenesis of myeloma and the mechanism of drug resistance have led to the development of novel targeted
therapies that are able to overcome resistance and show additive or synergistic effects with melphalan. Thalidomide, its immunomodulatory
derivative lenalidomide, and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous
melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.
N Oralmelphalan,dexamethasone,andthalidomideforthetreatmentofrefractorymultiplemyeloma.
Asou N, Izuno Y, Okubo T, Ide K, Ueno H, Kawakita M, Mitsuya H, Hata H.
Int J Hematol. 2007 Jul;86(1):69-71.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors present a patient with refractory multiple myeloma who shows a good response to a combination therapy with oral
melphalan, dexamethasone, and thalidomide.
We present a patient with refractory multiple myeloma who showed a good response to a combination therapy with oral melphalan,
dexamethasone, and thalidomide (MDT). A 48-year-old woman with myeloma refractory to thalidomide, dexamethasone, and clarithromycin
received 6 mg melphalan for 4 days every 6 weeks in combination with thalidomide (100 mg daily) and dexamethasone (5 mg daily for
2 days every week). Four months after the initiation of MDT therapy, a 78% reduction of monoclonal protein was achieved. Although
the efficacy of oral MDT combination therapy in elderly patients with newly diagnosed myeloma has been reported, the present data
demonstrate the effectiveness of MDT therapy for refractory myeloma and warrant further exploration with this MDT regimen to treat
myeloma.
N Multiplemyeloma:Aprototypicdiseasemodelforthecharacterizationandtherapeutictargetingof
interactionsbetweentumorcellsandtheirlocalmicroenvironment.
Mitsiades CS, Mitsiades NS, Richardson PG, Munshi NC, Anderson KC.
J Cell Biochem. 2007 Jul 1;101(4):950-68.
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tem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors highlight the recent advances in the understanding of cellular and molecular mechanisms of interactions between
myeloma cells and their milieu, and on the development the series of new classes of therapeutic agents, including thalidomide
and lenalidomide.
The interaction between tumor cells and the local milieu where are homing has recently become the focus of extensive research in a broad
range of malignancies. Among them, multiple myeloma (MM) is now recognized as a prototypical tumor model for the characterization
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of these interactions. This is due not only to the propensity of MM cells to target the skeleton and form lytic bone lesions, but because
interactions of MM cells with normal cells of the bone milieu can attenuate the anti-tumor activity of conventional therapies, such as
glucocorticoids and standard cytotoxic agents, including alkylators. Herein, we highlight the recent advances in our understanding of cellular
and molecular mechanisms of interactions between MM cells and their milieu. Particular emphasis is placed on the interface between MM
cells and normal cell compartments of the BM, especially bone marrow stromal cells (BMSCs), and on the development of a series of new
classes of therapeutic agents, including the proteasome inhibitor bortezomib, thalidomide and lenalidomide, which counteract specific
aspects of those MM-BM interactions. The significant clinical activity of these novel therapies has not only led to a new era in the therapeutic
management of this disease, but also underscored the importance of comprehensively characterizing the role of the local microenvironment
in the pathophysiology of human neoplasias.
N Community-AcquiredLungAbscessCausedbyLegionellamicdadeiinaMyelomaPatienton
Thalidomide.
Girard LP, Gregson DB.
J Clin Microbiol. 2007 Jul 3; [Epub ahead of print.]
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tem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors describe a case of cavitary L. micdadei community-acquired pneumonia in a myeloma patient on thalidomide
treatment and discuss the problems of diagnosing this pneumonia causation in the myeloma patient population.
Legionellae cause 2-14% of community-acquired pneumonia (CAP). Legionella micdadei constitutes < 1% of these infections. We describe a
case of cavitary L. micdadei CAP in a myeloma patient on thalidomide treatment. The importance of considering, and problems in diagnosing
pneumonia caused by L. micdadei in this patient population is reviewed.
N Invitrostudyofthehypercoagulablestateinmultiplemyelomapatientstreatedornotwiththalidomide.
Petropoulou AD, Gerotziafas GT, Samama MM, Hatmi M, Rendu F, Elalamy I.
Thromb Res. 2007 Jul 4; [Epub ahead of print.]
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No abstract available.
N Neurotoxicityofbortezomibtherapyinmultiplemyeloma:Asingle-centerexperienceandreviewofthe
literature.
Badros A, Goloubeva O, Dalal JS, Can I, Thompson J, Rapoport AP, Heyman M, Akpek G, Fenton RG.
Cancer. 2007 Jul 25; [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17654660&ordinalpos=37&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors investigate peripheral neuropathy (PN) with the use of bortezomib treatment in myeloma, and find that 6 of 9
patients with PN who received lenalidomide as salvage therapy after bortezomib had significant improvement in their symptoms.
BACKGROUND.: Bortezomib is active in heavily pretreated multiple myeloma patients; the dose-limiting toxicity is peripheral neuropathy
(PN). METHODS.: The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received
bortezomib. The median age was 57 years (range, 33-80 years), 62% of patients were men, and 37% of patients were African Americans.
Seventeen patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37%
of the patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36
patients) and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in
15% and 7%, respectively.
RESULTS.: Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and
cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory,
n = 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive
of PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses
included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses
were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer
for a median of 5 cycles (range, 2-36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1-19 cycles) for the
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other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage
therapy after bortezomib had significant improvement in their symptoms.
CONCLUSIONS.: The risk of bortezomib-related PN was greater in patients who had PN and DM at baseline. The authors concluded that an
unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation.
N Efficacyofsingle-agentbortezomibvs.single-agentthalidomideinpatientswithrelapsedorrefractory
multiplemyeloma:asystematiccomparison.
Prince HM, Adena M, Smith DK, Hertel J.
Eur J Haematol. 2007 Aug;79(2):93-9. [Epub 2007 Jun 28.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17608711&ordinalpos=36&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors conduct a review of the efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed/
refractory myeloma and find that bortezomib is associated with significantly higher response rate and complete remission rate
using both M-protein and EBMT criteria.
OBJECTIVE: To conduct a systematic review of the efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed/
refractory multiple.
METHODS: Publications in English from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication reference lists, Janssen-Cilag
data-on-file and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies containing at least a single arm
of either treatment group with n> or =30 were included. Studies adding dexamethasone for non-responders were excluded. Statistical
pooling was performed for response rate and overall survival.
RESULTS: One bortezomib study (n = 333, NEJM 2005, 352; 2487-98) and 15 thalidomide (n = 1007) studies met these criteria and were
included. Patient baseline characteristics including age, gender, IgG : IgA, disease duration and beta-2 microglobulin were well matched
except that 48% of bortezomib patients had received prior thalidomide. Response rate, defined as serum M-protein reduction > or =50%,
was 53% for patients receiving bortezomib vs. 32% for thalidomide (P < 0.001, n = 10 studies). Response rate determined by European
Group for Blood and Marrow Transplantation (EBMT) criteria was 41% for patients receiving bortezomib vs. 22% for thalidomide
(P < 0.001, n = 4 studies).
CONCLUSION: Bortezomib was associated with a significantly higher response rate and complete remission rate using both M-protein and
EBMT criteria.
N Lenalidomide:anewagentforpatientswithrelapsedorrefractorymultiplemyeloma.
Tariman JD.
Clin J Oncol Nurs. 2007 Aug;11(4):569-74.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This article discusses lenalidomide's mechanisms of action, clinical trial results, and the management of common adverse effects
in patients with myeloma.
Lenalidomide is a potent, novel thalidomide analog that has demonstrated promising clinical activity in patients with relapsed or refractory
multiple myeloma (MM). It is a lead immunomodulatory drug currently approved by the U.S. Food and Drug Administration. Neutropenia,
thrombocytopenia, and thromboembolic events are common adverse effects associated with lenalidomide therapy in patients with MM.
Careful monitoring of those known serious adverse effects is essential to prevent life-threatening complications. This article discusses
lenalidomide's mechanisms of action, clinical trial results, and the management of common adverse effects in patients with MM.
N Patientswithmultiplemyelomatreatedwiththalidomide:evaluationofclinicalparameters,cytokines,
angiogenicmarkers,mastcellsandmarrowCD57+cytotoxicTcellsaspredictorsofoutcome.
Mileshkin L, Honemann D, Gambell P, Trivett M, Hayakawa Y, Smyth M, Beshay V, Ritchie D, Simmons P, Milner AD,
Zeldis JB, Prince HM.
Haematologica. 2007 Aug;92(8):1075-82. [Epub 2007 Jul 20.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17640854&ordinalpos=38&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors assess laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic
markers and look for changes with therapy. Their findings support the suggestion that thalidomide has anti-angiogenic and
immunomodulatory effects in myeloma.
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BACKGROUND AND OBJECTIVES: In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow
microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic
markers and looked for changes with therapy.
DESIGN AND METHODS: Seventy-five patients with relapsed/refractory myeloma received thalidomide in a phase II trial. Serial samples of
platelet-poor plasma and bone marrow were tested for angiogenic cytokines including vascular endothelial growth factor (VEGF), marrow
microvessel-density (MVD), mast cells and CD57+ cell expression. The effects of these parameters on response rate (RR), progression-free
survival (PFS) and overall survival (OS) were analyzed.
RESULTS: Elevated baseline VEGF predicted for a superior RR (p=0.018) and PFS. Elevated CD57+ cells also predicted superior PFS
(p=0.012). MVD did not predict for RR, PFS or OS, but MVD and VEGF fell significantly in responders. Multivariate analysis identified that
inferior OS was associated with age >65 years (p=0.017), raised lactate dehydrogenase (p=0.001), raised hepatocyte growth factor levels
(p=0.012) and low pre-treatment CD57+ cells (p<0.001).
INTERPRETATION AND CONCLUSIONS: Our findings support the suggestion that thalidomide has anti-angiogenic and immunomodulatory
effects in myeloma. The preferred method for assessing angiogenesis is plasma VEGF levels and the assessment of CD57+ cells for patients
with myeloma receiving novel immunomodulatory drugs should be further investigated.
N VAD-doxilversusVAD-doxilplusthalidomideasinitialtreatmentformultiplemyeloma:resultsofa
multicenterrandomizedtrialoftheGreekmyelomastudygroup.
Zervas K, Mihou D, Katodritou E, Pouli A, Mitsouli Ch, Anagnostopoulos A, Delibasi S, Kyrtsonis M, Anagnostopoulos N,
Terpos E, Zikos P, Maniatis A, Dimopoulos M; On behalf of the Greek Myeloma Study Group.
Ann Oncol. 2007 Aug;18(8):1369-75.
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The authors find that the addition of thalidomide to VAD-doxil increases response and progression-free survival, and probably
overall survival in previously untreated myeloma patients.
BACKGROUND: We have previously demonstrated that vincristine, liposomal doxorubicin and dexamethasone (VAD-doxil) is equally
effective with VAD-bolus yielding objective response rates of 61% as first-line treatment in multiple myeloma (MM). In a phase II study, the
addition of thalidomide to VAD-doxil (TVAD-doxil) proved feasible and increased response rate to 74%. The aim of the present multicenter
prospective randomized clinical trial was to compare the efficacy and toxicity of VAD-doxil and TVAD-doxil in previously untreated MM
patients. PATIENTS AND METHODS: We enrolled 232 newly diagnosed MM patients aged <75 years, 115 randomized to VAD-doxil (arm
A) and 117 to TVAD-doxil (arm B). Patients in arm A received vincristine 2 mg i.v. and liposomal doxorubicin 40 mg/m(2) i.v., on day 1 and
dexamethasone 40 mg p.o. daily on days 1-4, 9-12 and 17-20 for the first cycle and on days 1-4 for the next three cycles. Patients in arm B
received additionally thalidomide 200 mg p.o. daily, at bedtime. Treatment was administered every 28 days. RESULTS: On an intention-to-
treat basis, at least partial response was observed, in 62.6% and in 81.2% of patients randomized to arms A and B, respectively (P = 0.003).
Progression-free survival (PFS) at 2 years was 44.8% in arm A and 58.9% in arm B (P = 0.013). Overall survival (OS) at 2 years was 64.6% and
77%, in arms A and B, respectively (P = 0.037). Considering overall toxicity, constipation, peripheral neuropathy, dizziness/somnolence, skin
rash and edema were significantly higher in arm B compared with arm A (P < 0.01), but grade 3-4 toxicities were low and similar in both
arms. CONCLUSIONS: The addition of thalidomide to VAD-doxil increases response and PFS rates and probably OS in previously untreated
myeloma patients. The superiority of efficacy counterbalances the higher overall toxicity of TVAD-doxil.
N PolymorphismsofCYP2C19geneareassociatedwiththeefficacyofthalidomidebasedregimensin
multiplemyeloma.
Li Y, Hou J, Jiang H, Wang D, Fu W, Yuan Z, Chen Y, Zhou L.
Haematologica. 2007 Aug 1; [Epub ahead of print.]
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
In this study, CYP2C19 genotypes are tested by the polymerase chain reaction-restriction fragment length polymorphism (PCR-
RFLP) method in 92 patients with myeloma. For the first time, the authors' primary data suggests that the polymorphisms of
CYP2C19 gene are associated with the efficacy of thalidomide-based regimens in myeloma.
In this study, CYP2C19 genotypes were tested by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)
method in 92 patients with multiple myeloma (MM). Sixty-two patients were treated with thalidomide plus dexamethasone (Thal+Dex) and
30 with thalidomide combined with chemotherapy (Thal+CC). The overall response rate of extensive metabolizers (EMs) was statistically
higher than that of poor metabolizers (PMs) (62.6% vs. 33.3%, p < 0.05). Similar results were also observed in the Thal+Dex cohort. For
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the first time, our primary data suggested that the polymorphisms of CYP2C19 gene are associated with the efficacy of thalidomide based
regimens in MM.
N Autologousstemcelltransplantationintheelderlyincludingpre-andpost-treatmentoptions.
Kumar SK, Hayman SR, Kyle RA.
Bone Marrow Transplant. 2007 Aug 6; [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17680019&ordinalpos=26&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors discuss the role of high-dose chemotherapy and autologous stem cell transplantation in the treatment of myeloma
patients over 65 years of age.
Multiple myeloma (MM) is a disease of the elderly with a median age at diagnosis of 67 years in a referral population. High-dose
chemotherapy (HDT) and autologous stem cell transplantation has been shown to improve survival in patients with MM in randomized trials
and remains the preferred option for eligible patients. However, the randomized clinical trials demonstrating an advantage for HDT included
only patients younger than 65 years and evidence supporting its role for the elderly patients has been based on retrospective reviews. The
introduction of thalidomide, lenalidomide and bortezomib has changed the paradigm for treatment of myeloma and improved the outcome
for these patients. Several ongoing clinical trials are evaluating the role of these novel agents in this population, specifically comparing these
to HDT-based approaches. Other trials are examining the role of maintenance therapy post-HDT with these novel drugs with or without
steroids. The role of HDT will be further redefined in the coming years with improvements in other therapies.
N High-dosechemotherapyandautologoushematopoieticstemcelltransplantationinmyelomapatients
undertheageof65years.
Mehta J, Singhal S.
Bone Marrow Transplant. 2007 Aug 6; [Epub ahead of print.]
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors discuss the uses of novel agents, such as thalidomide and lenalidomide, with respect to high-dose chemotherapy and
stem cell transplantation for myeloma patients under 65 years of age.
One or two cycles of high-dose chemotherapy with autologous hematopoietic stem cell transplantation have been shown to improve
response rates and survival in myeloma. While this observation has largely been made in patients under the age of 65 years, there is evidence
to suggest that the conclusions can be extrapolated to older individuals as well. In contrast to other hematologic malignancies treated with
high-dose therapy, autografted myeloma patients continue to relapse several years after transplantation, and few patients are cured with this
modality. However, up to a third of patients may be alive beyond a decade; some with excellent quality of life giving rise to the concept of
`operational cure'. Relapsing disease can be treated with novel agents or repeat high-dose chemotherapy and transplantation. The pressing
questions to which answers are not obvious at the moment are whether tandem transplantation should be offered to all patients, and
whether novel agents should be used before transplantation or reserved for relapse. Despite their excellent activity, there is no evidence so
far that novel agents such as thalidomide, bortezomib and lenalidomide can replace high-dose chemotherapy and stem cell transplantation.
N Neuropathyinmultiplemyelomatreatedwiththalidomide:aprospectivestudy.
Plasmati R, Pastorelli F, Cavo M, Petracci E, Zamagni E, Tosi P, Cangini D, Tacchetti P, Salvi F, Bartolomei I, Michelucci R,
Tassinari CA.
Neurology. 2007 Aug 7;69(6):573-81.
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors study the occurrence of both myeloma-related and thalidomide-induced neuropathy in 31 patients with newly-
diagnosed myeloma. They find that peripheral neuropathy was mild in their patients and is a common, early side effect of
thalidomide therapy.
BACKGROUND: Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by
peripheral neurotoxicity.
OBJECTIVE: To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly
diagnosed MM.
METHODS: Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months
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of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation,
the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and
electrophysiologic checkup.
RESULTS: At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly
during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild
sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic
pathology (>or=partial response).
CONCLUSIONS: Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide
therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total
dose, and duration of treatment.
N Post-transplantoutcomesofinductiontherapyformyeloma:Thalidomideanddexamethasoneversus
doxorubicin,vincristine,anddexamethasonepriortohigh-dosemelphalanwithautologousstemcell
support.
Vogl DT, Liu SV, Chong EA, Luger SM, Porter DL, Schuster SJ, Tsai DE, Perl A, Loren AW, Goldstein SC, Nasta SD,
Andreadis C, Mangan PA, Hummel K, Siegel DL, Glatstein E, Stadtmauer EA.
Am J Hematol. 2007 Aug 15; [Epub ahead of print.]
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stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors review the records of 69 patients who received high-dose melphalan conditioning as part of initial therapy for
myeloma and 28 patients who received thalidomide and dexamethasone induction. They find that the use of thalidomide during
induction therapy may lead to improved long-term outcomes after autologous stem cell transplant.
High-dose melphalan with autologous stem cell support improves survival as part of initial therapy for myeloma. Previous studies of pre-
transplant induction regimens have compared paraprotein response rates but not long-term outcomes after transplant. We reviewed the
records of all patients with multiple myeloma who received an autologous stem cell transplant at the University of Pennsylvania Medical
Center. We compared outcomes for 69 patients who received high-dose melphalan conditioning after January 1, 2003 as part of initial
therapy for myeloma, including 41 patients who received anthracycline-based induction (VAD or DVD) and 28 patients who received
thalidomide and dexamethasone induction. Baseline characteristics in these two groups were not different, though potentially clinically
important differences were apparent in assignment to post-transplant consolidation and maintenance therapy. Despite similar response rates
during induction therapy, thalidomide and dexamethasone induction was associated with better progression-free survival (hazard ratio 0.18,
P = 0.011) after transplant. This effect persisted in multivariable regression models including baseline characteristics and post-transplant
treatment. Overall survival was not different between the two groups. These results suggest that the use of thalidomide during induction
therapy may lead to improved long-term outcomes after transplant. Future trials comparing induction therapies should examine progression-
free and overall survival after transplant to confirm this benefit.
N Timetofirstdiseaseprogression,butnotbeta2-microglobulin,predictsoutcomeinmyelomapatientswho
receivethalidomideassalvagetherapy.
Palumbo A, Bringhen S, Falco P, Cavallo F, Ambrosini MT, Avonto I, Gay F, Caravita T, Bruno B, Boccadoro M.
Cancer. 2007 Aug 15;110(4):824-9.
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17594696&ordinalpos=22&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors find that patients with a time to first disease progression > 12 months was the best indicator of overall survival after
thalidomide treatment.
BACKGROUND: Baseline parameters that may be predictive of outcome after thalidomide treatment have been investigated to identify which
myeloma patient subgroups will most benefit from this drug.
METHODS: Thalidomide has been used as a salvage regimen at the study institution since 1999. A total of 102 myeloma patients who were
diagnosed between January 1999 and February 2005 were evaluable for intention-to-treat analysis; 78 patients received thalidomide (at a
dose of 100 mg/day continuously) and dexamethasone (at a dose of 40 mg/day on Days 1-4 each month) (TD) as salvage treatment whereas
24 patients died or were lost to follow-up before the initiation of TD. Several parameters such as serum beta2-microglobulin, serum C-
reactive protein, immunoglobulin A isotype, hemoglobin, stage of disease, bone marrow plasmacytosis, age, serum creatinine, gender, stem
cell transplantation at the time of diagnosis, and time to first disease progression were analyzed in association with overall survival (OS).
RESULTS: The OS from the time of diagnosis was 43.8 months. Using univariate analysis, factors found to be associated with a shorter OS
were a creatinine level > or =2 mg/dL (P = .05), stage III (P = .04), and time to first disease progression < or =12 months (P < .0001).
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The only factor that remained significantly associated with a shorter OS in multivariate models was time to first disease progression
< or =12 months (P = .0006). Elevated serum beta2-microglobulin was not found to be predictive of poor OS.
CONCLUSIONS: Time to first disease progression >12 months was found to be the best indicator of OS. Elevated serum beta2-
microglobulin, generally considered to be a poor prognostic factor, was not found to be predictive of outcome.
N LenalidomideinMyeloma.
Singhal S, Mehta J.
Curr Treat Options Oncol. 2007 Aug 23; [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17713723&ordinalpos=18&itool=EntrezSy
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The authors discuss and compare the use and history of lenalidomide as both induction and salvage myeloma therapy.
OPINION STATEMENT: The standard treatment approach to symptomatic myeloma consists of induction therapy, consolidation with high-
dose chemotherapy and autologous hematopoietic stem cell transplantation in appropriate patients, maintenance therapy, and salvage
therapy. Salvage therapy is of particular importance because not all patients respond to primary therapy, and relapse is virtually universal in
responding patients. Newer agents such as thalidomide, bortezomib, and lenalidomide are very active in patients with relapsed or refractory
disease. Their use singly and in combination results in excellent cytoreduction including complete remissions in patients relapsing - even
after extensive prior therapy. These novel agents have been usually used as salvage therapy in patients relapsing after standard treatment
options including transplantation; a setting in which they are thought to improve survival. However, there is an increasing trend to start
using them early in the course of the disease; for induction therapy. While early deployment of these agents is certainly associated with
high-response rates, evidence that this improves long-term outcome (survival) in patients who subsequently undergo intensive therapy and
transplantation is lacking. Toxicity, expense, and possible long-term consequences on the biology of the disease (for example, development
of refractory relapse) remain a concern. The most appropriate use of newer agents such as lenalidomide is as salvage therapy of relapsed or
refractory disease, and their use as part of induction therapy should be confined to clinical trials until additional data and long-term follow-
up are available.
N InitialTherapyofMultipleMyelomainPatientswhoareCandidatesforStemCellTransplantation.
Bensinger W.
Curr Treat Options Oncol. 2007 Aug 25; [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17721746&ordinalpos=16&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This article discusses the use of novel agents, including thalidomide and lenalidomide, in myeloma induction therapy.
OPINION STATEMENT: Multiple myeloma (MM), a B cell hematologic malignancy involving plasma cells, responds to a variety of drugs
including alkylators, steroids, anthracyclines, immunomodulators and proteosome inhibitors. The disease, however, remains largely incurable
for the majority of patients. For patients who are suitable candidates, high dose chemotherapy with autologous stem cell support (ASCT)
after induction therapy has been shown to improve response rates, progression free survival and overall survival compared to conventional
chemotherapy. The availability of new drugs including thalidomide, lenalidomide and bortezomib has rapidly changed induction strategies.
These drugs have been combined with corticosteroids, alkylators and anthracyclines to treat front-line patients with MM. Preliminary,
phase 1-2 studies have indicated very high response rates and complete response rates formerly only seen with ASCT. Emerging data from
randomized trials suggest that older regimens such as vincristine, adriamycin and dexamethasone (VAD) are not as effective for induction as
newer combinations. Thus new regimens incorporating novel agents should improve overall response rates, increase complete responders
which should translate into improved progression free and overall survival.
N Managementofmultiplemyeloma:Thechanginglandscape.
Reece DE.
Blood Rev. 2007 Aug 28; [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17761373&ordinalpos=15&itool=EntrezSy
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This report highlights some of the key recent findings in multiple myeloma, including the introduction of novel agents such as
thalidomide and lenalidomide, and describes areas for future research.
Many changes have been incorporated into the approach to multiple myeloma over the last few years, due to improvements in our
understanding of the disease biology. New diagnostic and prognostic criteria from the International Myeloma Working Group have clarified
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the initial clinical approach to this disease. The prognostic impact of chromosomal abnormalities is now recognized, and the detection of
specific abnormal cytogenetics is beginning to influence therapeutic decisions. The introduction of the novel agents thalidomide, bortezomib
and lenalidomide has expanded treatment options at different points in the disease course; these agents are being evaluated in conjunction
with conventional chemotherapy and stem cell transplantation. This report highlights some of the key recent findings in multiple myeloma,
and describes areas for future research.
N Theeffectofnovelanti-myelomaagentsonbonemetabolismofpatientswithmultiplemyeloma.
Terpos E, Dimopoulos MA, Sezer O.
Leukemia. 2007 Sep;21(9):1875-84. [Epub 2007 Jul 5.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17611556&ordinalpos=11&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This article discusses the use of thalidomide and lenalidomide in the management of patients with both newly diagnosed and
relapsed/refractory myeloma.
Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and
relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma
cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical
studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide
reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no
effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the
inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces
biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation
markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma
activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with
beneficial effects on bone and may alter the way of management of myeloma-related bone disease.
N Impactoflenalidomidetherapyonstemcellmobilizationandengraftmentpost-peripheralbloodstem
celltransplantationinpatientswithnewlydiagnosedmyeloma.
Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Gastineau DA, Litzow MR, Fonseca R, Roy V, Rajkumar SV,
Gertz MA.
Leukemia. 2007 Sep;21(9):2035-42. Epub 2007 Jun 21.
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17581613&ordinalpos=12&itool=EntrezSy
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The authors examine if lenalidomide has any impact on the ability to collect peripheral blood stem cells (PBSC) and conclude
with the recommendation of collecting PBSC within 6 months of initiation of therapy with lenalidomide containing regimens to
minimize the risk of mobilization failures.
While initial therapies have become highly effective with introduction of lenalidomide and bortezomib and patients may opt for delayed
stem cell transplantation, it is important to collect stem cells for future transplant. Given its increasing use as initial therapy, we examined
if lenalidomide had any impact on the ability to collect peripheral blood stem cells (PBSC). We studied the entire cohort of patients with
myeloma undergoing PBSC mobilization at our institution during a 5-year period, comparing the results between patients receiving different
initial therapies. Among those mobilized with granulocyte-colony stimulating factor (G-CSF) alone, there was a significant decrease in total
CD34(+) cells collected (P<0.001), average daily collection (P<0.001), day 1 collection (P<0.001) and increased number of aphereses
(P=0.004) in patients treated with lenalidomide compared to those receiving dexamethasone, thalidomide-dexamethasone or VAD. A similar
trend was seen in those mobilized with chemotherapy and G-CSF. A trend was seen towards decreased PBSC yield with increasing duration
of lenalidomide therapy as well as increasing age (P=0.002). There was no effect on quality of PBSC collected based on similar engraftment
across all groups. We recommend collection of PBSC within 6 months of initiation of therapy with lenalidomide containing regimens to
minimize the risk of mobilization failures.
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N Low-dosethalidomidepluslow-dosedexamethasonetherapyinpatientswithrefractorymultiple
myeloma.
Murakami H, Handa H, Abe M, Iida S, Ishii A, Ishikawa T, Ishida T, Oota M, Ozaki S, Kosaka M, Sakai A, Sawamura M,
Shimazaki C, Shimizu K, Takagi T, Hata H, Fukuhara T, Fujii H, Miyata A, Wakayama T, Takatsuki K.
Eur J Haematol. 2007 Sep;79(3):234-9. [Epub 2007 Jul 26.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17655699&ordinalpos=5&itool=EntrezSys
tem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The authors find that low-dose thalidomide plus low-dose dexamethasone therapy is as effective as high-dose thalidomide plus
high-dose dexamethasone therapy in patients with refractory multiple myeloma. In addition, they find that leukopenia is one of
the most serious adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.
We report the results of a non-randomized phase II study of low-dose thalidomide plus low-dose dexamethasone therapy in 66 patients with
refractory multiple myeloma. The overall response rate (near complete, partial and minimal response) was 63.6%, and progression-free and
overall survival periods were 6.2 and 25.4 months. In adverse events, the incidence of peripheral neuropathy and deep vein thrombosis was
lower than the data reported in USA and Europe. On the other hand, leukopenia was observed in 41% of patients, including 11% of those
with Grade 3. Leukopenia was closely related to pretreatment pancytopenia, especially thrombocytopenia. The incidence of adverse events
related to dexamethasone was low. In conclusion, low-dose thalidomide plus low-dose dexamethasone therapy was as effective as high-dose
thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. Leukopenia is one of the most serious
adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.
N Mini-Midi-Maxi?Howtoharnessthegraft-versus-myelomaeffectandtargetmolecularremissionafter
allogeneicstemcelltransplantation.
Kröger N.
Leukemia. 2007 Sep;21(9):1851-8. [Epub 2007 Jun 14.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17568819&ordinalpos=13&itool=EntrezSy
stem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
This review focuses on potential strategies of how treatment-related morbidity and mortality might be kept low without an
increased risk of relapse and how remission status after transplantation can be enhanced by using the newly established donor
immunosystems after allografting as a platform for post-transplant treatment strategies with new drugs (including thalidomide
and lenalidomide) or immunotherapy, in order to achieve remission on a molecular level.
Allogeneic stem cell transplantation in multiple myeloma after standard myeloablative conditioning induces a high rate of complete
remissions, but long-term freedom from disease is achieved in 30-40% of the cases only. The therapeutic effect of allogeneic stem cell
transplantation is due to cytotoxicity of high-dose chemotherapy and immune-mediated graft-versus-myeloma effect by donor T cells.
Retrospective studies clearly suggest that both (a) reducing the intensity of high-dose chemotherapy by using reduced-intensity or non-
myeloablative conditioning regimen or (b) reducing the immunotherapy of donor T cells by using T-cell depletion result in lower treatment-
related morbidity and mortality, but also in higher rate of relapse. Therefore, this review will focus on potential strategies of how treatment-
related morbidity and mortality might be kept low without an increased risk of relapse and how remission status after transplantation can be
enhanced by using the newly established donor immunosystems after allografting as a platform for post-transplant treatment strategies with
new drugs (thalidomide, lenalidomide, bortezomib) or immunotherapy (donor lymphocyte infusion, vaccination, tumor-specific T cells) in
order to achieve remission on a molecular level, which seems to be a `conditio sine qua non' to cure myeloma patients.
N Lenalidomideinthetreatmentofmultiplemyeloma.
Rao KV.
Am J Health Syst Pharm. 2007 Sep 1;64(17):1799-807.
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17724360&ordinalpos=3&itool=EntrezSys
tem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The author reviews the pharmacolog y, clinical use, adverse effects, dosage and administration, and cost of lenalidomide in the
treatment of multiple myeloma.
PURPOSE: The pharmacology, clinical use, adverse effects, dosage and administration, and cost of lenalidomide in the treatment of
multiple myeloma (MM) are reviewed. SUMMARY: Lenalidomide is an analogue of thalidomide and has been shown to be more potent
than thalidomide in the stimulation of T-cell, interleukin-2, and interferon-gamma production. Both drugs have direct cytotoxic effects
on myeloma cells and are capable of inducing apoptosis. They are also capable of reducing angiogenesis through the inhibition of the
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secretion of vascular endothelial growth factor (VEGF). Inhibition of VEGF leads to alterations in the microvasculature of the bone marrow
environment and inhibits myeloma cell growth and proliferation. Unlike thalidomide, lenalidomide has almost no sedative or constipative
properties and induces only minimal neurotoxicity; however, there is concern about lenalidomide's teratogenic potential. Phase I, II, and
III trials have been carried out with lenalidomide in patients with relapsed or refractory MM, and the drug has shown impressive response
rates in relapsed disease. The combination of lenalidomide and dexamethasone has shown superior patient survival. Lenalidomide's efficacy
in newly diagnosed MM is currently being studied. Neutropenia and thrombocytopenia were found to be the most common grade 3 or
higher toxicities. Rates of these toxicities varied among trials and may have been affected by the setting in which lenalidomide was used
(i.e., relapsed or refractory disease versus newly diagnosed MM). CONCLUSION: Lenalidomide, a thalidomide analogue, has produced good
results when used with dexamethasone in patients with relapsed or refractory MM. Lenalidomide is associated with hematologic toxicities,
and participation in a restricted-distribution program is required of prescribers, pharmacies, and patients because of the drug's teratogenic
potential.
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