Published by the IC
nternational M I
yeloma FT
oundation
INVOLUMEG
VII, ISSUE IV S
Q4/2010
Novel Therapies Issue
The International Myeloma Foundation (IMF) presents this edition of Citings, our premiere publication featuring the
most up-to-date information on myeloma treatment, focused on the novel therapies currently under study and in use. This
edition corresponds with articles published between September and November 2010.
It is our hope that CITINGS will be a valuable tool in keeping you informed on the latest developments in myeloma treatment.
Please feel free to contact us at (800) 452-CURE (2873) or visit us on the web at www.myeloma.org.
­ Susie Novis, President, IMF
Novel Therapies Publications
November 2010
NSchwann cell autophagy induced by SAHA, 17-AAG, or clonazepam can reduce bortezomib-induced
peripheral neuropathy.
Watanabe T, Nagase K, Chosa M, Tobinai K.
Br J Cancer. 2010 Nov 9;103(10):1580-7. [Epub 2010 Oct 19.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20959823
The authors present data that suggest that aggresome formation in Schwann cells is a possible mechanism of bortezomib-induced peripheral neuropathy,
and drugs that induce heat-shock protein 70 or LAMP-2A have the potential to alleviate this complication.
BACKGROUND: The proteasome inhibitor bortezomib has improved the survival of patients with multiple myeloma but bortezomib-induced peripheral
neuropathy (BiPN) has emerged as a serious potential complication of this therapy. Animal studies suggest that bortezomib predominantly causes patho-
logical changes in Schwann cells. A tractable system to evaluate combination drugs for use with bortezomib is essential to enable continuing clinical benefit
from this drug. METHODS: Rat schwannoma cells were pretreated with vincristine (VCR), histone deacetylase inhibitors, anticonvulsants, or a heat-
shock protein 90 (HSP90) inhibitor. To then monitor aggresome formation as a result of proteasome inhibition and the activation of chaperone-mediated
autophagy (CMA), we performed double-labeling immunofluorescent analyses of a cellular aggregation-prone protein marker. RESULTS: Aggresome
formation was interrupted by VCR, whereas combination treatments with bortezomib involving suberoylanilide hydroxamic acid, 17-allylamino-17-
demethoxy-geldanamycin, or clonazepam appear to facilitate the disposal of unfolded proteins via CMA, inducing HSP70 and lysosome-associated mem-
brane protein type 2A (LAMP-2A). CONCLUSIONS: This schwannoma model can be used to test BiPN-reducing drugs. The present data suggest that
aggresome formation in Schwann cells is a possible mechanism of BiPN, and drugs that induce HSP70 or LAMP-2A have the potential to alleviate this
complication. Combination clinical trials are warranted to confirm the relevance of these observations.
NBortezomib for post-allogeneic hematopoietic stem transplantation relapse and GVHD in multiple myeloma:
a single institute experience.
Kuroda J, Kobayashi T, Tsutsumi Y, Yamamoto M, Ohshiro M, Sasaki N, Shimura Y, Mizutani S, Nagoshi H, Kiyota M,
Nakayama R, Uchiyama H, Matsumoto Y, Horiike S, Shimazaki C, Taniwaki M.
Int J Hematol. 2010 Nov;92(4):669-72. [Epub 2010 Oct 27.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20978877
No abstract available.
www.myeloma.org
(800) 452 - CURE (2873)
Funded by unrestricted educational grants from Celgene Corporation and Onyx Pharmaceuticals.

---

NBortezomib plus dexamethasone for relapsed or treatment refractory multiple myeloma:
the collaborative study at six institutes in Kyoto and Osaka.
Kobayashi T, Kuroda J, Shimura K, Akaogi T, Kawata E, Kiyota M, Tanaka T, Kamitsuji Y, Murakami S, Hatsuse M,
Okano A, Iwai T, Ueda S, Koshida M, Uchiyama H, Matsumoto Y, Kaneko H, Uoshima N, Ueda Y, Kobayashi Y,
Shimazaki C, Horiike S, Taniwaki M.
Int J Hematol. 2010 Nov;92(4):579-86. [Epub 2010 Oct 7.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20924731
The authors conduct a retrospective collaborative investigation of bortezomib plus dexamethasone therapy (BD Tx) for 88 relapsed or refractory myeloma
patients at six institutes. They find that earlier BD Tx courses may be predictive for the subsequent therapeutic pathway of relapsed/refractory myeloma.
We conducted a retrospective collaborative investigation of bortezomib (Bor) plus dexamethasone (Dex) therapy (BD Tx) for 88 relapsed or refractory
(Rel/Ref) MM patients at six institutes. One cycle BD Tx comprised of Bor (1.3 mg/m2/day) on days 1, 4, 8 and 11, and Dex on days 1, 2, 4, 5, 8, 9,
11 and 12, every 21 days, and the mean number of BD Tx cycles was 3. The overall response rate was 66.9%, the median overall survival (OS) was 510
days, and the median progression-free survival (PFS) was 113 days. Attainment of partial response (PR) with the first course of BD Tx associated with
the longer OS and PFS and late good responder, while no patient who did not achieve PR with the first cycle attained better than very good PR (VGPR)
with the subsequent BD Tx. Patient age of less than 64 years old also associated with the longer OS and PFS. In addition, both an earlier disease stage and
Dex dosage had a significant impact on OS, while the attainment of VGPR within 2 cycles had a significantly longer PFS. Earlier BD Tx courses may be
predictive for the subsequent therapeutic pathway of Rel/Ref MM.
NManagement options for cast nephropathy in multiple myeloma.
Cockwell P, Hutchison CA.
Curr Opin Nephrol Hypertens. 2010 Nov;19(6):550-5.
:
http://www.ncbi.nlm.nih.gov/pubmed/20827195
This article reviews the relevance of the following areas to the contemporary management of cast nephropathy in myeloma: immunoassays that quantify
immunoglobulin free light chain, novel chemotherapy agents and high cut-off (protein-permeable) haemodialysis, which are under evaluation in patients
with cast nephropathy and myeloma.
PURPOSE OF REVIEW: This article reviews the relevance of the following areas to the contemporary management of cast nephropathy in multiple
myeloma: immunoassays that quantify immunoglobulin free light chain (FLC), novel chemotherapy agents and high cut-off (protein-permeable) haemo-
dialysis, which are under evaluation in patients with cast nephropathy and multiple myeloma. RECENT FINDINGS: Clonal serum FLC can be measured
with high sensitivity and specificity and used to rapidly screen for cast nephropathy. A sustained decrease in serum FLC levels within 3 weeks of starting
treatment is associated with renal recovery; novel chemotherapy agents can maximize this early response. Although plasma exchange does not produce
clinical benefit, pilot studies of high cut-off haemodialysis show high efficacy for serum FLC removal. SUMMARY: If a patient with cast nephropathy
and severe acute kidney injury remains dialysis-dependent, the prognosis is poor. A prompt diagnosis and commencement of effective chemotherapy is
a critical determinant of renal recovery. A randomized controlled trial of high cut-off haemodialysis in patients with cast nephropathy, who all receive
bortezomib-based chemotherapy, is underway.
NMechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly
diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial.
Broyl A, Corthals SL, Jongen JL, van der Holt B, Kuiper R, de Knegt Y, van Duin M, El Jarari L, Bertsch U,
Lokhorst HM, Durie BGM, Goldschmidt H, Sonneveld P.
Lancet Oncol. 2010 Nov;11(11):1057-65. [Epub 2010 Sep 21.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20864405
The results of this study strongly suggest an interaction between myeloma-related factors and the patient's genetic background in the
development of treatment-induced peripheral neuropathy, with different molecular pathways being implicated in bortezomib-induced and vincristine-
induced peripheral neuropathy.
BACKGROUND: Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity in patients with multiple myeloma, often requiring adjustment
of treatment and affecting quality of life. We investigated the molecular profiles of early-onset (within one treatment cycle) versus late-onset (after two or
three treatment cycles) bortezomib-induced peripheral neuropathy and compared them with those of vincristine-induced peripheral neuropathy during
the induction phase of a prospective phase 3 trial. METHODS: In the induction phase of the HOVON-65/GMMG-HD4 trial, patients (aged 18-65
years) with newly diagnosed Salmon and Durie stage 2 or 3 multiple myeloma were randomly assigned to three cycles of bortezomib-based or vincristine-
based induction treatment. We analysed the gene expression profiles and single-nucleotide polymorphisms (SNPs) of pretreatment samples of myeloma
plasma cells and peripheral blood, respectively. This study is registered, number ISRCTN64455289. FINDINGS: We analysed gene expression profiles
of myeloma plasma cells from 329 (39%) of 833 patients at diagnosis, and SNPs in DNA samples from 369 (44%) patients. Early-onset bortezomib-
induced peripheral neuropathy was noted in 20 (8%) patients, and 63 (25%) developed the late-onset type. Early-onset and late-onset vincristine-induced
peripheral neuropathy was noted in 11 (4%) and 17 (7%) patients, respectively. Significant genes in myeloma plasma cells from patients that were associ-
ated with early-onset bortezomib-induced peripheral neuropathy were the enzyme coding genes RHOBTB2 (upregulated by 1·59 times; p=4·5×10(-5)),
involved in drug-induced apoptosis, CPT1C (1·44 times; p=2·9×10(-7)), involved in mitochondrial dysfunction, and SOX8 (1·68 times; p=4·28×10(-
13)), involved in development of peripheral nervous system. Significant SNPs in the same patients included those located in the apoptosis gene caspase
9 (odds ratio [OR] 3·59, 95% CI 1·59-8·14; p=2·9×10(-3)), ALOX12 (3·50, 1·47-8·32; p=3·8×10(-3)), and IGF1R (0·22, 0·07-0·77; p=8·3×10(-3)). In
late-onset bortezomib-induced peripheral neuropathy, the significant genes were SOD2 (upregulated by 1·18 times; p=9·6×10(-3)) and MYO5A (1·93
times; p=3·2×10(-2)), involved in development and function of the nervous system. Significant SNPs were noted in inflammatory genes MBL2 (OR 0·49,
95% CI 0·26-0·94; p=3·0×10(-2)) and PPARD (0·35, 0·15-0·83; p=9·1×10(-3)), and DNA repair genes ERCC4 (2·74, 1·56-4·84; p=1·0×10(-3)) and
www.myeloma.org
(800) 452 - CURE (2873)

---

ERCC3 (1·26, 0·75-2·12; p=3·3×10(-3)). By contrast, early-onset vincristine-induced peripheral neuropathy was characterised by upregulation of genes
involved in cell cycle and proliferation, including AURKA (3·31 times; p=1·04×10(-2)) and MKI67 (3·66 times; p=1·82×10(-3)), and the presence of SNPs
in genes involved in these processes-e.g., GLI1 (rs2228224 [0·13, 0·02-0·97, p=1·18×10(-2)] and rs2242578 [0·14, 0·02-1·12, p=3·00×10(-2)]). Late-
onset vincristine-induced peripheral neuropathy was associated with the presence of SNPs in genes involved in absorption, distribution, metabolism, and
excretion-e.g., rs1413239 in DPYD (3·29, 1·47-7·37, 5·40×10(-3)) and rs3887412 in ABCC1 (3·36, 1·47-7·67, p=5·70×10(-3)). INTERPRETATION:
Our results strongly suggest an interaction between myeloma-related factors and the patient's genetic background in the development of treatment-induced
peripheral neuropathy, with different molecular pathways being implicated in bortezomib-induced and vincristine-induced peripheral neuropathy.
NPolymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event
outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin.
Buda G, Ricci D, Huang CC, Favis R, Cohen N, Zhuang SH, Harousseau JL, Sonneveld P, Bladé J, Orlowski RZ.
Ann Hematol. 2010 Nov;89(11):1133-40. [Epub 2010 Jun 8.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20532504
The authors retrospectively evaluate the influence of single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and
P-glycoprotein 1 (MDR1) genes on outcomes in relapsed and/or refractory myeloma patients treated with bortezomib or bortezomib with peg ylated liposo-
mal doxorubicin (PLD). Their findings suggest a potential role for MRP1 and MDR1 SNPs in modulating the long-term outcome of relapsed and/or refractory
myeloma patients treated with PLD + bortezomib.
Single nucleotide polymorphisms (SNPs) in the multiple drug resistance protein 1 (MRP1) and P-glycoprotein 1 (MDR1) genes modulate their ability to
mediate drug resistance. We therefore sought to retrospectively evaluate their influence on outcomes in relapsed and/or refractory myeloma patients treated
with bortezomib or bortezomib with pegylated liposomal doxorubicin (PLD). The MRP1/R723Q polymorphism was found in five subjects among the
279 patient study population, all of whom received PLD + bortezomib. Its presence was associated with a longer time to progression (TTP; median 330
vs. 129 days; p = 0.0008), progression-free survival (PFS; median 338 vs. 129 days; p = 0.0006), and overall survival (p = 0.0045). MDR1/3435(C > T),
which was in Hardy-Weinberg equilibrium, showed a trend of association with PFS (p = 0.0578), response rate (p = 0.0782) and TTP (p = 0.0923) in PLD
+ bortezomib patients, though no correlation was found in the bortezomib arm. In a recessive genetic model, MDR1/3435 T was significantly associated
with a better TTP (p = 0.0405) and PFS (p = 0.0186) in PLD + bortezomib patients. These findings suggest a potential role for MRP1 and MDR1 SNPs
in modulating the long-term outcome of relapsed and/or refractory myeloma patients treated with PLD + bortezomib. Moreover, they support prospective
studies to determine if such data could be used to tailor therapy to the genetic makeup of individual patients.
NPomalidomide (CC4047) plus low dose dexamethasone (Pom/dex) is active and well tolerated in lenalidomide
refractory multiple myeloma (MM).
Lacy MQ, Hayman SR, Gertz MA, Short KD, Dispenzieri A, Kumar S, Greipp PR, Lust JA, Russell SJ, Dingli D,
Zeldenrust S, Fonseca R, Bergsagel PL, Roy V, Mikhael JR, Stewart AK, Laumann K, Allred JB, Mandrekar SJ,
Rajkumar SV, Buadi F.
Leukemia. 2010 Nov;24(11):1934-9. [Epub 2010 Sep 9.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20827286
The authors find that the combination of pomalidomide and dexamethasone is highly active and well tolerated in patients with lenalidomide-refractory
myeloma.
Patients with multiple myeloma progressing on current therapies have limited treatment options. Pomalidomide (CC4047), an immunomodulatory
drug, has significant activity in relapsed myeloma and previous studies suggest activity in lenalidomide refractory disease. To better define its efficacy in
this group, we treated a cohort of lenalidomide refractory patients. Pomalidomide was given orally (2 mg) daily, continuously in 28-day cycles along with
dexamethasone (40 mg) given weekly. Responses were assessed by the International Myeloma Working Group Criteria. Thirty-four patients were enrolled.
The best response was very good partial response in 3 (9%), partial response (PR) in 8 (23%), best responses (MR) in 5 (15%), stable disease in 12 (35%)
and progressive disease in 6 (18%), for an overall response rate of 47%. Of the 14 patients that were considered high risk, 8 (57%) had responses including
4 PR and 4 MR. The median time to response was 2 months and response duration was 9.1 months, respectively. The median overall survival was 13.9
months. Toxicity was primarily hematologic, with grade 3 or 4 toxicity seen in 18 patients (53%) consisting of anemia (12%), thrombocytopenia (9%) and
neutropenia (26%). The combination of pomalidomide and dexamethasone (Pom/dex) is highly active and well tolerated in patients with lenalidomide-
refractory myeloma.
NProteasome inhibitors: Dozens of molecules and still counting.
de Bettignies G, Coux O.
Biochimie. 2010 Nov;92(11):1530-45. [Epub 2010 Jul 6.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20615448
The authors discuss the success of bortezomib as a new drug for the treatment of myeloma, and the ongoing clinical trials to evaluate the effect of several
other proteasome inhibitors in various human pathologies, which illustrate the interest for human health of these compounds.
The discovery of the proteasome in the late 80's as the core protease of what will be then called the ubiquitin-proteasome system, rapidly followed by the
development of specific inhibitors of this enzyme, opened up a new era in biology in the 90's. Indeed, the first proteasome inhibitors were instrumental for
understanding that the proteasome is a key actor in most, if not all, cellular processes. The recognition of the central role of this complex in intracellular
proteolysis in turn fuelled an intense quest for novel compounds with both increased selectivity towards the proteasome and better bioavailability that could
be used in fundamental research or in the clinic. To date, a plethora of molecules that target the proteasome have been identified or designed. The success
of the proteasome inhibitor bortezomib (VELCADE®) as a new drug for the treatment of Multiple Myeloma, and the ongoing clinical trials to evaluate
the effect of several other proteasome inhibitors in various human pathologies, illustrate the interest for human health of these compounds.
www.myeloma.org
(800) 452 - CURE (2873)

---

NRecent advances of IMiDs in cancer therapy.
Li S, Gill N, Lentzsch S.
Curr Opin Oncol. 2010 Nov;22(6):579-85.
:
http://www.ncbi.nlm.nih.gov/pubmed/20689431
This review discusses the recent advances in the development of IMiDs, including lenalidomide, as well as newly-established guidelines for venous throm-
boembolism prophylaxis and stem cell mobilization failure associated with lenalidomide.
PURPOSE OF REVIEW: Immunomodulatory derivatives of thalidomide (IMiDs) have been used for the treatment of myelodysplastic syndrome and
multiple myeloma; however, the mechanism of action of IMiDs is largely unknown. The purpose of this review is to provide an overview of recent find-
ings on the mechanism of action of IMiDs, its use as a new treatment modality for various hematologic malignancies, and problems associated with
stem cell mobilization after lenalidomide treatment. RECENT FINDINGS: Recent clinical trials revealed lenalidomide as a promising new agent for the
treatment of follicular non-Hodgkin's lymphoma (NHL) and also diffuse large B-cell lymphoma. Pomalidomide was shown to be even more effective in
refractory multiple myeloma than lenalidomide. New guidelines for the management of venous thromboembolism have been established. The chemokine
receptor 4 (CXCR4) inhibitor, AMD-3100, is recommended for patients who have received lenalidomide and failed to mobilize stem cells after G-SCF
and cyclophosphamide. Preclinical studies investigated the pleiotropic functions of IMiDs, with a particular focus on immune modulation, their effects
on new targets, stem cells and disruption of plasma cell microenvironment interactions. SUMMARY: More and more indications for the use of IMiDs
in hematologic malignancies have been identified. In order to establish better clinical usage of IMiDs, it is of utmost importance to clarify the antitumor
mechanism of IMiDs. Here, we provide a review on the recent advances in the development of IMiDs. New guidelines for venous thromboembolism
prophylaxis and stem cell mobilization failure associated with lenalidomide treatment have been established.
NRole of the TNF- promoter polymorphisms for development of multiple myeloma and clinical outcome in
thalidomide plus dexamethasone.
Du J, Yuan Z, Zhang C, Fu W, Jiang H, Chen B, Hou J.
Leuk Res. 2010 Nov;34(11):1453-8. [Epub 2010 Jan 31.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20122728
The authors study the role of TNF-alpha promoter polymorphisms in the development of myeloma, evaluating patients treated with
a thalidomide-dexamethasone regimen.
The role of TNF-alpha promoter polymorphisms in the development of multiple myeloma (MM) were tested in 210 patients and 218 healthy individuals
and their impact on the clinical outcome were evaluated in 98 patients treated with thalidomide and dexamethasone (Thal+Dex) regimen. MM patients
carrying the GA genotype (p = 0.01) or GA+AA genotypes (p = 0.02) at the TNF-alpha -308 polymorphism were associated with a reduced risk for MM.
The TNF-alpha -238 GA+AA genotypes were associated with a significant enhancement in the progression-free survival (PFS) (p = 0.009) and a better
overall survival (OS) (p = 0.088).
NSafety and efficacy of bortezomib, melphalan and low doses dexamethasone (VM-dex) in newly diagnosed patients
with multiple myeloma.
Gozzetti A, Defina M, Bocchia M, Fabbri A, Marchini E, Chitarrelli I, Lauria F.
Leuk Res. 2010 Nov;34(11):e288-9. [Epub 2010 Jun 16.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20557933
No abstract available.
NTreatment-related peripheral neuropathy in multiple myeloma: the challenge continues.
Delforge M, Bladé J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, Palumbo A, Van Damme P, San Miguel JF,
Sonneveld P.
Lancet Oncol. 2010 Nov;11(11):1086-95.
:
http://www.ncbi.nlm.nih.gov/pubmed/20932799
This review discusses all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.
Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved out-
comes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after
several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological
side-effect associated with thalidomide and bortezomib. Maximizing treatment benefit while preserving quality of life therefore requires a careful balance
between achieving optimum activity and minimizing toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of
drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.
www.myeloma.org
(800) 452 - CURE (2873)

---

NWeekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular
lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia.
Agathocleous A, Rohatiner A, Rule S, Hunter H, Kerr JP, Neeson SM, Matthews J, Strauss S, Montoto S, Johnson P,
Radford J, Lister A.
Br J Haematol. 2010 Nov;151(4):346-53. doi: 10.1111/j.1365-2141.2010.08340.x. [Epub 2010 Sep 29.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20880120
The authors find that the combination of bortezomib and rituximab has significant toxicity but is effective, particularly in patients with Waldenström
macroglobulinaemia.
The combination of bortezomib and rituximab was evaluated in patients with mantle cell lymphoma (MCL), follicular lymphoma (FL) and Waldenström
macroglobulinaemia (WM), in a Phase I and later, a randomized Phase II study. In the randomized study, 42 patients with recurrent/refractory disease
received either: bortezomib 1·3mg/m2 on days 1, 4, 8 and 11 of a 3-week cycle with rituximab 375 mg/m2 on day 1 (21 patients) or: bortezomib
1·6 mg/m2 and rituximab on days 1, 8, 15 and 22 of a 5-week cycle (with rituximab being given only in cycles 1 and 4).Twenty-eight patients were with-
drawn (toxicity 16, progression 7, and `patient choice' 5). The main toxicities were neurological, gastro-intestinal and haematological. The overall response
rate was 28/42(67%) and by histology: MCL 11/19, FL 8/15, and WM 9/10. Ten of 28 responding patients remained progression-free at 1-3·5 years.
Toxicity and efficacy were equivalent between the two groups. The combination has significant toxicity but is effective, particularly in patients with WM.
October 2010
NImmunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow
accessory cells in multiple myeloma.
Görgün G, Calabrese E, Soydan E, Hideshima T, Perrone G, Bandi M, Cirstea D, Santo L, Hu Y, Tai YT, Nahar S,
Mimura N, Fabre C, Raje N, Munshi N, Richardson P, Anderson KC.
Blood. 2010 Oct 28;116(17):3227-37. [Epub 2010 Jul 22.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20651070
The authors examine the in vitro immunomodulatory effects of immunomodulatory agents (IMiDs) on cytokine signaling triggered by interaction of effec-
tor cells with myeloma cells and bone marrow stromal cells. Their data demonstrate that modulation of suppressor of cytokine signaling 1 may enhance
immune response and efficacy of IMiDs in myeloma.
The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma
(MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target
not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signal-
ing triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferon , and IL-6 regulator suppres-
sor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In
addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the
SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-
cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to
re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing-MM cells than unmodified MM cells. These data therefore
demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.
NThe immuno-stimulatory effect of lenalidomide on NK cell function is profoundly inhibited by concurrent
dexamethasone therapy.
Hsu AK, Quach H, Tai T, Prince HM, Harrison SJ, Trapani JA, Smyth MJ, Neeson P, Ritchie DS.
Blood. 2010 Oct 26. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20978269
The authors assess NK cell number and function in 25 patients with myeloma participating in a clinical trial of lenalidomide/dexamethasone. Their findings
indicate lenalidomide's immunostimulatory effects on patient NK cells are severely blunted by concurrent dexamethasone administration.
Lenalidomide combined with dexamethasone is an effective treatment for refractory/relapsed multiple myeloma (MM). Lenalidomide stimulates natural
killer (NK) cells and enhances anti-tumor responses. We assessed NK cell number and function in 25 patients with MM participating in a clinical trial of
lenalidomide/dexamethasone. NK cell numbers increased from a mean of 2.20±0.05 x 10(5)/ml (baseline) to a mean of 3.90±0.03 x 105 /ml (cycle 6) (p =
0.05), however, in vitro NK cell-mediated cytotoxicity decreased from 48.9±6.8% to 27.6±5.1% (p = 0.0028) and could not be rescued by lenalidomide re-
treatment. Lenalidomide increased normal donor NK cell cytotoxicity in vitro from 38.5% to 53.3% but this was completely abrogated by dexamethasone.
Dexamethasone suppression of NK cell-mediated cytotoxicity was partially reversed by a 3 day wash out, but the cells remained refractory to lenalidomide-
induced enhanced function. Lymphocyte subset depletion experiments revealed that lenalidomide's enhancement of NK cell-mediated cytotoxicity was
mediated by CD4(+) T cell production of IL-2 and that dexamethasone acted by suppressing IL-2 production. Similarly, the reduced ability of NK cells
from patients with MM to respond to lenalidomide was due to impaired CD4 T cell function. Our findings indicate lenalidomide's immunostimulatory
effects on patient NK cells are severely blunted by concurrent dexamethasone administration.
www.myeloma.org
(800) 452 - CURE (2873)

---

NBortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome
of patients with del(17p).
Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D, Marit G, Benboubker L, Voillat L,
Mathiot C, Kolb B, Macro M, Campion L, Wetterwald M, Stoppa AM, Hulin C, Facon T, Attal M, Minvielle S,
Harousseau JL.
J Clin Oncol. 2010 Oct 20;28(30):4630-4. [Epub 2010 Jul 19.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20644101
The authors find that short-term bortezomib induction improves outcome of myeloma patients with t(4;14) but not the outcome of patients with del(17p).
However, both abnormalities remain prognostic factors predicting both event-free survival and overall survival despite bortezomib induction.
PURPOSE: Cytogenetics is an important prognostic parameter in multiple myeloma (MM). Patients presenting with either t(4;14) or del(17p) are known
to have a short event-free survival (EFS) and overall survival (OS). Some preliminary data suggest that bortezomib is able to overcome these prognostic
parameters. PATIENTS AND METHODS: A series of 507 patients with newly diagnosed MM who received four cycles of bortezomib-dexamethasone
induction therapy before high-dose melphalan were analyzed for both t(4;14) and del(17p). RESULTS: We found that both t(4;14) and del(17p) remain
prognostic parameters, even in the context of bortezomib treatment. However, it is important to note that bortezomib significantly improves the prog-
nosis (in terms of both EFS and OS) of patients with t(4;14), compared with patients treated with vincristine, doxorubicin, and dexamethasone induc-
tion therapy. In contrast, no improvement was observed for del(17p) patients. CONCLUSION: Short-term bortezomib induction improves outcome of
patients with t(4;14) but not the outcome of patients with del(17p). However, both abnormalities remain prognostic factors predicting both EFS and OS
despite bortezomib induction.
NBortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as
induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma:
results of the IFM 2005-01 phase III trial.
Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P,
Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P.
J Clin Oncol. 2010 Oct 20;28(30):4621-9. [Epub 2010 Sep 7.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20823406
The authors compare efficacy and safety of bortezomib plus dexamethasone versus vincristine plus doxorubicin plus dexamethasone ( VAD) as induction
before stem-cell transplantation in previously untreated myeloma. They find that bortezomib plus dexamethasone significantly improves postinduction
and post-transplantation complete response (CR)/nearCR and at least very good partial response rates compared with VAD, and results in a trend for longer
progression free survival. They conclude that bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.
PURPOSE: To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction
before stem-cell transplantation in previously untreated myeloma. PATIENTS AND METHODS: Four hundred eighty-two patients were randomly
assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus
dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achiev-
ing very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete
response (CR/nCR) rate. RESULTS: Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%)
rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage
or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0%
v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival
(PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and
77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths
related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral
neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone. CONCLUSION: Bortezomib
plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in
a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.
NLight chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple
myeloma: results of a phase II study.
Ludwig H, Adam Z, Hájek R, Greil R, Tóthová E, Keil F, Autzinger EM, Thaler J, Gisslinger H, Lang A, Egyed M,
Womastek I, Zojer N.
J Clin Oncol. 2010 Oct 20;28(30):4635-41. [Epub 2010 Sep 7.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20823423
The authors assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with myeloma with light chain-induced acute renal
failure. They find that BDD induces a high rate of myeloma and renal responses and that treatment is well tolerated.
PURPOSE: To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain-induced
acute renal failure. PATIENTS AND METHODS: Sixty-eight patients with light chain-induced acute renal failure and glomerular filtration rate (GFR)
less than 50 mL/min received bortezomib (1.0 mg/m2 on days 1, 4, 8, and 11), doxorubicin (9 mg/m2 on days 1 and 4), and dexamethasone (40 mg on
days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m2 and doxorubicin administered on days 1, 4, 8, and
11. RESULTS: By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete
response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response
www.myeloma.org
(800) 452 - CURE (2873)

---

was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement
correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free
survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal
response but was inferior in previously treated patients (p < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response,
and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection
(19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%). CONCLUSION: BDD induced a
high rate of myeloma and renal responses, and treatment was well tolerated.
NRenal Impairment in Patients With Multiple Myeloma: A Consensus Statement on Behalf of the International
Myeloma Working Group.
Dimopoulos MA, Terpos E, Chanan-Khan A, Leung N, Ludwig H, Jagannath S, Niesvizky R, Giralt S, Fermand JP,
Bladé J, Comenzo RL, Sezer O, Palumbo A, Harousseau JL, Richardson PG, Barlogie B, Anderson KC, Sonneveld P,
Tosi P, Rajkumar SV, Durie BGM, San Miguel J.
J Clin Oncol. 2010 Oct 18. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20956629
The authors discuss renal impairment as a common complication of myeloma, and discuss various treatment choices (including bortezomib, thalidomide,
and lenalidomide) in this context.
Renal impairment is a common complication of multiple myeloma (MM). The estimated glomerular filtration rate (eGFR) using the Modification of Diet
in Renal Disease formula is the recommended method for the assessment of renal function in patients with MM with stabilized serum creatinine. In acute
renal injury, the RIFLE (risk, injury, failure, loss and end-stage kidney disease) and Acute Renal Injury Network criteria seem to be appropriate to define
the severity of renal impairment. Novel criteria based on eGFR measurements are recommended for the definition of the reversibility of renal impairment.
Rapid intervention to reverse renal dysfunction is critical for the management of these patients, especially for those with light chain cast nephropathy.
Bortezomib with high-dose dexamethasone is considered as the treatment of choice for such patients. There is limited experience with thalidomide in
patients with myeloma with renal impairment. Thus, thalidomide can be carefully administered, mainly in the context of well-designed clinical trials, to
evaluate if it can improve the rapidity and probability of response that is produced by the combination with bortezomib and high-dose dexamethasone.
Lenalidomide is effective in this setting and can reverse renal insufficiency in a significant subset of patients, when it is given at reduced doses, according
to renal function. The role of plasma exchange in patients with suspected light chain cast nephropathy and renal impairment is controversial. High-dose
melphalan (140 mg/m2) and autologous stem-cell transplantation should be limited to younger patients with chemosensitive disease.
NThe impact of bortezomib on the risk of thrombosis in multiple myeloma.
Connolly G.
Leuk Res. 2010 Oct 15. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20952063
No abstract available.
NA phase I/II trial combining high-dose melphalan and autologous transplant with bortezomib for multiple
myeloma: a dose- and schedule-finding study.
Lonial S, Kaufman J, Tighiouart M, Nooka A, Langston AA, Heffner LT, Torre C, McMillan S, Renfroe H, Harvey RD,
Lechowicz MJ, Khoury HJ, Flowers CR, Waller EK.
Clin Cancer Res. 2010 Oct 15;16(20):5079-86. [Epub 2010 Aug 25.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20739431
The authors find that use of bortezomib in conjunction with high dose melphalan is safe, with data suggesting improved efficacy. They recommend a single
dose of bortezomib administered after high dose melphalan, and schedule for future clinical investigation.
PURPOSE: We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-
dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma. EXPERIMENTAL DESIGN: Enrolled patients were
limited to those who did not achieve a very good partial remission (VGPR) following one or more induction regimens, and were randomized to receive
a single escalating dose of bortezomib (1.0, 1.3, or 1.6 mg/m2) either 24 hours before or 24 hours after high-dose melphalan. Dose escalation was based
on the escalation with overdose control (EWOC), a Bayesian statistical model. Bone marrow aspirates were collected before initiation of therapy and at
the time of transplant to evaluate which sequence resulted in maximal plasma cell apoptosis, and response to transplant was assessed by the International
Myeloma Working Group criteria. RESULTS: Among 39 randomized patients, 20 received bortezomib after melphalan and 19 received bortezomib before
melphalan. Toxicities and post-transplant hematopoietic recovery rates were similar between arms. The overall response rate for all patients was 87%, with
51% achieving a VGPR or better. Pharmacodynamic studies showed greater plasma cell apoptosis among patients who received bortezomib following
melphalan. CONCLUSIONS: The use of bortezomib in conjunction with high-dose melphalan is safe, with data suggesting improved efficacy. A single
dose of bortezomib administered after high-dose melphalan is the recommended dose and schedule for future clinical investigation.
www.myeloma.org
(800) 452 - CURE (2873)

---

NA prospective evaluation of the biochemical, metabolic, hormonal and structural bone changes associated
with bortezomib response in multiple myeloma patients.
Zangari M, Yaccoby S, Pappas L, Cavallo F, Kumar NS, Ranganathan S, Suva LJ, Gruenwald JM, Kern S, Zhan F, Esseltine
DL, Tricot G.
Haematologica. 2010 Oct 15. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20952514
The authors prospectively evaluate the bone changes associated with proteasome inhibition using single agent bortezomib in relapsed or refractory
myeloma patients and demonstrate that the myeloma control produced by proteasome inhibition is associated with bone changes and to a discrete pattern
of hormonal variation.
BACKGROUND: We prospectively evaluated the bone changes associated with proteasome inhibition using single agent bortezomib in relapsed or
refractory myeloma patients. DESIGN AND METHODS: Ten patients received bortezomib 1.3 mg/m2 per day 1, 4, 8 and 11 x three 21-day cycles,
and six patients received 1 mg/m2 per day with the same schedule. Bone architecture and metabolism changes were assessed by bone markers, micro
CT, bone histomorphometry, tetracycline labeling and serum parathormone levels. Bone parameter variations were compared by response to treatment.
Microarchitectural changes were observed in all evaluable responsive patients. Results: Bone alkaline phosphatase changes were associated with disease
response, (>PR vs. others p = 0.03 cycle 1 day 11) serum parathormone levels were also significantly increased (p = 0.04 on days 11, 21, 33) in responding
individuals. CONCLUSIONS: This study demonstrates that the myeloma control produced by proteasome inhibition is associated with bone changes and
to a discrete pattern of hormonal variation.
NLow-dose Acyclovir is Effective for Prevention of Herpes Zoster in Myeloma Patients Treated with Bortezomib:
A Report from the Korean Multiple Myeloma Working Party (KMMWP) Retrospective Study.
Kim SJ, Kim K, Do YR, Bae SH, Yang DH, Lee JJ.
Jpn J Clin Oncol. 2010 Oct 14. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20947927
In this retrospective review, the authors find that the administration of acyclovir 400 mg once daily during bortezomib treatment is an effective prophylaxis
for herpes zoster in patients receiving bortezomib, irrespective of disease state and the type of chemotherapy regimen.
OBJECTIVE: Acyclovir prophylaxis has been considered as mandatory for patients receiving bortezomib because herpes zoster is a common adverse event
associated with the use of bortezomib. Although the minimal effective dose of acyclovir for prophylaxis has not yet established, the efficacy of low-dose
acyclovir prophylaxis, 400 mg once daily, has been suggested. METHODS: We retrospectively reviewed the patients receiving the low-dose acyclovir
which was defined as the once daily administration of acyclovir 400 or 200 mg. All patients received bortezomib-containing chemotherapy in the setting
of relapsed or refractory myeloma. RESULTS: Eighty patients received bortezomib-containing treatment as a salvage therapy. All patients received at least
one or more treatments prior to bortezomib treatment, including autologous stem cell transplantation. Sixty-one patients received 400 mg of acyclovir once
daily while 19 patients received 200 mg. Although seven cases of herpes zoster were observed from 80 patients (7/80, 8.75%), two cases of herpes zoster
received 400 mg during the limited period from the first to the fourth cycle, and the other five received 200 mg. Therefore, there was no herpes zoster
in patients who received 400 mg of acyclovir till the last cycle of bortezomib treatment. There were no adverse events associated with the use of acyclovir
prophylaxis. CONCLUSIONS: The administration of acyclovir 400 mg once daily during the bortezomib treatment is an effective prophylaxis for herpes
zoster in patients receiving bortezomib irrespective of disease state and the type of chemotherapy regimen.
NBortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide
Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized
Controlled Trial.
Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, Offidani M, Patriarca F, Nozzoli C, Guglielmelli T,
Benevolo G, Callea V, Baldini L, Morabito F, Grasso M, Leonardi G, Rizzo M, Pia Falcone A, Gottardi D,
Montefusco V, Musto P, Petrucci MT, Ciccone G, Boccadoro M.
J Clin Oncol. 2010 Oct 12. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20940200
This phase III study examines the efficacy of the four-drug combination of bortezomib-melphalan-prednisone-thalidomide ( VMPT) followed by maintenance
with bortezomib-thalidomide ( VMPT-VT) compared with VMP treatment alone in untreated myeloma patients who are ineligible for autologous stem-cell
transplantation. The authors find that VMPT followed by VT as maintenance is superior to VMP alone.
PURPOSE: The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for newly diagnosed multiple myeloma. This phase
III study examined the efficacy of the four-drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance with
bortezomib-thalidomide (VMPT-VT) compared with VMP treatment alone in untreated multiple myeloma patients who are ineligible for autologous
stem-cell transplantation. PATIENTS AND METHODS: A total of 511 patients were randomly assigned to receive nine cycles of VMPT followed by
continuous VT as maintenance, or nine cycles of VMP at the same doses with no additional therapy. The primary end point was progression-free survival.
RESULTS: The 3-year estimates of progression-free survival were 56% in patients receiving VMPT-VT and 41% in those receiving VMP (hazard ratio
[HR], 0.67; 95% CI, 0.50 to 0.90; p = .008). At 3 years, the cumulative proportions of patients who did not go on to the next therapy were 72% with
VMPT-VT and 60% with VMP (HR, 0.58; 95% CI, 0.50 to 0.90; p = .007). Complete response rates were 38% in the VMPT-VT group and 24% in
the VMP group (p < .001). The 3-year overall survival was 89% with VMPT-VT and 87% with VMP (HR, 0.92; 95% CI, 0.53 to 1.60; p = .77). Grade
3 to 4 neutropenia (38% v 28%; p = .02), cardiologic events (10% v 5%; p = .04), and thromboembolic events (5% v 2%; p = .08) were more frequent
among patients assigned to the VMPT-VT group than among those assigned to the VMP group; treatment-related deaths were 4% with VMPT-VT and
3% with VMP. CONCLUSION: VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible
for autologous stem-cell transplantation.
www.myeloma.org
(800) 452 - CURE (2873)

---

NA phase II open-label trial of bortezomib in patients with multiple myeloma who have undergone an autologous
peripheral blood stem cell transplant and failed to achieve a complete response.
Rifkin RM, Greenspan A, Schwerkoske JF, Mandanas RA, Stephenson JJ, Kannarkat GT, Zhan F, Boehm KA, Asmar L,
Beveridge R.
Invest New Drugs. 2010 Oct 12. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20938715
This study aims to determine the feasibility, safety, tolerability, and efficacy of bortezomib following high-dose melphalan therapy and peripheral blood
stem cell transplantation (PBSCT). The study closed early due to widespread availability of bortezomib and the lack of bortezomib-naïve patients, but the
authors conclude that bortezomib monotherapy after melphalan and autologous PBSCT is feasible, safe and well-tolerated (toxicities were manageable),
yet failed to produce the hypothesized response rates.
BACKGROUND: A majority of multiple myeloma (MM) patients fail to achieve complete response (CR) to peripheral blood stem cell transplantation
(PBSCT); effective options following autologous transplantation are needed. Bortezomib (B) is active against MM. This study was conducted to determine
the feasibility, safety, tolerability, and efficacy of B following high-dose melphalan therapy and PBSCT. METHODS: Fifty patients enrolled (48 evaluable)
and 49 were treated (safety population). Treatment: 4 cycles B 1.3 mg/m2 Days 1, 4, 8, and 11/21-days; 4 additional cycles were permitted for stable or
responding patients. RESULTS: Median age was 55 years (range, 38-73), 68% male, 64% ECOG PS = 0, 44% Durie-Salmon Stage IIIA prior to induction,
42% had symptomatic IgG MM; 74% had prior single transplant (26% tandem). Responses post-transplant: 70% PRs, 18% MRs. A median of 4 cycles
(range, 2-8) of B were administered. Responses: CR 8%, uCR 2%, PR 23%, uPR 19%, MR 10%, and no change 35%; median time-to-treatment failure
(TTF) was 6.2 months (range, 1.0-19.4). Three deaths occurred (n = 1 sepsis, n = 2 disease progression). Grade 3-4 treatment-related toxicities included:
thrombocytopenia, neuropathy (14%, each); asthenia, neutropenia (10%, each); and nausea (4%). Twelve patients (24%) discontinued treatment due to
toxicity and 30 patients (60%) completed the study; 20 patients started new treatment (median 5.8 months [range, 1.5-20.3]). CONCLUSIONS: The
study closed early due to widespread availability of B, and the lack of B-naïve patients. Bortezomib monotherapy after melphalan and autologous PBSCT
was feasible, safe and well-tolerated (toxicities were manageable), but failed to produce the hypothesized response rates.
NBortezomib, cyclophosphamide, and dexamethasone: highly effective for rapid reversal of myeloma-associated
hyperammonemic encephalopathy.
Howman R, Thakerer A, Pitman M, Ding N, Thompson PA, Khot A, Harrison SJ.
Leuk Lymphoma. 2010 Oct 7. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20929329
No abstract available.
NComplete remission following treatment with bortezomib, doxorubicin, dexamethasone and autologous stem cell
transplant in patient with immunoglobulin E multiple myeloma.
Pog DR, Kraj M, Kruk B, Hagedorna-Tronina R, Towska M, Warzocha K.
Leuk Lymphoma. 2010 Oct 7. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20929320
No abstract available.
NImpact of genomic aberrations including chromosome 1 abnormalities on the outcome of patients with relapsed
or refractory multiple myeloma treated with lenalidomide and dexamethasone.
Chang H, Jiang A, Qi C, Trieu Y, Chen C, Reece D.
Leuk Lymphoma. 2010 Oct 7. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20929319
The authors evaluate genetic risk factors including chromosome 1q gain and 1p loss by cIg-FISH in 143 patients with relapsed/refractory myeloma treated
with lenalidomide and dexamethasone, and correlate the genomic aberrations with patient clinical outcomes. Their data suggest that chromosome 17p and
1p21 deletions adversely impact the outcome of lenalidomide and dexamethasone treated patients with relapsed/refractory myeloma; improved therapeutic
strategies are required for these patients.
Previous literature suggests that cytogenetics may be used for risk-adapted therapy in patients with relapsed/refractory multiple myeloma (MM) treated
with lenalidomide and dexamethasone. However, the significance of each abnormality is still unclear, and chromosome 1 abnormalities have yet to be
studied in this population. We therefore evaluated genetic risk factors including chromosome 1q gain and 1p loss by cIg-FISH in 143 patients with
relapsed/refractory MM treated with lenalidomide and dexamethasone, and correlated the genomic aberrations with patient clinical outcomes. Patients had
a median of two previous therapies in this cohort. A total of 119 out of 143 (83%) patients had an objective response, with median time to progression
(TTP) and overall survival (OS) of 11 and 28 months, respectively. Patients with del(1p21) or del(17p) (p53) deletions had a significantly shorter TTP.
OS was shorter in patients with 1p21 or 17p deletions, but did not reach statistical significance. Prior bortezomib or thalidomide treatment was associated
with shorter TTP and OS. Multivariate analysis identified del(17p), del(1p21), and prior bortezomib or thalidomide therapy as independent risk factors
for shorter TTP. Our data suggest that chromosome 17p and 1p21 deletions adversely impact the outcome of lenalidomide and dexamethasone treated
patients with relapsed/refractory MM. Improved therapeutic strategies are required for these patients.
www.myeloma.org
(800) 452 - CURE (2873)

---

NStability of unused reconstituted bortezomib in original manufacturer vials.
Vanderloo JP, Pomplun ML, Vermeulen LC, Kolesar JM.
J Oncol Pharm Pract. 2010 Oct 6. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20926455
This study aims to examine the stability of unused reconstituted bortezomib when stored at 4°C for up to 15 days. The authors find that unused reconsti-
tuted bortezomib is stable under these conditions when stored in the original manufacturer vial.
BACKGROUND: Bortezomib is a modified dipeptidyl boronic acid analogue used to treat multiple myeloma, mantle cell lymphoma, and, more recently,
renal transplantation graft rejection. As per manufacturer recommendations, bortezomib is to be administered within 8 h of preparation or may be stored
for up to 8 h in the vial or a syringe following reconstitution. Preserving unused reconstituted bortezomib beyond these 8 h may allow for cost savings.
This study aims to examine the stability of unused reconstituted bortezomib when stored at 4°C for up to 15 days. METHODS: Using an LC-MS/MS
assay, the concentration of reconstituted bortezomib was measured at predetermined time points following storage at 4°C in the manufacturer vial. Percent
bortezomib remaining at a time point was calculated versus initial bortezomib concentration. RESULTS: The concentrations of bortezomib were found to
be 51.93 ng/mL ± 4.60 after 1 day of storage, 57.40 ng/mL ± 4.77 after 8 days of storage, and 49.43 ng/mL ± 2.85 after 15 days of storage. The percent
of bortezomib remaining was 110.53% and 95.19% after 8 days and 15 days, respectively. CONCLUSION: Unused reconstituted bortezomib is stable
for up to 15 days stored at 4°C in the original manufacturer vial. Such use of bortezomib may improve cost efficiency by reducing bortezomib waste.
NTreatment-related peripheral neuropathy in multiple myeloma: the challenge continues.
Delforge M, Bladé J, Dimopoulos MA, Facon T, Kropff M, Ludwig H, Palumbo A, Van Damme P, San Miguel JF,
Sonneveld P.
Lancet Oncol. 2010 Oct 5. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20932799
In this review, the authors discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.
Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved out-
comes for patients with multiple myeloma. As a result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after
several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological
side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance
between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of
drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.
NOutcome and toxicity in the modern era of new drugs for multiple myeloma: a reappraisal for comparison
with future investigational trials.
Offidani M, Leoni P, Corvatta L, Polloni C, Gentili S, Liberati AM, Pulini S, Gozzetti A, Ballanti S, Nozzoli C, Palumbo A.
Clin Lymphoma Myeloma Leuk. 2010 Oct 1;10(5):353-60.
:
http://www.ncbi.nlm.nih.gov/pubmed/21030348
The authors review the results of a series of phase I, II, III studies with thalidomide, lenalidomide, and bortezomib combinations for newly diagnosed
myeloma in order to define a reasonable standard in terms of activity, efficacy, and toxicity and to have a potentially useful starting point for comparisons
with future investigational trials.
The introduction of new drugs such as thalidomide, lenalidomide, and bortezomib has led to novel treatment strategies and significantly improved the
outcome of patients with multiple myeloma (MM). The enhanced knowledge of myeloma pathogenesis has allowed the identification of new therapeutic
targets and many clinical trials are either planned or in progress to evaluate these more selective drugs in the near future. The results of these studies,
however, will have to be compared with the results of existing novel therapies for the treatment of MM in order to define whether new protocols do not
duplicate current new standards and constitute a real improvement. We reviewed the results of a series of phase I, II, III studies with thalidomide, lenalido-
mide, and bortezomib combinations for newly diagnosed MM in order to define a reasonable standard in terms of activity, efficacy, and toxicity and to have
a potentially useful starting point for comparisons with future investigational trials. Three-drug regimens appear to double the complete remission (CR)
rate (20%), though regimens containing 4 drugs triple the CR rate (30%), compared with those containing only 2 agents (10%). These improvements
in the depth and quality of response translate into a progressive increase in the progression-free survival rate at 2 years (from approximately 54%-62% to
75%, respectively). Conversely, by using additional agents, a marked increase in hematologic toxicity has been described (8%, 28%, and 28% respectively),
whereas nonhematologic toxicity appears to be similar (26%, 24%, and 27%, respectively). These results suggest that new trials in the future will constitute
significant progress if they can improve on the current relatively favorable efficacy/toxicity ratio. Nonetheless, exciting new combinations in development
do hold promise and results from these studies are eagerly awaited.
NAn abnormal nonhyperdiploid karyotype is a significant adverse prognostic factor for multiple myeloma
in the bortezomib era.
Tan D, Teoh G, Lau LC, Lim A, Lim TH, Yap KC, Premalatha P, Lao ZT, Wee N, Choo C, Wee HC, Su S, Lee YS,
Lee LH, Hwang W, Goh YT.
Am J Hematol. 2010 Oct;85(10):752-6.
:
http://www.ncbi.nlm.nih.gov/pubmed/20721886
The authors study the survival data of 261 previously untreated myeloma patients at their institution, where bortezomib became available from 2004 for the
treatment of relapse disease. Their findings suggest that bortezomib used at relapse is better able to overcome adverse risk related to high tumor burden
(as measured by the ISS) than adverse cytogenetics on conventional karyotyping.
www.myeloma.org
(800) 452 - CURE (2873)

---

Multiple myeloma is clinically heterogeneous and risk stratification is vital for prognostication and informing treatment decisions. As bortezomib is able
to overcome several high-risk features of myeloma, the validity of conventional risk-stratification and prognostication systems needs to be reevaluated.
We study the survival data of 261 previously untreated myeloma patients managed at our institution, where bortezomib became available from 2004 for
the treatment of relapse disease. Patient and disease characteristics, and survival data were evaluated overall, and with respect to bortezomib exposure.
Overall, the international staging system (ISS), metaphase karyotyping and interphase fluorescence in situ hybridization (FISH) were discerning of survival
outcomes, where the median for the entire cohort was 5.2 years. However, when stratified by bortezomib exposure, only metaphase karyotyping was still
discriminating of long-term prognosis. The presence of an abnormal nonhyperdiploid karyotype overrides all other clinical and laboratory parameters in
predicting for a worse outcome on multivariate analysis (median survival 2.6 years, p = 0.001), suggesting that bortezomib used at relapse is better able to
overcome adverse risk related to high tumor burden (as measured by the ISS) than adverse cytogenetics on conventional karyotyping. Metaphase karyotyp-
ing provides additional prognostic information on tumor kinetics where the presence of a normal diploid karyotype in the absence of any high-risk FISH
markers correlated with superior survival and could act as a surrogate for lower plasma cell proliferation.
NActivity and safety of lenalidomide and dexamethasone in patients with multiple myeloma requiring dialysis:
a Spanish multicenter retrospective study.
de la Rubia J, Roig M, Ibáñez A, García I, Vera JA, Aguilar C, del Campo R, González N, Martínez R, Palomera L,
Picón I, Rodríguez JN, Sanz MA.
Eur J Haematol. 2010 Oct;85(4):363-5. doi: 10.1111/j.1600-0609.2010.01500.x. [Epub 2010 Aug 30.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20662900
No abstract available.
NBetter quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in
patients with relapsed or refractory multiple myeloma.
Harousseau JL, Dimopoulos MA, Wang M, Corso A, Chen C, Attal M, Spencer A, Yu Z, Olesnyckyj M, Zeldis JB,
Knight RD, Weber DM.
Haematologica. 2010 Oct;95(10):1738-44. [Epub 2010 May 11.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20460639
This retrospective pooled analysis of two phase III trials compares clinical outcomes of patients who achieved a complete response or very good partial
response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response. The authors find that
continuing treatment with lenalidomide plus dexamethasone to achieve best response, in the absence of disease progression and toxicity, provides deeper
remissions and greater clinical benefit over time for patients in this study.
BACKGROUND: This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved
a complete response or very good partial response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a
partial response. DESIGN AND METHODS: Patients (n = 353) received lenalidomide (25 mg/day for 21 days of each 28-day cycle) plus dexamethasone
(40 mg on days 1-4, 9-12, and 17-20 for four cycles, and only on days 1-4 after the first four cycles). Time to response, duration of response, time-to-
progression, overall survival, and adverse events were investigated for patients who had a complete or very good partial response and compared with those
of patients who had a partial response. RESULTS: At the time of unblinding, 32% of patients had achieved a complete or very good partial response and
28% had a partial response. Half (50.5%) of the patients who had a partial response as their initial response achieved a complete or very good partial
response with further treatment. The probability of achieving a complete or very good partial response with continued lenalidomide treatment decreased
with delayed achievement of a partial response (by cycle 4 versus later); however, it remained clinically significant. With an extended follow-up of 48
months, the median response duration, time-to-progression, and overall survival were longer in patients with a complete or very good partial response
than in those with a partial response (24.0 versus 8.3 months, P<0.001; 27.7 versus 12.0 months, p < 0.001; not reached versus 44.2 months, p = 0.021,
respectively). The benefit of a complete or very good partial response was independent of when it was achieved. CONCLUSIONS: Continuing treatment
with lenalidomide plus dexamethasone to achieve best response, in the absence of disease progression and toxicity, provided deeper remissions and greater
clinical benefit over time for patients in this study.
NBortezomib and dexamethasone for Japanese patients with relapsed and refractory multiple myeloma:
a single center experience.
Igarashi N, Chou T, Hirose T, Imai Y, Ishiguro T.
Int J Hematol. 2010 Oct;92(3):518-23. [Epub 2010 Oct 2.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20886379
The authors retrospectively investigate 60 Japanese patients with relapsed or refractory myeloma who underwent bortezomib and dexamethasone (BD)
therapy. They find that BD therapy is well tolerated, and produces significant response in relapsed or refractory myeloma patients.
Bortezomib is a novel proteasome inhibitor, which has shown high antimyeloma activity. APEX trial, phase III randomized study for relapsed or refractory
myeloma established efficacy and feasibility of bortezomib. In our study, we retrospectively investigated 60 Japanese patients with relapsed or refractory
multiple myeloma (MM) who underwent bortezomib and dexamethasone (BD) therapy in our institution. Overall response rate was 75%, including 7
cases (11.7%) of complete response and 13 cases (21.7%) of very good partial response. Stable disease and progressive disease were observed in 15 patients
(25%). Major grade 3 adverse events were hematological toxicities and grade 3 non-hematological toxicities included appetite loss, diarrhea and periph-
eral neuropathy. BD therapy was well tolerated, and produced significant response in relapsed or refractory MM patients. Recently, many worldwide trials
including bortezomib or other new agents are ongoing to evaluate its efficacy not only as a therapy for relapsed or refractory disease but also as a frontline
therapy. Further investigations are required to define how to use new antimyeloma agents for Japanese MM patients.
www.myeloma.org
(800) 452 - CURE (2873)

---

NBortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy
followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in
elderly patients with untreated multiple myeloma: a randomised trial.
Mateos MV, Oriol A, Martínez López J, Gutiérrez N, Teruel AI, de Paz R, García Laraña J, Bengoechea E, Martín A,
Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM,
Martín Mateos ML, García Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ,
Bladé J, San Miguel JF.
Lancet Oncol. 2010 Oct;11(10):934-41. [Epub 2010 Aug 23.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20739218
The authors find that reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly
myeloma patients.
BACKGROUND: Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients
with untreated multiple myeloma; however, toxic effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain effi-
cacy and to reduce toxic effects. METHODS: Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and
older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n = 130) or bortezomib plus thalidomide and prednisone (VTP; n
= 130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m² on days 1, 4, 8, 11, 22, 25, 29, and 32), plus
either melphalan (9 mg/m² on days 1-4) or daily thalidomide (100 mg), and prednisone (60 mg/m² on days 1-4). The first cycle was followed by five
cycles of bortezomib once per week for 5 weeks (1.3 mg/m² on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide
plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone
(n = 87) or bortezomib plus thalidomide (n = 91), consisting of one conventional cycle of bortezomib for 3 weeks (1.3 mg/m² on days 1, 4, 8, and 11)
every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with
a computerized random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response
rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00443235.
FINDINGS: In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p =
0.9), including 36 (28%) and 26 (20%) complete remissions, respectively (p = 0·2). Treatment with VTP resulted in more serious adverse events (40 [31%]
vs. 20 [15%], p = 0.01) and discontinuations (22 [17%] vs. 15 [12%], p = 0.03) than did treatment with VMP. The most common toxicities (grade 3
or worse) were infections (one [1%] in the VTP group vs nine [7%] in the VMP group), cardiac events (11 [8%] vs 0), and peripheral neuropathy (nine
[7%] vs. 12 [9%]). After maintenance therapy, the complete remission rate was 42% (40 [44%] patients in complete remission in the bortezomib plus
thalidomide group, 34 [39%] in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance
therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neu-
ropathy. INTERPRETATION: Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment
for elderly patients with multiple myeloma.
NClarithromycin attenuates autophagy in myeloma cells.
Nakamura M, Kikukawa Y, Takeya M, Mitsuya H, Hata H.
Int J Oncol. 2010 Oct;37(4):815-20.
:
http://www.ncbi.nlm.nih.gov/pubmed/20811702
The authors describe a phenomenon that may explain how clarithromycin combined with thalidomide augments the cytotoxic effects of the latter on
myeloma cells, and suggest that modification of autophag y might represent a new approach for therapy of myeloma.
It has been reported that clarithromycin (CAM) augments the anti-tumor activity of thalidomide against multiple myeloma (MM) cells, while the
mechanism remains unclear. A myeloma cell line or primary myeloma cells were treated with CAM. Autophagy was analyzed by morphological changes,
LC3 expression and lysotracker staining. CAM induced vacuoles in the cytoplasm of MM cells which resembled autolysosomes. The manifestation of the
CAM-induced vacuoles was blocked by treatment with PI3-kinase inhibitor. CAM induced an accumulation of LC3-II without affecting the mTOR or
AKT pathways, eventually leading to cell death. CAM may halt the autophagy process after fusion of autophagosomes with lysosomes. This phenomenon
may explain how CAM, combined with thalidomide, augments the cytotoxic effects of the latter on MM cells and suggests that modification of autophagy
might represent a new approach for therapy of MM.
NCurrent treatment strategies for multiple myeloma. [Article in German]
Mey UJ.
Ther Umsch. 2010 Oct;67(10):527-35.
:
http://www.ncbi.nlm.nih.gov/pubmed/20886459
This article summarizes the most relevant results of large clinical trials with a special focus on the integration of novel agents, especially thalidomide,
bortezomib, and lenalidomide in the treatment of newly diagnosed as well as relapsed/ refractory myeloma.
The treatment of multiple myeloma has undergone significant changes in the last few years. The availability of novel agents - especially thalidomide, bort-
ezomib and lenalidomide - has expanded treatment options and has substantially improved the prognosis of affected patients. This article summarizes the
most relevant results of large clinical trials with a special focus on the integration of novel agents in the treatment of newly diagnosed as well as relapsed/
refractory multiple myeloma in patients eligible for high-dose chemotherapy followed by autologous transplantation as well as in older patients not eligible
for autologous transplantation. Recommendations for the use of novel agents in different treatment stages based on currently available clinical data are
provided.
www.myeloma.org
(800) 452 - CURE (2873)

---

NDiscordance between serum cardiac biomarker and immunoglobulin-free light-chain response in patients
with immunoglobulin light-chain amyloidosis treated with immune modulatory drugs.
Dispenzieri A, Dingli D, Kumar SK, Rajkumar SV, Lacy MQ, Hayman S, Buadi F, Zeldenrust S, Leung N,
Detweiler-Short K, Lust JA, Russell SJ, Kyle RA, Gertz MA.
Am J Hematol. 2010 Oct;85(10):757-9.
:
http://www.ncbi.nlm.nih.gov/pubmed/20872958
The authors evaluate the capability of soluble cardiac biomarkers to predict tolerability and outcomes of IMiD-containing treatments among light
106 amyloidosis patients treated on clinical trials. Their observations prompt two questions: (1) does IMiD-based therapy lead to increased fluid retention
and/or cardiac toxicity and (2) is an N-terminal brain naturietic protein-driven cardiac response system valid in IMiD-treated amyloidosis patients?
We evaluated the capability of soluble cardiac biomarkers to predict tolerability and outcomes of IMiD-containing treatments among 106 patients treated
on clinical trials. Baseline elevations in troponin T (TnT) and N-terminal brain naturietic protein (NT-proBNP) predicted for an inability to tolerate
IMiD-based regimens. The best predictors for early attrition during cycle 1 were TnT 0.07 g/L and NT-proBNP 11,939 ng/L. NT-proBNP-response
underperformed TnT-response as a predictor for overall survival (OS), but both predicted for early protocol attrition. Despite hematologic response,
IMiD-treated patients were at higher risk for NT-proBNP rises and early drug discontinuation than a control population but not for early death. These
observations prompt two questions: (1) does IMiD-based therapy lead to increased fluid retention and/or cardiac toxicity and (2) is an NT-proBNP-driven
cardiac response system valid in IMiD-treated amyloidosis patients? Recognition of potential drug-induced cardiac toxicity is important so that increased
cardiac surveillance and drug dose-adjustment or discontinuation may be implemented.
NThe efficacy and safety of the low-thalidomide dose CTD (cyclophosphamide, thalidomide, dexamethasone)
regimen in patients with multiple myeloma- a report by the Polish Myeloma Study Group.
Dmoszynska A, Walter-Croneck A, Hus I, Grzasko N, Manko J, Jedrzejczak WW, Charlinski G, Usnarska-Zubkiewicz L,
Skotnicki A, Wolska-Smolen T, Piszcz J, Kloczko J.
Leuk Res. 2010 Oct;34(10):1330-5. [Epub 2010 Jun 2.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20627385
The authors evaluate time to progression, event-free survival, and overall survival in myeloma patients treated with a combination of cyclophosphamide,
thalidomide and dexamethasone (CTD). They find that an outpatient low-thalidomide dose CTD regimen is well tolerated and produces a significant
response rate both in untreated and relapsing/resistant myeloma patients.
Multiple myeloma (MM) remains an incurable disease, but response rates to new drugs are promising, offering the majority of patients a significant pro-
longation of overall survival. The objective of this study was to evaluate time to progression (TTP), event-free survival (EFS), and overall survival (OS) in
MM patients treated with a combination of cyclophosphamide (CY), thalidomide (THAL) and dexamethasone (DEX). This study included 132 untreated
and relapsing/resistant patients treated with the low-thalidomide dose CTD regimen. The patients received CY 500 mg/m2 i.v. or 625 mg/m2 orally
at day 1, THAL 100mg/day á la longue and DEX 20mg/day at days 1-4 and 8-11, every 28 days. Patients received 6-9 cycles; ORR by 3 months was
59.1%, by 6 months 65.6% and by 9 months 75.6%. In patients responding to CTD therapy (CR, nCR, PR), the probability of survival for 20 months
was 89.3%. The outpatient low-thalidomide dose CTD regimen is well tolerated and produces a significant response rate both in untreated and relapsing/
resistant MM patients.
NFirst-line treatment with bortezomib rapidly stimulates both osteoblast activity and bone matrix deposition
in patients with multiple myeloma, and stimulates osteoblast proliferation and differentiation in vitro.
Lund T, Søe K, Abildgaard N, Garnero P, Pedersen PT, Ormstrup T, Delaissé JM, Plesner T.
Eur J Haematol. 2010 Oct;85(4):290-9. doi: 10.1111/j.1600-0609.2010.01485.x. [Epub 2010 Jul 22.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20528908
The authors investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix deposition for the first time in
bisphosphonate-naïve, previously untreated patients with myeloma. They find that bortezomib used as first-line treatment significantly increased collagen
deposition in patients with multiple myeloma and osteolytic lesions, but the addition of a glucocorticoid to the treatment transiently inhibited the positive
effect of bortezomib, suggesting that bortezomib may result in better healing of osteolytic lesions when used without glucocorticoids in patients that have
obtained remission with a previous therapy.
OBJECTIVES: The aim of the study was to investigate the effect of bortezomib on osteoblast proliferation and differentiation, as well as on bone matrix
deposition for the first time in bisphosphonate-naïve, previously untreated patients with myeloma. METHODS: Twenty newly diagnosed patients received
four cycles of bortezomib treatment, initially as monotherapy and then combined with a glucocorticoid from cycle two to four. Bone remodeling markers
were monitored closely during treatment. Furthermore, the effects of bortezomib and a glucocorticoid on immature and mature osteoblasts were also stud-
ied in vitro. RESULTS: Treatment with bortezomib caused a significant increase in bone-specific alkaline phosphatase and pro-collagen type I N-terminal
propeptide, a novel bone formation marker. The addition of a glucocorticoid resulted in a transient decrease in collagen deposition. In vitro bortezomib
induced osteoblast proliferation and differentiation. Differentiation but not proliferation was inhibited by glucocorticoid treatment. CONCLUSIONS:
Bortezomib used as first-line treatment significantly increased collagen deposition in patients with multiple myeloma and osteolytic lesions, but the addi-
tion of a glucocorticoid to the treatment transiently inhibited the positive effect of bortezomib, suggesting that bortezomib may result in better healing of
osteolytic lesions when used without glucocorticoids in patients that have obtained remission with a previous therapy. The potential bone-healing proper-
ties of single-agent bortezomib are currently being explored in a clinical study in patients who have undergone high-dose therapy and autologous stem
cell transplantation.
www.myeloma.org
(800) 452 - CURE (2873)

---

NLenalidomide: a synthetic compound with an evolving role in cancer management.
Saloura V, Grivas PD.
Hematology. 2010 Oct;15(5):318-31.
:
http://www.ncbi.nlm.nih.gov/pubmed/20863427
This review outlines the mechanisms of action, the toxicity profile and the efficacy of lenalidomide, reviewing the current literature and focusing on the
current status of the compound in cancer management.
Lenalidomide is a functional and structural analogue of thalidomide with a relatively benign toxicity profile and pleiotropic anti-tumor activity, exhibiting
anti-angiogenic and immunomodulatory effects. Lenalidomide has already been approved for the management of low or intermediate-1 risk myelodysplas-
tic syndrome with chromosome 5q31 deletion and relapsed/refractory multiple myeloma in combination with dexamethasone. During the last five years,
multiple clinical trials have been conducted to explore its potential efficacy in hematologic as well as in solid malignancies, revealing a significant benefit
in clinical outcomes. This review outlines the mechanisms of action, the toxicity profile and the efficacy of lenalidomide, reviewing the current literature
and focusing on the current status of the compound in cancer management. The determination of molecular biomarkers, predictive of clinical response to
lenalidomide may reveal a more substantial role of this agent in the treatment of hematologic as well as solid malignancies.
NLong-term results of single-agent thalidomide as initial therapy for asymptomatic (smoldering or indolent) myeloma.
Detweiler-Short K, Hayman S, Gertz MA, Lacy MQ, Dispenzieri A, Kumar S, Zeldenrust SR, Russell SJ, Lust JA,
Kyle RA, Greipp PR, Witzig TE, Vincent Rajkumar S.
Am J Hematol. 2010 Oct;85(10):737-40.
:
http://www.ncbi.nlm.nih.gov/pubmed/20730790
The authors report the long-term follow-up results of a phase II trial of thalidomide for early-stage myeloma. Median overall survival from diagnosis was 86
months; median survival from onset of symptomatic myeloma was 49 months. Grade 3-4 non-hematologic adverse events were noted in 55% of patients.
We report the long-term follow-up results of a phase II trial of thalidomide for early-stage multiple myeloma (MM). Patients were eligible if they had
smoldering multiple myeloma (SMM) or indolent MM without the need for immediate therapy. Thalidomide was initiated at a dose of 200 mg/day and
adjusted as tolerated. Disease progression was defined using modified American Society of Hematology/Food and Drug Administration consensus panel
criteria for SMM. Thirty-one patients were enrolled; 29 (19 SMM and 10 indolent MM) were eligible. The median age was 61 years. Median follow-up
of living patients was 10.2 years (range, 7.5-11.0 years). Ten patients (34%) had a partial response (PR) and nine had minimal response (MR) for an MR
plus PR rate of 66%. The median time to progression (TTP) to symptomatic myeloma was 35 months. Median TTP was 61 months in those achiev-
ing PR, 39 months with MR, and 9 months among those failing to achieve either MR or PR, p = 0.005. Median overall survival from diagnosis was 86
months; median survival from onset of symptomatic myeloma was 49 months. Grade 3-4 nonhematologic adverse events were noted in 55% of patients.
Randomized trials are needed to determine the role of early therapy in SMM.
NMultiple myeloma.
Bladé J, Cibeira MT, Fernández de Larrea C, Rosiñol L.
Ann Oncol. 2010 Oct;21 Suppl 7:vii313-vii319.
:
http://www.ncbi.nlm.nih.gov/pubmed/20943635
The authors discuss the nature of myeloma and potential courses of treatment for various patient groups, including the use of bortezomib, thalidomide,
and lenalidomide.
Multiple myeloma (MM) constitutes 1% of malignant diseases and 15% of haematological malignancies. In virtually all patients MM is preceded by
monoclonal gammopathy of undetermined significance (MGUS). The cause of monoclonal gammopathies and the mechanisms of progression are
unknown. The diagnosis of MM requires the presence of an M-protein in serum and/or urine, increased bone marrow plasma cells and related organ or
tissue impairment. Cytogenetic status, serum 2-microglobulin and response to therapy are the key prognostic factors. The treatment of younger patients
with MM should include a triple-agent induction regimen (i.e. bortezomib/thalidomide/dexamethasone), autologous stem cell transplantation (ASCT) and
consolidation and maintenance incorporating novel agents along with sequential minimal residual disease studies to determine for how long treatment is
still of benefit. Allogeneic transplantation with reduced-intensity conditioning is promising but remains experimental. For patients not eligible for ASCT
the best initial regimens are melphalan/prednisone/thalidomide (MPT), melphalan/prednisone/bortezomib (MPV) and lenalidomide/dexamethasone. In
relapsing patients, the choice of salvage therapy should depend on: (i) the components of initial therapy, (ii) the degree and duration of response, (iii) type
of relapse: aggressive versus indolent, (iv) previous toxicities and (v) age and performance status. A sequential approach is preferred over combination of
multiple agents. Supportive measures include the use of bisphosphonates and erythropoietin according to the updated guidelines.
NMultiple myeloma.
Dimopoulos MA, Terpos E.
Ann Oncol. 2010 Oct;21 Suppl 7:vii143-vii150.
:
http://www.ncbi.nlm.nih.gov/pubmed/20943607
The authors discuss how better knowledge of myeloma disease biolog y has led to the introduction and various uses of novel agents, including bortezomib,
thalidomide and lenalidomide.
Multiple myeloma (MM) is the second most common hematological malignancy, with an incidence of 6/100 000 in Europe. Interactions between
myeloma cells and the microenvironment are essential for MM cell survival. Better knowledge of disease biology has led to the introduction of novel
agents for the management of myeloma patients. Patients with asymptomatic MM may remain stable for a long time without any therapy, and treatment
is needed only in symptomatic disease. Patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT) are usually treated
with bortezomib- or immunomodulatory drug (IMiD)-based regimens as induction therapy pre-ASCT. In elderly patients, the combination of melphalan
and prednisone with either thalidomide (MPT) or bortezomib (MPV) is considered as the standard of care in this setting. Novel agent-based therapies are
www.myeloma.org
(800) 452 - CURE (2873)

---

used for the management of relapsed/refractory disease. However, previous therapies, age, comorbidities and drug safety have to be taken into consideration
before deciding the appropriate therapy for patients with relapsed/refractory myeloma. Patients with renal impairment or with extended bone disease may
be treated with bortezomib-based regimens, while patients with pre-existing peripheral neuropathy may be treated with lenalidomide-based combinations.
Maintenance therapy with thalidomide can be administered post-ASCT; however, caution is needed due to thalidomide toxicity.
NOptimising bortezomib in newly diagnosed multiple myeloma.
Rajkumar SV.
Lancet Oncol. 2010 Oct;11(10):909-10. [Epub 2010 Aug 23.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20739219
Comment on: Lancet Oncol. 2010 Oct;11(10):934-41.
NA phase I study of bortezomib in combination with doxorubicin and intermediate-dose dexamethasone
(iPAD therapy) for relapsed or refractory multiple myeloma.
Takamatsu Y, Sunami K, Hata H, Nagafuji K, Choi I, Higuchi M, Uozumi K, Masaki Y, Tamura K;
Kyushu Hematology Organization for Treatment Study Group (K-HOT).
Int J Hematol. 2010 Oct;92(3):503-9. [Epub 2010 Sep 8.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20824401
The authors conduct a dose finding study of bortezomib in combination with a fixed dose of doxorubicin and intermediate-dose dexamethasone
(iPAD therapy) in patients with relapsed or refractory myeloma and conclude that bortezomib at the dose of 1.0 mg/m2 is recommended.
Bortezomib and doxorubicin have synergistic activity against myeloma cells in vitro. We underwent a dose finding study of bortezomib in combination
with a fixed dose of doxorubicin and intermediate-dose dexamethasone (iPAD therapy) in patients with relapsed or refractory myeloma. Bortezomib was
administered on days 1, 4, 8 and 11 at a dose of 1.0 and 1.3 mg/m² in cohorts 1 and 2, respectively. Doxorubicin 9 mg/m² was given by rapid intravenous
infusion on days 1-4, and dexamethasone 20 mg on days 1-2, 4-5, 8-9 and 11-12. Treatment was repeated at a 3-week interval and the dose-limiting toxic-
ity (DLT), defined as grade 4 hematological toxicity lasting more than 5 days and/or grade 3 or higher non-hematological toxicity, was evaluated. In cohort
1, 2 of 6 patients developed DLTs including grade 4 hyponatremia and grade 3 infection with appropriate neutrophil counts. No DLT was observed in
the remaining 4 patients, indicating this dose was tolerable. In cohort 2, 3 of 5 patients developed DLTs including grade 4 thrombocytopenia lasting more
than 5 days, grade 3 hepatic transaminase elevation and grade 3 ileus, indicating this dose was intolerable. It is concluded that bortezomib at the dose of
1.0 mg/m² is recommended in combination with doxorubicin and intermediate-dose dexamethasone.
NProgress in allogeneic transplantation for multiple myeloma.
Gahrton G.
Eur J Haematol. 2010 Oct;85(4):279-89. doi: 10.1111/j.1600-0609.2010.01495.x.
:
http://www.ncbi.nlm.nih.gov/pubmed/20608964
The author discusses the progression of allogeneic hematopoietic stem cell transplantation in the treatment of myeloma, and concludes that adding donor
lymphocyte infusions post-transplant, new drugs like bortezomib, thalidomide, lenalidomide or pomalidomide pre- and/or post-transplant, and more spe-
cific antimyeloma cell therapy like NK cells post-transplant, may improve future results.
Allogeneic hematopoietic stem cell transplantation to treat multiple myeloma has been attempted since the early 1980s. The original conditioning regi-
men including high-dose total body irradiation (TBI) plus cyclophosphamide was myeloablative and associated with a relatively low relapse/progression
rate, but high transplant-related mortality and no obvious improvement in progression-free survival or overall survival. Some risk groups may benefit from
this transplant modality and occasional patients may be cured, but due to the high-transplant-related mortality it is mainly abandoned. Reduced intensity
conditioning (RIC), non-myeloablative allogeneic transplantation reduces transplant-related mortality significantly when compared with myeloablative
conditioning, but the relapse/progression rate is somewhat higher. However although the treatment-related mortality is higher than after autologous
transplantation, the progression-free and overall survival was better or tended to be better in three of five prospective trials comparing tandem autolo-
gous/RIC allogeneic transplantation to single or tandem autotransplantation due to lower relapse/progression rate. Adding donor lymphocyte infusions
post-transplant, new drugs like bortezomib, thalidomide, lenalidomide or pomalidomide pre- and/or post-transplant, and more specific antimyeloma cell
therapy like NK cells post-transplant, may in future studies prove to improve results.
NProteasome inhibitors. [Article in Japanese]
Saeki Y, Fukunaga K, Tanaka K.
Nippon Rinsho. 2010 Oct;68(10):1818-22.
:
http://www.ncbi.nlm.nih.gov/pubmed/20954323
This review provides an overview of the current state of the use of bortezomib and second- generation proteasome inhibitors for the treatment of relapsed
and refractory myeloma.
The 26S proteasome is a multicatalytic enzyme responsible for degradation of a large fraction of intracellular proteins. Targeting the proteasome activity
is a rational and novel strategy for cancer therapy that can lead to cell death for transformed cells. Today, bortezomib, a first-in-class proteasome inhibitor,
has established clinical efficacy and an approved clinical indication for the treatment of relapsed and refractory multiple myeloma. Since bortezomib has
also shown to induce chemosensitization, the drug is utilized for combination with a variety of chemotherapeutics. In this review, we provide an overview
of the current state of the use of bortezomib and second generation proteasome inhibitors.
www.myeloma.org
(800) 452 - CURE (2873)

---

NReversibility of renal failure in newly diagnosed patients with multiple myeloma and the role of novel agents.
Roussou M, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Grapsa I, Psimenou E, Gika D, Terpos E,
Dimopoulos MA.
Leuk Res. 2010 Oct;34(10):1395-7. [Epub 2010 May 26.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20510452
The authors find that bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients with renal impairment.
The purpose of this analysis was to assess the effect of novel agent-based regimens on the improvement of renal impairment (RI) in newly diagnosed
patients with multiple myeloma. Ninety-six consecutive patients with RI received conventional chemotherapy (CC)-based regimens (n = 32), IMiDs-based
regimens (n = 47) or bortezomib-based regimens (n = 17) as frontline therapy. Improvement of RI was more frequent in patients treated with novel agents
(79% in IMiD- and 94% in bortezomib-treated groups versus 59% in CC-treated group; p = 0.02). Bortezomib-based regimens and CrCl>30 ml/min at
baseline independently correlated with a higher probability of at least renal partial response (PRrenal) and with a shorter time to PRrenal or better. Thus
bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients with RI.
NA staged approach with vincristine, adriamycin, and dexamethasone followed by bortezomib, thalidomide, and
dexamethasone before autologous hematopoietic stem cell transplantation in the treatment of newly diagnosed
multiple myeloma.
Chim CS, Lie AK, Chan EY, Leung YY, Cheung SC, Chan SY, Liang R, Kwong YL.
Ann Hematol. 2010 Oct;89(10):1019-27. [Epub 2010 Apr 29.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20428873
The authors test the efficacy of a total therapy with a staged approach where newly diagnosed myeloma patients received vincristine/adriamycin/dexameth-
sone ( VAD). They find that their approach reduces the use of bortezomib without compromising the ultimate complete response rate, which is also of
financial significance for less affluent communities.
Bortezomib-based regimens have significant activities in multiple myeloma (MM). In this study, we tested the efficacy of a total therapy with a staged
approach where newly diagnosed MM patients received vincristine/adriamycin/dexamethsone (VAD). VAD-sensitive patients (> or =75% paraprotein
reduction) received autologous hematopoietic stem cell transplantation (auto-HSCT), whereas less VAD-sensitive patients (<75% paraprotein reduction)
received bortezomib/thalidomide/dexamethasone (VTD) for further cytoreduction prior to auto-HSCT. On an intention-to-treat analysis, a progressive
increase of complete remission (CR) rates was observed, with cumulative CR rates of 48% after HSCT. Seven patients progressed leading to three fatali-
ties, of which two had central nervous system disease. The 3-year overall survival and event-free survival were 75.1% and 48.3%, respectively. Six patients
developed oligoclonal reconstitution with new paraproteins. In the absence of anticoagulant prophylaxis, no patients developed deep vein thrombosis.
The staged application of VAD+/-VTD/auto-HSCT resulted in an appreciable response rate and promising survivals. Our approach reduced the use of
bortezomib without compromising the ultimate CR rate and is of financial significance for less affluent communities.
NStatistical identification of predictors for peripheral neuropathy associated with administration of bortezomib,
taxanes, oxaliplatin or vincristine using ordered logistic regression analysis.
Kanbayashi Y, Hosokawa T, Okamoto K, Konishi H, Otsuji E, Yoshikawa T, Takagi T, Taniwaki M.
Anticancer Drugs. 2010 Oct;21(9):877-81.
:
http://www.ncbi.nlm.nih.gov/pubmed/20679888
This study aims to statistically identify predictors for chemotherapy-induced peripheral neuropathy (CIPN). The authors find that CIPN will be alleviated
by the co-administration of dexamethasone with bortezomib and non-steroidal anti-inflammatory drugs with oxaliplatin.
Chemotherapy-induced peripheral neuropathy (CIPN) is a major drug-induced adverse reaction that becomes a dose-limiting toxicity. However, effective
strategies for preventing or treating CIPN are lacking. Accordingly, this study aimed to statistically identify predictors for CIPN. Retrospective analysis was
carried out for 190 patients who had been treated with bortezomib (n = 28), taxanes (paclitaxel or docetaxel; n = 58), oxaliplatin (n = 52) or vincristine
(n = 52) at our hospital between April 2005 and December 2008. The severity of CIPN was assessed at the time of chemotherapy completion, graded as
grade 0-5 in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Multivariate ordered logistic regres-
sion analysis was used to investigate predictors for CIPN. Predictors for CIPN in patients that were administered bortezomib were no co-administration
of dexamethasone [odds ratio (OR), 0.455; confidence interval (CI), 0.208-0.955; p = 0.0376] and sex (male) (OR, 3.035; CI, 1.356-6.793; p = 0.0069).
For taxanes (paclitaxel or docetaxel), the predictor for CIPN was a large number of chemotherapy cycles (OR, 2.379; CI, 1.035-5.466; p = 0.0412). For
oxaliplatin, the predictors for CIPN were a large number of chemotherapy cycles (OR, 3.089; CI, 1.598-5.972; p = 0.0008) and no co-administration
of non-steroidal anti-inflammatory drugs (OR, 0.393; CI, 0.197-0.785; P=0.0082). For vincristine, predictors for CIPN were a large number of chemo-
therapy cycles (OR, 6.015; CI, 1.880-19.248; p = 0.0025) and co-administration of an analgesic adjuvant (OR, 3.907; CI, 1.383-11.031; p = 0.0101).
In conclusion, our study indicates that CIPN will be alleviated by the co-administration of dexamethasone with bortezomib and non-steroidal anti-
inflammatory drugs with oxaliplatin.
www.myeloma.org
(800) 452 - CURE (2873)

---

NTreatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone
with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and
of previous therapies.
Dimopoulos MA, Kastritis E, Christoulas D, Migkou M, Gavriatopoulou M, Gkotzamanidou M, Iakovaki M,
Matsouka C, Mparmparoussi D, Roussou M, Efstathiou E, Terpos E.
Leukemia. 2010 Oct;24(10):1769-78. [Epub 2010 Aug 26.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20739955
The authors find that the presence of cytogenetic abnormalities is an important adverse prognostic factor for patients with relapsed/refractory myeloma,
but resistance to previous thalidomide, elevated elevated lactate dehydrogenase, and presence of extramedullary disease remain of major prognostic impor-
tance; the outcome of patients with del 17p remains extremely poor even with a bortezomib-lenalidomide-dexamethasone combination.
We prospectively studied the impact of several cytogenetic abnormalities (CAs) in patients with relapsed/refractory myeloma who received lenalidomide
and dexamethasone (RD) with or without the addition of bortezomib (V). On the basis of the presence of previous neuropathy, 50 patients were treated
with RD and 49, without preexisting neuropathy, with VRD. The overall response rate was 63%, similar for RD and VRD. Poor risk cytogenetics were
associated with lower response rates in RD (p = 0.01), but not in VRD (p = 0.219). The median progression-free survival (PFS) was similar for RD (9
months) and VRD (7 months). The median overall survival (OS) for all patients was 16 months, with no differences between RD or VRD regimens. Poor
risk cytogenetics, especially del 17p, resistance to previous thalidomide, elevated lactate dehydrogenase (LDH) and presence of extramedullary disease were
associated with inferior response to therapy and shorter PFS and OS. The impact of other CAs on OS was more pronounced in RD. In conclusion, the
presence of CAs is an important adverse prognostic factor for patients with relapsed/refractory myeloma, but resistance to previous thalidomide, elevated
LDH and presence of extramedullary disease remain of major prognostic importance. The outcome of patients with del 17p remains extremely poor even
with VRD combination.
September 2010
NAssessing lenalidomide for treating multiple myeloma, myelofibrosis and myelodysplastic syndrome.
[Article in Spanish]
Hernández Prats C, Romero Iborra F, Arroyo Domingo E, Castillo Valero I, Real Panisello M, Sánchez Casado MI.
Farm Hosp. 2010 Sep-Oct;34(5):218-23. [Epub 2010 Jul 7.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20615740
The authors find that lenalidomide is well-tolerated and produces sustained clinical benefits, especially in myeloma patients.
OBJECTIVE: Lenalidomide (LDM) is an immunomodulatory and anti-angiogenic drug which has been shown to be effective in several haematological
disorders (multiple myeloma [MM], myeloid metaplasia with myelofibrosis [MF] and myelodysplastic syndrome [MDS]). The objective of this study is
to evaluate the effectiveness and tolerability of LDM in our patients. METHOD: Retrospective observational study which included patients at our hos-
pital who were monitored by the haematology unit, diagnosed with MM, MF and MDS and candidates for LDM treatment. Treatment effectiveness was
assessed after approximately 4 cycles of treatment. RESULTS: Between February 2007 and March 2008, 16 patients were listed as candidates for receiving
treatment with LDM (50% female/50% male, with a mean age of 69.6 years); of these candidates, 3 never initiated treatment. Five of the six patients with
MM treated at our hospital obtained some sort of response (83.3%). Of the 4 patients with MF, 2 (66.6%) experienced some sort of response to treat-
ment. Of the 6 patients diagnosed with MDS, treatment was initiated in 3, and it had to be suspended in 2 cases due to different reasons. Treatment only
had to be suspended in two of the 13 patients who began it (15.4%) due to adverse effects (AE). CONCLUSION: LDM is well-tolerated and produces
sustained clinical benefits, especially in MM and MF. More studies are needed for in-depth examination of treatment duration, new indications and the
use of treatments combined with other drugs.
NThe PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target
for CT-011, a novel monoclonal anti-PD-1 antibody.
Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK,
Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA.
Blood. 2010 Sep 30;116(13):2286-94. [Epub 2010 May 11.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20460501
The authors demonstrate a role for CT-011 in enhancing the natural killer cell versus myeloma effect and conclude that a phase 2 clinical trial of CT-011 in
combination with lenalidomide for patients with myeloma should be considered.
T-cell expression of programmed death receptor-1 (PD-1) down regulates the immune response against malignancy by interacting with cognate ligands
(e.g., PD-L1) on tumor cells; however, little is known regarding PD-1 and natural killer (NK) cells. NK cells exert cytotoxicity against multiple myeloma
(MM), an effect enhanced through novel therapies. We show that NK cells from MM patients express PD-1 while normal NK cells do not, and confirm
PD-L1 on primary MM cells. Engagement of PD-1 with PD-L1 should down modulate the NK cell versus MM effect. We demonstrate that CT-011,
a novel anti-PD-1 antibody, enhances human NK cell function against autologous, primary MM cells seemingly through effects on NK cell trafficking,
immune complex formation with MM cells, and cytotoxicity specifically towards PD-L1(+) MM tumor cells but not normal cells. We show that lenalido-
mide down regulates PD-L1 on primary MM cells, and may augment CT-011's enhancement of NK cell function against MM. We demonstrate a role for
the PD-1/PD-L1 signaling axis in the NK cell immune response against MM, and a role for CT-011 in enhancing the NK cell versus MM effect. A phase
2 clinical trial of CT-011 in combination with lenalidomide for patients with MM should be considered.
www.myeloma.org
(800) 452 - CURE (2873)

---

NRisk factors for, and reversibility of, peripheral neuropathy associated with bortezomib-melphalan-prednisone
in newly diagnosed multiple myeloma patients: subanalysis of the phase III VISTA study.
Dimopoulos MA, Mateos MV, Richardson PG, Schlag R, Khuageva NK, Shpilberg O, Kropff M, Spicka I, Palumbo A,
Wu KL, Esseltine DL, Liu K, Deraedt W, Cakana A, Van De Velde H, San Miguel JF.
Eur J Haematol. 2010 Sep 28. doi: 10.1111/j.1600-0609.2010.01533.x. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20874823
This subanalysis of the phase III VISTA trial aims to assess the frequency, characteristics and reversibility of, and prognostic factors for, bortezomib-associ-
ated peripheral neuropathy (PN) in newly diagnosed myeloma patients ineligible for high-dose therapy who received bortezomib plus melphalan-predni-
sone. The authors find that rates of bortezomib-induced PN in the front-line setting are similar to those in relapsed patients, and resolved in most cases.
OBJECTIVES: This subanalysis of the phase III VISTA trial aimed to assess the frequency, characteristics and reversibility of, and prognostic factors for,
bortezomib-associated peripheral neuropathy (PN) in newly diagnosed multiple myeloma patients ineligible for high-dose therapy who received bortezo-
mib plus melphalan-prednisone. METHODS: Patients received nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 , days 1, 4, 8, 11, 22, 25, 29, 32,
cycles 1-4, and days 1, 8, 22, 29, cycles 5-9; melphalan 9 mg/ m2, days 1-4, cycles 1-9; and prednisone 60 mg/ m2, days 1-4, cycles 1-9). RESULTS:
Overall, 47% of patients receiving VMP developed PN, including 19% grade 2 and 13% grade 3 (<1% grade 4). The PN incidence was dose-related and
reached a plateau at a cumulative bortezomib dose of approximately 45 mg/m2. Median time to PN onset was 2.3 months. Bortezomib-associated PN was
reversible; 79% of events improved by at least one NCI CTCAE grade within a median of 1.9 months and 60% completely resolved within a median of
5.7 months, with reversibility similar in responding and non-responding patients. By multivariate analysis, baseline neuropathy was the only consistent risk
factor for any PN (HR 1.785, p = 0.0065), grade 2 PN (HR 2.205, p = 0.0032), and grade 3 PN (HR 2.438, p = 0.023); age, pre-existing diabetes, ISS
stage, obesity, and creatinine clearance did not affect the overall rate of PN. CONCLUSIONS: Rates of bortezomib-induced PN in the front-line setting
were similar to those in relapsed patients and resolved in most cases. (Clinicaltrials.gov identifier: NCT00111319).
NThromboembolism with Immunomodulatory Agents in the Treatment of Multiple Myeloma.
Singh A, Gajra A.
Cardiovasc Hematol Agents Med Chem. 2010 Sep 28. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20874693
This review discusses incidence, pathogenesis and management of thrombotic events with the use of immunomodulatory agents, including thalidomide and
lenalidomide, in the setting of myeloma, as well as recent recommendations regarding appropriate prophylaxis and preventive measures.
Immunomodulatory agents which include thalidomide and its analogue lenalidomide have recently emerged as an effective chemotherapy option for
patients with Multiple Myeloma. The anti-tumor property of these molecules is probably related to action on tumor microenvironment, anti-angioenesis
and several other hitherto less understood mechanisms. Despite promising efficacy, their progress has been complicated by reports of venous thrombo-
embolism in patients receiving these agents. The background rate of thromboembolism is 4-11% in patients with multiple myeloma, which increases to
15-20% in patients who received intensive treatment with Thalidomide. The exact mechanism of this phenomenon is not clear but possible explanations
include up-regulation of pro-coagulant factors and selective endothelial damage. The development of thromboembolism is also influenced by disease state,
performance status, type of chemotherapy and supportive therapy. Multiple treatment strategies for prevention of thromboembolic events in these patients
have been proposed including aspirin, heparins and warfarin but there have been no prospective controlled trials comparing the superiority of one pro-
phylactic measure over another. The diagnosis and treatment of thromboses in these patients involves standard guidelines but the optimal duration is not
certain. This review discusses incidence, pathogenesis and management of thrombotic events with the use of immunomodulatory agents in the setting of
multiple myeloma as well as recent recommendations regarding appropriate prophylaxis and preventive measures.
NLenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple
myeloma: a randomized Southwest Oncology Group trial (S0232).
Zonder JA, Crowley J, Hussein MA, Bolejack V, Moore DF Sr, Whittenberger BF, Abidi MH, Durie BGM, Barlogie B.
Blood. 2010 Sep 27. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20876454
This randomized trial compares lenalidomide (LEN) plus dexamethasone (DEX) to placebo plus DEX in newly diagnosed myeloma. The authors find that
one-year progression-free survival, overall response rate, and very good partial response rate were superior with LEN-DEX, but that its toxicities were also
more pronounced.
The Southwest Oncology Group (SWOG) conducted a randomized trial comparing lenalidomide (LEN) plus dexamethasone (DEX) (n = 97) to placebo
(PLC) plus DEX (n = 95) in newly diagnosed myeloma. Three 35-day induction cycles applied DEX 40 mg/day on days 1-4, 9-12, 17-20 together with
LEN 25 mg/d for 28 days or PLC. Monthly maintenance employed DEX 40 mg/d on days 1-4 and 15-18 along with LEN 25 mg/d for 21 days or PLC.
Cross-over from PLC-DEX to LEN-DEX was encouraged upon progression. One-year progression-free survival, overall response rate, and very good partial
response rate were superior with LEN-DEX (78% vs. 52%, p = 0.002; 78% vs. 48%, p < 0.001; 63% vs. 15%, p < 0.001), while 1-year overall survival
was similar (94% vs. 88%; p = 0.25). Toxicities were more pronounced with LEN-DEX (neutropenia grade 3-4: 21% vs. 5%, p = < 0.001; thromboem-
bolic events despite aspirin prophylaxis: 23.5% [initial LEN-DEX or cross-over] vs. 5%; p = < 0.001). This trial was registered at www.clinicaltrials.gov
as #NCT00064038.
www.myeloma.org
(800) 452 - CURE (2873)

---

NHigh expression levels of the mammalian target of rapamycin inhibitor DEPTOR are predictive of response
to thalidomide in myeloma.
Boyd KD, Walker BA, Wardell CP, Ross FM, Gregory WM, Davies FE, Morgan GJ.
Leuk Lymphoma. 2010 Sep 21. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20858096
No abstract available.
NLenalidomide in combination with dexamethasone: effective regimen in patients with relapsed or refractory
multiple myeloma complicated by renal impairment.
Klein U, Neben K, Hielscher T, Heiß C, Ho AD, Goldschmidt H.
Ann Hematol. 2010 Sep 21. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20857112
This retrospective study analyzes the outcome of lenalidomide plus dexamethasone in 167 patients with relapsed or refractory myeloma, with focus on renal
insufficiency (RI). The authors conclude that lenalidomide plus dexamethasone is an effective regimen for relapsed or refractory patients with myeloma,
complicated by RI with manageable toxicity.
Over the past decade, treatment options for patients with multiple myeloma (MM) have improved substantially, resulting in better response rates and
prolonged overall survival (OS). Nevertheless, MM remains a challenging disease, especially if renal insufficiency (RI) or extensive pre-treatment aggravates
the assignment of the optimal treatment schedule. In this retrospective study, we analyzed the outcome of lenalidomide plus dexamethasone in 167 patients
with relapsed or refractory MM with focus on RI. The baseline creatinine clearance (CL(Cr)) was normal in 94 patients (CL(Cr) 80 ml/min), while RI
was observed in 73 patients, including 40 patients with mild RI (50 CL(Cr) < 80 ml/min) and 33 patients with moderate or severe RI (CL(Cr) < 50 ml/
min). Response rates declined depending on the severity of RI, being 67% among patients with normal kidney function, 60% among patients with mild
RI and 49% among patients with moderate or severe RI. Time to progression (TTP) was significantly reduced in patients with severe RI and in case of >
2 previous treatment lines. OS was not significantly different between patients with normal and impaired renal function. In contrast, the number of previ-
ous treatment lines (2 vs. < 2) and the use of novel agents like bortezomib or thalidomide prior to lenalidomide plus dexamethasone therapy had a more
adverse effect on OS. In conclusion, lenalidomide plus dexamethasone is an effective regimen for relapsed or refractory patients with MM complicated by
RI with manageable toxicity.
NTreatment of relapsed and refractory multiple myeloma in the era of novel agents.
van de Donk NW, Lokhorst HM, Dimopoulos M, Cavo M, Morgan G, Einsele H, Kropff M, Schey S, Avet-Loiseau H,
Ludwig H, Goldschmidt H, Sonneveld P, Johnsen HE, Bladé J, San Miguel JF, Palumbo A.
Cancer Treat Rev. 2010 Sep 20. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20863623
This review provides an overview of the various salvage regimens and gives recommendations for treatment of patients with relapsed/refractory myeloma
in different clinical settings.
The introduction of the Immunomodulatory drugs (IMiDs) and proteasome inhibitors, used either as a single-agent or combined with classic anti-
myeloma therapies, has improved the outcome for patients with relapsed myeloma. However, there is currently no generally accepted standard treatment
for relapsed/refractory myeloma patients, partly because of the absence of trials comparing the efficacy of the novel agents in relapsed/refractory myeloma.
Choice of a new treatment regimen depends on both patient and disease-specific characteristics. A lenalidomide-based regimen is the first choice in patients
with neuropathy, while bortezomib has the highest efficacy in patients with renal insufficiency and is not associated with increased risk of thromboembo-
lism. A second autologous stem cell transplantation (auto-SCT) can be applied in patients with a progression-free period of 18-24months after the first
auto-SCT. In high-risk relapse such as occurring early after auto-SCT consolidation with allogeneic SCT can be considered. In this review we provide an
overview of the various salvage regimens and give recommendations for treatment of patients with relapsed/refractory myeloma in different clinical settings.
NThe Cost-Effectiveness of Bortezomib in Relapsed/Refractory Multiple Myeloma: Swedish Perspective.
Hornberger J, Rickert J, Dhawan R, Liwing J, Aschan J, Löthgren M.
Eur J Haematol. 2010 Sep 16. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20846301
The authors seek to estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN/
DEX) for the treatment of relapsed/refractory myeloma in Sweden. They find that both BTZ and LEN/DEX are projected to prolong survival relative to DEX
and ­ from a Swedish perspective ­ BTZ is cost-effective compared to DEX and LEN/DEX.
OBJECTIVE: To estimate the cost-effectiveness of bortezomib (BTZ) compared with dexamethasone (DEX) and lenalidomide plus dexamethasone (LEN/
DEX) for the treatment of relapsed/refractory multiple myeloma in Sweden. METHODS: We used partitioned survival analysis to assess survival data
decomposed into 3 states: (1) alive before disease progression; (2) alive after progression; and (3) dead. The effects of treatment on time to progression
(TTP) and overall survival (OS) were obtained from published reports of the APEX, MM-009, and MM-010 randomized clinical trials. Costs included
drug and administration costs, adverse events, treatment of relapses, and end-of-life costs. Utility estimates were derived from the literature. RESULTS:
BTZ mean OS was 57.4 months compared with 44.6 and 54.1 months for DEX and LEN/DEX, respectively. Mean lifetime direct medical costs per patient
were approximately 2010 SEK 1,904,462, 1,278,854, and 2,450,588 for BTZ, DEX, and LEN/DEX, respectively. Mean incremental cost per QALY of
BTZ compared to DEX was 2010 SEK 902,874 (95,073) (95% C.I.: 514,791, 962,416) and was dominant with respect to LEN/DEX. Conclusion: BTZ
and LEN/DEX are projected to prolong survival relative to DEX. From a Swedish perspective, BTZ is cost-effective compared to DEX and LEN/DEX.
www.myeloma.org
(800) 452 - CURE (2873)

---

NDurable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis.
Sanchorawala V, Finn KT, Fennessey S, Shelton A, Doros G, Zeldis JB, Seldin DC.
Blood. 2010 Sep 16;116(11):1990-1.
:
http://www.ncbi.nlm.nih.gov/pubmed/20847211
Comment on: Blood. 2007 Jan 15;109(2):492-6.
NIntegrating novel agents into multiple myeloma treatment ­ current status in Switzerland and treatment
recommendations.
Taverna C, Bargetzi M, Betticher D, Gmür J, Gregor M, Heim D, Hess U, Ketterer N, Lerch E, Matthes T,
Mey U, Pabst T, Renner C.
Swiss Med Wkly. 2010 Sep 13;140:w13054. doi: 10.4414/smw.2010.13054.
:
http://www.ncbi.nlm.nih.gov/pubmed/20458652
This article aims to assist in treatment decisions in daily clinical practice, including the use of thalidomide, bortezomib, and lenalidomide, to achieve the
best possible outcome for patients with myeloma.
The treatment of multiple myeloma has undergone significant changes in the recent past. The arrival of novel agents, especially thalidomide, bortezomib
and lenalidomide, has expanded treatment options and patient outcomes are improving significantly. This article summarises the discussions of an expert
meeting which was held to debate current treatment practices for multiple myeloma in Switzerland concerning the role of the novel agents and to provide
recommendations for their use in different treatment stages based on currently available clinical data. Novel agent combinations for the treatment of newly
diagnosed, as well as relapsed multiple myeloma are examined. In addition, the role of novel agents in patients with cytogenetic abnormalities and renal
impairment, as well as the management of the most frequent side effects of the novel agents are discussed. The aim of this article is to assist in treatment
decisions in daily clinical practice to achieve the best possible outcome for patients with multiple myeloma.
NCoagulation profiles and thromboembolic events of bortezomib plus thalidomide and dexamethasone therapy
in newly diagnosed multiple myeloma.
Shen Y, Zhou X, Wang Z, Yang G, Jiang Y, Sun C, Wang J, Tong Y, Guo H.
Leuk Res. 2010 Sep 10. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20832859
The authors characterize coagulation profiles and evaluate the incidence of thromboembolic events associated with the combination therapy of bortezomib-
thalidomide-dexamethasone ( VTD) in Chinese patients with newly diagnosed myeloma. They do not recommend routine thromboprophylaxis for VTD
therapy in Chinese patients with myeloma.
Patients with multiple myeloma (MM) are at relatively high risk of developing thromboembolic event (TEE), especially during treatment with immno-
modulatory agents. We characterized coagulation profiles and evaluate the incidence of TEE associated with the combination therapy of bortezomib-
thalidomide-dexamethasone (VTD) in Chinese patients with newly diagnosed MM. The results indicated that the platelet count and platelet aggregation
induced by the agonists were decreased after a short exposure to bortezomib in vivo. The incidence of TEE was low in VTD therapy for an overall rate of
3%. We do not recommend routine thromboprophylaxis for VTD therapy in Chinese patients with MM.
NClarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose
dexamethasone (Rd) for newly diagnosed myeloma.
Gay F, Rajkumar SV, Coleman M, Kumar S, Mark T, Dispenzieri A, Pearse R, Gertz MA, Leonard J, Lacy MQ,
Chen-Kiang S, Roy V, Jayabalan DS, Lust JA, Witzig TE, Fonseca R, Kyle RA, Greipp PR, Stewart AK, Niesvizky R.
Am J Hematol. 2010 Sep;85(9):664-9.
:
http://www.ncbi.nlm.nih.gov/pubmed/20645430
The authors compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs. lenalidomide/
low-dose dexamethasone (Rd) for newly diagnosed myeloma. Results of this case-matched analysis suggest that there is significant additive value when
clarithromycin is added to Rd.
The objective of this case-matched study was to compare the efficacy and toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose
dexamethasone (BiRd) vs. lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York
Presbyterian Hospital-Cornell Medical Center were retrospectively compared with an equal number of matched pair mates selected among patients seen
at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-
treat analysis, complete response (45.8% vs. 13.9%, p < 0.001) and very-good-partial-response or better (73.6% vs. 33.3%, p < 0.001) were significantly
higher with BiRd. Time-to-progression (median 48.3 vs. 27.5 months, p = 0.071), and progression-free survival (median 48.3 vs. 27.5 months, p = 0.044)
were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs. 73.0%, p = 0.170). Main grade 3-4 toxicities of BiRd were
hematological, in particular thrombocytopenia (23.6% vs. 8.3%, p = 0.012). Infections (16.7% vs. 9.7%, p = 0.218) and dermatological toxicity (12.5%
vs. 4.2%, p = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added
to Rd. Randomized phase III trials are needed to confirm these results.
www.myeloma.org
(800) 452 - CURE (2873)

---

NEnhancing activity and overcoming chemoresistance in hematologic malignancies with bortezomib:
preclinical mechanistic studies.
Reddy N, Czuczman MS.
Ann Oncol. 2010 Sep;21(9):1756-64. [Epub 2010 Feb 4.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20133382
This review indicates the potential utility of proteasome inhibition, explains the mechanisms responsible for the observed clinical activity of bortezomib-
based regimens, and elucidates novel therapeutic approaches through identification of combinations of agents with complimentary mechanisms of action.
BACKGROUND: Proteasome inhibition results in antitumor activity through various mechanisms, including disruption of cell cycle progression and
control, induction of apoptosis, and inhibition of proliferation. Design: This review assesses preclinical data on the ability of bortezomib, the first protea-
some inhibitor approved for clinical use, to enhance antitumor activity of other agents and to overcome chemoresistance in hematologic malignancies and
discusses mechanisms by which such activity arises. RESULTS: Bortezomib has been shown to affect multiple cellular pathways and levels of numerous
intracellular proteins, including targets of importance in hematologic malignancies. These mechanisms have shown additive or synergistic effects in vitro
and in vivo with those of conventional therapeutic and novel targeted agents. Additionally, targets of proteasome inhibition are implicated in resistance or
lack of sensitivity to different therapies. Bortezomib in combination with other agents has been shown to overcome resistance to those agents and to resen-
sitize cells to agents to which they were previously unresponsive. CONCLUSIONS: This review indicates the potential utility of proteasome inhibition for
substantially enhancing activity of other therapeutic approaches. It explains the mechanisms responsible for the observed clinical activity of bortezomib-
based regimens and elucidates novel therapeutic approaches through identification of combinations of agents with complimentary mechanisms of action.
NPhase II trial of weekly bortezomib in combination with rituximab in untreated patients
with Waldenström Macroglobulinemia.
Ghobrial IM, Xie W, Padmanabhan S, Badros A, Rourke M, Leduc R, Chuma S, Kunsman J, Warren D, Poon T,
Harris B, Sam A, Anderson KC, Richardson PG, Treon SP, Weller E, Matous J.
Am J Hematol. 2010 Sep;85(9):670-4.
:
http://www.ncbi.nlm.nih.gov/pubmed/20652865
This study aims to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia and
finds that the combination exhibits significant activity and minimal neurological toxicity.
This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia
(WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m2 on days 1, 8, 15, q 28
days × 6 cycles, and rituximab 375 mg/m2 weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR).
Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70-98%) with 1 complete response (4%), 1 near-complete
response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least
MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common
grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neu-
ropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with
untreated WM.
www.myeloma.org
(800) 452 - CURE (2873)

---

(800)452-CURE (2873)
www.myeloma.org

---