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Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Improving outcomes in multiple myeloma will involve not only development of new therapies but also better use of existing treatments. We performed RNA sequencing on samples from newly diagnosed patients enrolled in the phase 2 PADIMAC (Bortezomib, Adriamycin, and Dexamethasone Therapy for Previously Untreated Patients with Multiple Myeloma: Impact of Minimal Residual Disease in Patients with Deferred ASCT) study. Using synthetic annealing and the large margin nearest neighbor algorithm, we developed and trained a 7-gene signature to predict treatment outcome. We tested the signature in independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass data set, patients who were treated correctly according to the signature had a better progression-free survival (median, 20.1 months vs not reached; hazard ratio [HR], 0.40; confidence interval [CI], 0.23-0.72; P = .0012) and overall survival (median, 30.7 months vs not reached; HR, 0.41; CI, 0.21-0.80; P = .0049) than those who were not. Indeed, the outcome for these correctly treated patients was noninferior to that for those treated with combined bortezomib, lenalidomide, and dexamethasone, arguably the standard of care in the United States but not widely available elsewhere. The small size of the signature will facilitate clinical translation, thus enabling more targeted drug regimens to be delivered in myeloma.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Background

Introduction:The Office of National Statistics (London, UK) has reported 4040 new patients in the year 2007, with an annual age standardized incidence rate of 4.8 per 100,000 population (range 4.7 –– 5.0). Overall survival (OS) in the last decade has improved from 2 –– 3 years to 7 –– 8 years in the UK. The introduction of IMids for the treatment of myeloma has had a significant impact on outcomes in this life-threatening disease.Areas covered:Pomalidomide, a thalidomide analogue, is a promising anti-myeloma agent with encouraging responses in relapsed/refractory myeloma patients. Pomalidomide has a potent anti-myeloma activity in vitroand in vivo,acting both directly on myeloma cells and on the cells in the bone marrow microenvironment. We have reviewed the chemistry and mechanisms of action of pomalidomide and the literature on pre-clinical and early Phase I and II clinical trials that demonstrates significant clinical efficacy in the relapsed setting and in lenalidomide refractory myeloma patients.Expert opinion:Pomalidomide has shown significant activity in relapsed/refractory disease and is now being taken into Phase III trials in combination with dexamethasone. The exact place of pomalidomide in the management of myeloma, however, is evolving as more clinical experience is gained with this agent and further data published from clinical trials.

The HDACis (histone deacetylation inhibitors) are an active class of drugs that have been used to treat a wide variety of tumours including breast cancer, prostate cancer, multiple myeloma, thyroid cancer and Hodgkin's and non‐Hodgkin's lymphoma. One HDAC, vorinostat, has been licensed by the FDA, but more work is needed to identify and delineate the histone and nonhistone targets of these agents. In this article, Dr Steve Schey considers the place of HDACis in future cancer therapy. Copyright © 2010 John Wiley & Sons, Ltd.

Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%,P< .001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P= .006) and chronic GVHD (5% versus 66.7%, P< .001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P< .001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P= .43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI.

A novel nonmyeloablative conditioning regimen was investigated in 44 patients with hematologic malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. Recipient conditioning consisted of CAMPATH-1H, 20 mg/day on days -8 to -4; fludarabine, 30 mg/m2 on days -7 to -3; and melphalan, 140 mg/m2 on day -2. Thirty-six recipients received unmanipulated granculocyte colony-stimulating factor–mobilized peripheral blood stem cells from HLA-identical siblings, and 8 received unmanipulated marrow from matched unrelated donors. GVHD prophylaxis was with cyclosporine A alone for 38 patients and cyclosporine A plus methotrexate for 6 sibling recipients. Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite polymerase chain reaction indicate that 18 of 31 patients studied were full-donor chimeras while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range 3 to 29 months), 33 patients remain alive in complete remission or with no evidence of disease progression. Seven patients relapsed or progressed post-transplantation, and 4 of them subsequently died. Four patients died of regimen-related complications. There were no cases of grades III-IV acute GVHD. Only 2 patients developed grade II acute GVHD, and only 1 had chronic GVHD. The estimated probability of nonrelapse mortality was 11%. Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity, and low incidence of GVHD.

Ramasamy: Oncopeptides and Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NAPP Pharmaceuticals Ltd.: Research Funding; Janssen-Cilag Ltd.: Research Funding. Drayson:Abingdon Health: Consultancy, Equity Ownership.

Introduction:The role of autologous stem cell transplantation (ASCT) as first-line therapy for newly diagnosed transplant eligible (NDTE) patients with multiple myeloma remains under evaluation. The primary objective of this study was to evaluate the progression-free survival (PFS) according to MRD status of patients achieving ≥VGPR following induction therapy followed by no further treatment. Those who achieved PR proceeded to ASCT. PADIMAC (ISRCTN no: 03381785) was designed to provide baseline data for a future response-adapted therapy trial in NDTE patients.

Background

Maciocia: Autolus: Equity Ownership, Patents & Royalties: TRBC1 and 2 Targeting for the Diagnosis and Treatment of T-cell Malignancies. Ramasamy:Celgene: Honoraria, Research Funding. Jenner:Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support; Amgen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel support, Research Funding. Schey:Celgene, Takeda: Honoraria; Celgene, Johnson & Johnson: Speakers Bureau; Celgene: Consultancy. Yong:Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.

Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding. Streetly:Guys and St. Thomas' NHS Trust: Honoraria. Schey:Celgene, Takeda: Honoraria; Celgene: Consultancy; Celgene, Johnson & Johnson: Speakers Bureau. Cook:Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria. Cook:Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Myeloma UK: Membership on an entity's Board of Directors or advisory committees.

Background: In recent years there has been an increasing focus on the costs of managing patients with Multiple Myeloma (MM). Novel agents such as immunomodulators and proteasome inhibitors have been added into the treatment pathway alongside conventional management options including intensive chemotherapy, stem cell transplantation, and supportive care. Commissioners of healthcare have evaluated these additional costs in the context of clinical outcomes such as response rates, progression free survival and overall survival. However, relatively little attention has been paid to disease burden which we argue is an important dimension alongside costs and outcomes.

Tornatore: Kesios Therapeutics Ltd.: Consultancy, Equity Ownership, Honoraria, Patents & Royalties. Adams:Kesios Therapeutics Ltd.: Consultancy. Kelly:Kesios Therapeutics Ltd.: Consultancy. Ruvo:Kesios Therapeutics Ltd.: Equity Ownership, Patents & Royalties. Oakervee:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Schey:Celgene Corporation: Honoraria. Apperley:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Franzoso:Kesios Therapeutics Ltd.: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Schey: Celgene Corporation: Honoraria. Montero:Celgene Corporation: Honoraria. Stengel-Tosetti:Celgene Corporation: Consultancy. Gibson:Celgene Corporation: Employment, Equity Ownership. Dhanasiri:Celgene Corporation: Employment, Equity Ownership.

Popat: Janssen: Honoraria. Cavenagh:Janssen: Honoraria. Schey:Janssen: Consultancy, Honoraria. Cook:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cook:Janssen: Honoraria, Research Funding. Yong:Janssen: Honoraria.

Bendamustine has efficacy as first-line treatment in multiple myeloma (MM) (in combination with prednisone), and in refractory patients who have been heavily pre-treated. Dose finding studies have not been performed for bendamustine in heavily pre-treated relapsed/refractory patients. MUK one is a randomised phase II selection trial assessing the activity & tolerability of two doses of bendamustine (B), 60mg/m2 vs 100mg/m2, in combination with thalidomide (T) & dexamethasone (D) in patients with relapsed/refractory MM.Patients were randomised to receive B(60)TD or B(100)TD (B days 1 & 8 ; T 100mg od; D 20mg d1, 8, 15 & 22; 28 day cycle). Eligibility was based on confirmed MM with measurable disease, ECOG 0-3, platelets >75x109/L & neutrophils >1.5x109/L at 1st or later relapse. In the initial protocol, patients with lower platelets/neutrophils attributable to myeloma were eligible. Activity and tolerability were joint primary endpoints. The primary activity endpoint was ≥PR within 6 cycles. Tolerability was defined as the ability to receive at least 2 cycles of treatment at full dose with no delays of >2 weeks, without primary growth-factor support. Response rates <20% & tolerability rates <75% were deemed unacceptable based on previous data.95 patients were randomised: B60TD n=66, B100TD n=29. In the primary analysis population, 56% (25/45, 80% CI [45-66]) of B60TD patients achieved ≥PR, the median progression free survival (PFS) was 8.2 months (95% CI [7.2-10.6]). In the B100TD primary population, 36% (5/14, 80% CI [19-56]) achieved ≥PR, median PFS was 5.1 months (95% CI [2.3-9.0]).Following an interim analysis the B100TD arm was discontinued due to tolerability. Thereafter, patients were recruited to B60TD arm only, and included only with unsupported neutrophil >1.5x109/L and platelets >75x109/L, regardless of marrow infiltration. Consequently, two analysis populations are defined. (i) Primary analysis population: patients fulfilling amended eligibility criteria without PD after 1 cycle, having ≥1 dose of study drug, (B60TD evaluable n=45; B100TD evaluable n=14). (ii) Combined population: as for (i) but including patients with PD after cycle 1, (B60TD combined n=54; B100TD combined n=20). This group represents an intention to treat population with the amended criteria.46% (80% CI [37-56]) of patients in the B60TD combined population achieved ≥PR, with a median PFS of 7.5 months (95% CI [5.3-8.7]). In the B100TD combined population 25% (80% CI [13-42]) of patients achieved ≥PR, with a median PFS of 2.6 months (95% CI [1.7-5.6]).In the assessment of tolerability, 70% (80% CI [59-79]) of B60TD primary patients assessable for tolerability received ≥2 cycles of full-dose treatment with no delay >2 weeks. Median number of B60TD cycles was 6 (range 1-9), with 64% patients receiving ≥6 cycles. 32% patients experienced ≥ grade 3 neutropenia, 25% ≥ grade 3 thrombocytopenia, & 14% ≥ grade 3 anaemia. There was 1 grade 3 neurotoxicity, & no grade 3 nausea or GI disturbance.Of the B100TD primary patients 71% (80% CI [51-87]) met tolerability criteria. Median number of cycles was 4 (range 1-9), 29% patients receiving ≥6 cycles. 64% patients experienced ≥ grade 3 neutropenia, 21% ≥ grade 3 thrombocytopenia, & 21% ≥ grade 3 anaemia. There were 3 grade 3 neurotoxicities, no grade 3 nausea & 1 grade 3 diarrhoea. Thromboembolism rates with prophylactic anticoagulation was 4% overall.84% of patients had ≥3 prior therapies, PS 0/1 (85%) & relapsed MM (78%); 37% were ISS 3 at entry, mean b2M=5.6. Most had prior T (90%), Lenalidomide (74%) & Bortezomib (84%); 74% had ≥1 prior autograft.The combination of BTD shows promising response rates at the 60mg/m2 dose, despite only 70% of evaluable patients receiving at least 2 full cycles of bendamustine with ≤2 week delay, in this challenging multi-treated group of patients. The B100TD arm closed to recruitment at interim analysis due to lack of tolerability on the basis of pre-defined stopping rules. Responses were also lower in this arm compared to B60TD arm, which may reflect the ability of patients to receive more cycles of treatment to schedule at 60mg/m2 than at 100mg/m2. Although not passing the strict pre-specified tolerability boundaries, B60TD appears deliverable beyond 2 cycles in multiply-pretreated MM, with PR in excess of 45%, comparing favourably other novel agent combinations in this heavily pre-treated population.Schey: Napp: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Cook:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Cavet:Celgene: Consultancy, Research Funding.

No relevant conflicts of interest to declare.

CRBN, a target of thalidomide and IMiDs® immunomodulatory agents lenalidomide (LEN) and pomalidomide (POM), is a component of the E3 ubiquitin cullin 4 ring ligase (CRL4) complex that also includes DDB1, Roc1, and Cul4. Two CRBN mutations have been reported in multiple myeloma (MM) patients: truncating mutation (Q99) and point mutation (R283K). One copy of the CRBN gene was shown to be deleted in the MM1S and MM1S.R cell lines. No DDB1 mutation has been described previously.We investigated the incidence of CRBN and DDB1 mutations by next-generation sequencing in 20 MM cell lines and MM subjects. Of 90 MM patients, 24 were newly diagnosed and 66 were relapsed and refractory of which 36 patients were LEN resistant. Out of the cell lines tested, 1 heterozygous CRBN mutation (D249Y) was found in the LEN-resistant ANBL6R cells, which is located in the putative DDB1 binding domain, and 2 single silent mutations were identified in the KMS-12-BM (rs17027638) and OPM-2 cells. One DDB1 heterozygous mutation (E303D) was identified in ANBL6 cells. In the cohort of patients assessed, no CRBN mutation was detected; however, 5 single nucleotide variations (SNV) were identified. Three of the 5 SNVs were at position 735 (Y245Y) and 1 each at position 219 (H73H) and 939 (C313C), respectively. The first 2 SNVs (rs17027638 and rs1045309) are described but not the last. We found a single SNV (P51P; rs2230356) in DDB1 gene the patient samples.Mutations within the coding sequences of CRBN and DDB1 are rare in MM patients and cell lines. Most intrinsically LEN-resistant cells and cell lines made resistant to LEN or POM do not have CRBN or DDB1 mutations, suggesting the potential role of other sources, such as genetic or epigenetic pathways in developing resistance to IMiD drug–based therapy.Thakurta: Celgene: Employment, Equity Ownership. Gandhi:Celgene: Employment, Equity Ownership. Waldman:Celgene: Employment, Equity Ownership. Bjorklund:Celgene: Employment, Equity Ownership. Lentzsch:Celgene: Research Funding. Schey:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; NAPP: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Madan:Covance Genomics Lab: Employment. Ning:Celgene: Employment, Equity Ownership. Mendy:Celgene: Employment, Equity Ownership. Lopez-Girona:Celgene: Employment, Equity Ownership. Schafer:Celgene: Employment, Equity Ownership. Avet-Loiseau:Celgene: Research Funding. Chopra:Celgene: Employment, Equity Ownership.

Ghobrial: Millennium pharmaceuticals Inc.: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Landesman:Karyopharm Therapeutics Inc: Employment. Shacham:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics Inc: Employment. Anderson:Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon, Oncopep: Scientific Founder, Scientific Founder Other.

No relevant conflicts of interest to declare.

Landesman: Karyopharm Therapeutics Inc: Employment. Senapedis:Karyopharm Therapeutics Inc: Employment. Saint-Martin:Karyopharm Therapeutics Inc: Employment. Kashyap:Karyopharm Therapeutics Inc: Employment. Ying:Karyopharm Therapeutics Inc: Employment. McCauley:Karyopharm Therapeutics Inc: Employment. Shacham:Karyopharm Therapeutics: Employment. Kauffman:Karyopharm Therapeutics Inc: Employment. Munshi:Celgene: Consultancy; Millenium: Consultancy; Merck: Consultancy; Onyx: Consultancy. Richardson:Millenium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Anderson:Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees; Acetylon, Oncopep: Scientific Founder, Scientific Founder Other.

Lenalidomide plus dexamethasone (Len+Dex) is approved by EMA for patients with multiple myeloma (MM) who have received at least 1 prior therapy. In the wake of NICE's guidance on Thalidomide and Bortezomib TA 228 for 1st-line treatment of MM, Len+Dex may be the only available novel therapy option with potential to extend survival beyond traditional therapies for patients failing the NICE recommended initial treatments; thalidomide or bortezomib both in combination with melphalan and prednisone. Therefore, economic modelling was undertaken to evaluate the cost-effectiveness of Len+Dex from the perspective of the National Health Service (NHS), England and Wales.An Excel-based individual simulation model was developed to account for disease history which affects time-to-progression (TTP) and overall survival (OS) in relapse refractory MM patients. The OS for each individual within the model was calculated as the combination of that patient's TTP and post progression survival (PPS). The TTP efficacy was derived from a subgroup analysis of patients from the MM-009/010 pivotal trials who had received only 1 prior therapy. The derived equation for TTP included parameters for treatment response, Len+Dex treatment effect and certain baseline characteristics of patients with only 1 prior therapy. The PPS for patients within the model was also derived from the MM-009/010 trials; however, since 47% of patients on Dex switched to Len+Dex at progression, there was a significant Len+Dex effect in the Dex PPS. To account for this, the Dex PPS was calibrated using the longer follow up from the UK Medical Research Council (MRC) trials. Resource use for monitoring and adverse events was obtained via a survey of expert hematologists in the UK. Costs were taken from NHS sources and included a Patient Access Scheme where patients received Len free of charge beyond 26 cycles of use. Utility values were taken from published literature and applied to patients prior to progression (based on their best response rate achieved) and after progression. The robustness of the model results were assessed by sensitivity analyses whereby individual model parameters were varied across their confidence intervals (CI). Results reported include life-years (LY), quality-adjusted life-years (QALY), costs, cost per LY gained and cost per QALY gained. NICE technology appraisal methodology guidelines were followed when modelling over a lifetime horizon and applying a 3.5% discount rate for future benefits and costs. All costs presented are in British pounds.Len+Dex had a substantial increase in health-related outcomes compared to Dex alone, with LYs of 5.37 vs. 2.15 and QALYs of 3.69 vs. 1.49, respectively. The associated drug costs for Len+Dex over the patients' lifetime were higher: however, survival benefits accrued over the same time period offset the cost differences between the two regimens, resulting in a cost per LY gained of 20,639 and per QALY gained of 30,153. The model results remained robust to sensitivity analysis conducted on most parameters and utility estimates. The only parameter that affected the results was the adjustment factor for Dex survival when varied across its 95% CI (see table).These results indicated that Len+Dex at 2nd line is cost-effective for a novel drug in an orphan disease compared to Dex alone. Despite Len+Dex only being recommended by NICE for use in MM patients with 2 or more prior therapies (with the recent NICE decision to allow thalidomide and Velcade in de novo patients), treatment alternatives for 2nd line therapy with novel agents is more limited. It is important for clinicians to consider the costs and benefits of 2nd line therapy. This analysis demonstrated that Len+Dex is cost-effective for 2nd line patients and meets the commonly quoted cost per QALY threshold of 30,000.Schey: Celgene: Consultancy. Stern:United BioSource Corporation: Employment; Celgene: Consultancy. Dhanasiri:Celgene: Employment. Brown:United BioSource Corporation: Employment; Celgene: Consultancy.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Risk adapted CTD, oral MD and high dose melphalan with autologous stem cell transplantation (SCT) (in selected cases) have emerged as important frontline treatments in AL amyloidosis. We report the interim results of a randomised prospective pilot study designed to estimate response rates and test feasibility of two randomisations using these treatments for patients with newly-diagnosed systemic AL amyloidosis. The final analysis is due in October 2009 and final full study results will be presented at the meeting.The trial recruited for 14 months from January 2008 in the UK. Twenty four patients each were planned to enter a high intensity (SCT versus CTD) or a low intensity randomization (MD versus CTD) respectively, depending on suitability for SCT. Eligibility for the high-intensity arm was deliberately stringent in order to minimize risk of transplant-related mortality. Primary endpoints were haematologic response by free light chain assay (measured at each cycle with landmark assessments at 3 and 7 months), safety and recruitment rate. A myeloma quality of life (QOL) questionnaire was piloted in the absence of a disease-specific questionnaire for AL amyloidosis at baseline and 7 months post randomisation.The high intensity arm was closed early due to lack of recruitment, mostly from clinical ineligibility and no further results from this arm are reported. The low intensity arm successfully recruited the required 24 patients (12 in each group). Median (range) age at randomization was 66 (42-85) years and stratification was by ECOG performance status which ranged from 0 to 3 (21%, 33%, 33% and 13% of patients respectively). 24 (100%) and 16 (67%) patients have response assessments (or are not evaluable) at 3 months and 7 months respectively at the time of submission. One patient in each arm died and one patient in the MD arm withdrew prior to the 3 month assessment. Overall haematological response rate at 3 months (at least a PR) was similar between the two arms; 9 (75.0% (95% Confidence Interval 43% to 95%)) in the CTD arm versus 8 (66.7% (95% CI 35% to 90%)) in the MD arm. At 3 months, CR was achieved in 7 (58.3% (95% CI 28% to 85%)) CTD and 3 (25.0% (95% CI 6% to 57%)) MD patients. Final response data at 7 months will be presented at the meeting. Median (range) time to achieve at least a PR from commencement of chemotherapy was 88 (34-218) and 95 (74-133) days in the CTD and MD groups respectively. To date, 17 of the 24 patients have reached their maximal clonal response (10 CTD, 7 MD patients), two patients died before achieving maximal response and one patient is not evaluable as they withdrew prior to the first response assessment. 4 patients could still achieve maximal response once 7 month follow up is completed. Of those currently evaluable for a maximal response, 8 (80%) CTD patients had CR versus 3 (43%) MD patients and 1 (1%) CTD patient had PR compared with 4 (57%) MD patients. There were no treatment-related deaths in either arm. Seventeen of 24 (71%) patients experienced grade = 3 toxicities during chemotherapy (10 CTD patients (83%) versus 7 MD patients (58%)) though only 9 were classified as trial medication related SAEs (serious adverse events) which appeared to be similar in each arm - 5 CTD versus 4 MD. Lethargy (n=6), worsening congestive heart failure/fluid overload (n=5), infections (n=7) and pain (n=4) were the most common grade 3/4 toxicities, again with no noticeable differences between the treatment groups. The EORTC QLQ-MY20 myeloma QOL questionnaire appeared valid for use in AL amyloidosis patients and showed comparable QOL among both groups.Randomisation to SCT versus combination chemotherapy is not feasible using the current criteria in the UK. These interim results suggest that CTD may compare favourably with MD with possible higher early CR rates with CTD. There is a general perception that CTD has greater toxicity than MD but in this study there was no evidence of increased SAEs in either group and the QOL was comparable. Further comparison of CTD and MD is warranted in a large phase III randomized trial, but in order to be feasible would require international collaboration.Off Label Use: Off label use of thalidomide.

Off Label Use: Dasatinib is not licensed for Myeloma.

Abstract 2813

Background: The optimal therapy for patients with relapsed/refractory multiple myeloma remains controversial. Lenalidomide, an oral immunomodulatory drug, has been shown to be an effective treatment in this setting, with in-vitro laboratory data suggesting that its effect is synergistic with a number of established chemotherapeutic agents. The primary objective of this study was to determine the maximum tolerated dose and toxicity of cyclophosphamide when used in combination with lenalidomide and dexamethasone for patients with relapsed/refractory myeloma. The secondary objective was to determine clinical response rates. Methods: Cyclophosphamide was given at increasing doses from 300 mg po in cohort 1, up to the maximum planned dose of 700 mg po in cohort 5 on days 1 and 8 of a 28 day cycle, in combination with dexamethasone (20mg po, daily on days 1–4 and 8–11) and Lenalidomide (25mg po, daily on days 1–21). Maximum tolerated dose (MTD) was established as one dose level below that at which 2 or more patients suffered dose limiting toxicity (DLT). DLT was defined as Grade 4 haematological toxicity or febrile neutropenia occurring during cycle 1 of treatment, or Grade 3/4 non-haematological toxicity during cycle 1, or a failure to start cycle 2 within 7 days of scheduled day due to toxicity. Once the MTD had been established, a further ten patients were enrolled at that dose. Safety assessments were performed weekly during cycle 1, and at the end of every cycle thereafter. Response data was collected on day 28 of each cycle. Results: Toxicity The most commonly observed adverse events were; neutropenia (grade 1–3), cramps (grade 1–2), somnolence (grade 1–2), constipation/diarrhoea (grade 1–2), minor infections (grade 1–2), and musculoskeletal aches and pains (grade 1). The most common reason for dosing delays and dose reductions was grade 3 neutropenia. Maximum tolerated dose No patients receiving doses of 300 to 600mg cyclophosphamide have experienced dose limiting toxicity during the first month of treatment. 2 patients receiving 700mg qualified as having dose limiting toxicity (One patient with febrile neutropenia, pneumonia and syncope (all grade 3)), and another with grade 4 pancytopenia). The maximum tolerated dose of cyclophosphamide in combination with lenalidomide and dexamethasone has therefore been established at 600mg daily on days 1 and 8 of a 28 day cycle. Response: A total of 31 patients were enrolled into the study. Median age at enrolment was 57 years (range 42–79). Median ISS at trial entry was 1 (range 1–3). Median time since last therapy was 7 months (range 1–84). To date, 36% of patients have achieved CR or VGPR, and 81% PR or better. Responses were assessed at the end of each cycle. 25 of the 31 patients have so far achieved PR or better. Of these 25 patients, 76% had achieved their maximum response by cycle 3 day 28. Patients had received 1–6 prior lines of therapy (median 3). 28/31 patients had previously received thalidomide, 20 had received autologous stem cell transplant, and 8 received velcade. 7 patients had received all 3 and, of these, 1 achieved SD, 3 PR, and 3 CR. This suggests that lenalidomide in combination with cyclophosphamide and dexamethasone is an effective therapy for heavily pre-treated patients. Conclusion: 600mg cyclophosphamide on days 1 and 8 of a 28 day cycle is well tolerated in combination with Lenalidomide and dexamethasone. The combination is a highly effective therapy for relapsed/refractory myeloma. The majority of patients achieved a maximal response during the first 4 courses of treatment. CRD is also an effective treatment for patients who have received extensive prior chemotherapy. Whether patients need to continue treatment to nine cycles remains to be tested. Figure Figure

Hepatocyte growth factor (HGF) augments proliferation, survival and increases migration of plasma cells in vitro and in addition it induces haemangiogeneis and lymphangiogenesis. C-met (HGF receptor) is expressed on plasma cells and HGF is constitutively elevated in serum of patients with myeloma (MM) and MGUS patients. We investigated the distribution of HGF in bone marrow biopsies to better understand its role in progression of monoclonal gammopathy. Materials and methods: Bone marrow trephines were analysed by immunohistochemistry of paraffin embedded bone marrow (BM) trephine specimens. Trephines were dewaxed without antigen retrieval. Plasma cell enumeration was done using CD38 staining (Novocastra, UK). HGF (Goat antihuman IgG, R&D systems) staining was performed using Vectastain® ABC kit with DAB reactivity. Slides were analysed using an Optical microscope (Zeiss Standard 20, Germany). Results: Archived BM specimens of MM (n= 7), MGUS (n= 5) and normal controls (n=6) were stained in duplicate. Trephines were graded from Grade 1–3 (weak, moderate, strong) based on the intensity of staining. The localisation of staining to paratrabecular, perivascular and intertrabecular areas was analysed. Interstitial and cytoplasmic staining patterns were analysed. HGF staining localised to paratrabecular regions was observed in all normal individuals with staining intensity of Grade 1–2 in 3/6(50%) and Grade 3 in 3/6(50%). In 4/5(80%) patients with MGUS a distinct intertrabecular pattern of staining was observed in discrete regions, where plasma cells were localised. Intensity of staining was Grade 2 in 3/5(60%) and Grade 3 in 2/5(40%) MGUS patients. Plasma cell percentages were between 5–20% in MGUS patients. In MM patients we found a correlation between the plasma cell counts and the degree of HGF staining. In 2/7 (28.5%) patients plasma cell percentages ranged between 5% and 15% and Grade 1–2 discrete paratrabecular staining was observed with none or low perivascular staining. In 5/7 (71.5%) MM patients plasma cell percentages were >20% and Grade 3 confluent staining with interstitial and cytoplasmic location of HGF was observed. In addition, patients with Grade 3 staining presented a strong perivascular localisation of HGF. Conclusion: HGF distribution in bone marrow microenvironment of MGUS and MM patients is non random. We observed that MGUS patients have a discrete intertrabecular pattern and MM patients have a confluent interstitial pattern of staining with strong perivascular localisation. Other groups have shown that high HGF levels increase angiogenesis. We hypothesise that HGF localisation and pattern of distribution in BM microenvironment leads to neo angiogenesis and progression from MGUS to MM. Ongoing studies are evaluating this hypothesis.

Allogeneic transplantation is the only potentially curative treatment option for myeloma (MM). While reduced intensity conditioning (RIC) regimens are associated with lower transplant related morbidity and mortality (TRM), this approach is offset by an increase in relapse rates in myeloma. Method & Materials: We conducted a prospective study on the use of pDLI in myeloma patients with declining donor T cell chimerism following alemtuzumab based RIC allogeneic transplants. 19 consecutive patients were recruited. Patients received 100mg of Alemtuzumab 1H in total over 5 days in vivo as part of the pre-transplant conditioning regimen. There were 8 females and 11 males with a median age of 54 years (range: 41–63). Median lines of prior therapy was 2 (1–4), and 17(84%) had at least one prior autograft. 15 patients were transplanted with related donors and 4 unrelated. The median followed up of the cohort was 25.5 months (4–82). Fractionated peripheral blood (PB) and unfractionated bone marrow (BM) chimerism was performed on day 30, 60, 100 and 3–6 monthly thereafter using promega powerplex 16 genetic identity system. The samples were electrophoresed on an ABI 3130 XL capillary sequencer and analysed using Genemapper 4.0 software. Metaphase cytogenetics of unfractionated BM overnight cultures and Y-FISH for sex mismatch transplants was performed at various time points. Escalating doses of pDLI was given to patients with falling donor T cell chimerism (<50%) after Day 100. The starting dose of DLI was 1 × 105 CD3 cells/kg. 6 patients received pDLI with a median number of pDLI infusions of 2.5 (1–4). Overall survival (OS) and PFS was calculated from date of transplant using Kaplan-Meier cumulative survival plot using SPSS 14.0 software in pDLI receiving (Cohort I) and non-pDLI receiving cohort (Cohort II). Results: 17 patients (84%) responded with CR rate at 100 days of 57%. One patient had primary graft failure and 1 patient had stable disease for a year post transplant. Median OS and PFS for all patients was 24 months (17.6–30.3) and 12 months (7.7–16.2) respectively. TRM at 2 years was 15.5%. In Cohort I, 13 patients did not receive pDLI. 1 patients (7.6%) experienced limited chronic graft versus host disease (cGVHD) with no cases of acute GVHD. In Cohort II, escalated doses of pDLI were administered to 6 patients at declining levels of donor CD3 chimerism in PB without evidence of morphological or cytogenetic relapse. 2/6(33.3%) patients developed cGVHD post DLI. Full donor chimerism was achieved in 4/6 patients, all of whom are long-term survivors. Median OS in Cohort I is 24 months (8.9–41.0) and 17 months (11.3–22.6) in Cohort II (p=NS). Median PFS in Cohort I is 25 months vs 9 months in Cohort II (p= 0.02). Cytogenetics was not helpful in determining requirement for DLI even in sex-mismatched patients. The presence of GvHD did not have a significant impact on OS. Conclusion: pDLI administration guided by PB CD3 chimerism significantly improves PFS in Alemtuzumab conditioned RIC transplants for myeloma. Monitoring CD3 chimerism and early application of pDLI improves survival with a 5-year survival rate of 20% in multiply treated high risk patients.

Lenolidamide (Revlimid®) is an oral immunomodulatory drug that has been shown to be effective for the treatment of relapsed refractory myeloma, and in-vitro laboratory studies suggest that its action may be synergistic with a number of conventional chemotherapeutic agents. The aim of this study is to assess the efficacy and toxicity profile when lenolidamide is used in combination with cyclophosphamide and dexamethasone for patients with relapsed refractory disease. Multiply relapsed patients were given Revlimid 25mg po on days 1–21, dexamethasone 40mg po days 1–4 and days 12–15, and cyclophosphamide 500 mg po days 1, 8, 15 and 21 of a 28 day cycle for a maximum of 6 cycles of treatment. Prophylaxis with acyclovir, septrin and proton pump inhibitors was routinely used, 1 high risk patient received prophylactic anticoagulation. Toxicity profiles and response were assessed every 4 weeks. To date 18 patients have been included in the study with median age of 60.5 years (range 34–76). All were heavily pre-treated with a median of 4 previous lines of therapies (range 2–8). 12 patients had received high dose melphalan, 18 patients thalidomide and 16 patients bortezomib. One case had undergone an allogeneic BMT. The median time from diagnosis to treatment initiation was 55.5 months (range 11–122). To date 81 complete courses of therapy have been given to 18 patients with median number of 5 courses (range 1–6). 8 patients experienced neutropenia with the neutophil count falling below 0.5×109/L in a total number of 14 cycles, which resulted in a dose reduction or stopping of cyclophosphamide in 8 patients. 12 patients received GCSF to maintain their neutrophil count. 5 patients required dose reduction/omit of Revlimid. 4 patients required intravenous antibiotics for neutropenic fever. The side effect profile was manageable, importantly no patient experienced sedation, constipation or worsening of peripheral neuropathy. 2 patients with a heavy myeloma load suffered a DVT, but continued on therapy achieving a PR once anti-coagulation had been commenced. 14 of the 17 patients assessable for response achieved a response with 1 CR, 3 VGPR, 8 PR and 2 MR according to EBMT criteria. The median time to response was prompt at 32 days (range 21–68). To date only 2 patients have discontinued therapy because of a failure to respond to therapy and 1 stopped due to liver toxicity. 13 patients have completed treatment and 5 still remain on treatment. The combination of CRD is effective in heavily pretreated myeloma patients and has a manageable toxicity profile. In view of the neutropenia further studies using this combination are currently being investigated using cyclophosphamide on days 1 and 8 only.

41 yr old male presented with pain and weakness of upper and lower limbs. He was bed bound with ECOG score 4. Investigations confirmed the diagnosis of POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) syndrome. He had typical features including glomerular hemangiomas on the skin, mild hepatosplenomegaly, sensorimotor polyneuropathy, IgG lambda paraprotein 3.3g/l, elevated FSH, LH and TSH. A course of cyclophosphamide and dexamethasone was given with no clinical response. He was also given a trial of plasma exchange and parenteral Immunoglobulins. Symptoms plateaued and he was followed up with rehabilitation support. He re-presented 18 months later with widespread low-grade lymphadenopathy, stable paraprotein, ascites, poor appetite and weight loss. Lymph node biopsy showed Castleman’s disease like changes along with osteosclerotic lesions in pelvis and raised CSF protein of 3.13g/l with rest of CSF analysis being normal. Bone marrow trephine showed paratrabecular deposits of lambda light chain restricted CD38 positive plasma cells. Ascitic fluid was sterile consistent with a transudate. Vascular endothelial growth factor (VEGF) level prior to treatment was elevated at 4587 pg/ml (Normal: 72–704 pg/ml). Large volume abdominal paracentesis ranging between 2–3 litres of clear fluid was performed weekly. In view of the raised VEGF, 4 doses of Bevacizumab (anti-VEGF) 2.5mg/kg were administered as an intravenous infusion over one hour fortnightly. VEGF level normalised after first dose of bevacizumab (131.2 pg/ml) and remained normal prior to the fourth dose (136.5 pg/ml). There were no infusional reactions or haematologic adverse effects. Frequency of paracentesis decreased to three weekly, his appetite and performance status improved with ECOG score 2. 3 weeks after the fourth dose he was readmitted with tense ascites, pleural effusion, diarrhoea, pyrexia and severe abdominal pain. Meropenem resistant pseudomonas was grown from ascitic fluid. After therapeutic paracentesis and antibiotics a Leveen shunt from abdomen to right internal jugular vein was performed to prevent reaccumulation. Despite shunting, he reaccumulated fluid in the third space and developed respiratory and pre renal failure and succumbed to it. At post mortem there were non-specific changes in the lungs and heart with no evidence of pulmonary embolism or bowel perforation and Leveen shunt remained patent. Bevacizumab promptly reduced VEGF levels with significant reduction in pleural and peripheral effusion with subjective improvement in neurological status. Bevacizumab appears to induce clinical response in a proportion of patients with POEMS syndrome. We suggest that a Phase I study should be considered to identify dose, duration of therapy and safety of Bevacizumab.

The marrow stromal cells in multiple myeloma activate multiple signalling pathways via stimulation by the cytokines they secrete. This leads to upregulation of anti-apoptosis, drug resistance, cell cycle and metabolic pathways. Disruption of these signalling networks can lead to myeloma cell death and make them attractive targets for novel therapies. In addition, Bcl-2 family proteins, mcl-1 and bcl-xLare important for the survival of myeloma cells. The modified citrus pectin, GCS-100 has been used safely in Phase I studies for solid tumors, can induce cell death in lymphoma via blocking galectin-3 / Bcl-2 dimerisation and in myeloma cells by mechanisms not fully understood. GCS-100 as well as pro-apoptotic effects, also demonstrates anti-proliferative and anti-angiogenic properties, all of which may be useful in the therapy of myeloma. This study was aimed at elucidating the mechanism of action of this novel agent so as to apply it most effectively to myeloma therapy. Myeloma cell lines RPMI8226 and U266 treated with GCS-100 show induction of apoptosis in a dose and time dependent manner with a loss of cells in the G1 and S phase of cell cycle and a significant increase in G0 / sub-G1 cells. Treatment of RPMI8226 led to a marked reduction of mcl-1 and bcl-xLafter 24 hours of treatment. There was no change observed in protein levels of bcl-2 or galectin-3. Activation of NFκB in myeloma cells is associated with proliferation and adhesion molecule upregulation. GCS-100 treatment led to a time dependent reduction in activated IκBα and p65NFκB. Furthermore pre-treatment of myeloma cells with GCS-100 prior to stimulation with TNFα, a known activator of IκBα, inhibited this activation. Similarly, treatment with GCS-100 led to a reduction in the amount of activated Akt (a regulator of cell cycle) and inhibited IGF-1 associated activation of Akt. The effect of GCS-100 on cell cycle regulatory proteins revealed downregulation of cyclin D1, p16INK4Aand CDK6 at 24hrs, however, there was no change in expression of CDK4 and p15INK4B. The p21CIP1was upregulated with a corresponding decrease in protein levels of cyclin E2 and CDK2 but there was no change in p27KIP1. GCS-100 clearly inhibits progression through G1 / S phase of cell cycle. Studies are currently ongoing for primary cells. In conclusion GCS-100 is a novel complex carbohydrate that is effective for the induction of myeloma cell death. It has multi faceted effects in reducing proliferation and induces apoptosis by down regulating crucial anti-apoptotic proteins, cell cycle regulators and signalling proteins and may also act by interfering with the myeloma cell microenvironment. Phase I studies in myeloma have been commenced.

The marrow stromal cells in multiple myeloma activate multiple signalling pathways via stimulation by the cytokines they secrete. This leads to upregulation of anti-apoptosis, drug resistance, cell cycle and metabolic pathways. Disruption of these signalling networks can lead to myeloma cell death and make them attractive targets for novel therapies. In addition, Bcl-2 family proteins, mcl-1 and bcl-xL are important for the survival of myeloma cells. The modified citrus pectin, GCS-100 has been used safely in Phase I studies for solid tumors, can induce cell death in lymphoma via blocking galectin-3 / Bcl-2 dimerisation and in myeloma cells by mechanisms not fully understood. GCS-100 as well as pro-apoptotic effects, also demonstrates anti-proliferative and anti-angiogenic properties, all of which may be useful in the therapy of myeloma. This study was aimed at elucidating the mechanism of action of this novel agent so as to apply it most effectively to myeloma therapy. Myeloma cell lines RPMI8226 and U266 treated with GCS-100 show induction of apoptosis in a dose and time dependent manner with a loss of cells in the G1 and S phase of cell cycle and a significant increase in G0 / sub-G1 cells. Treatment of RPMI8226 led to a marked reduction of mcl-1 and bcl-xL after 24 hours of treatment. There was no change observed in protein levels of bcl-2 or galectin-3. Activation of NFκB in myeloma cells is associated with proliferation and adhesion molecule upregulation. GCS-100 treatment led to a time dependent reduction in activated IκBα and p65NFκB. Furthermore pre-treatment of myeloma cells with GCS-100 prior to stimulation with TNFα, a known activator of IκBα, inhibited this activation. Similarly, treatment with GCS-100 led to a reduction in the amount of activated Akt (a regulator of cell cycle) and inhibited IGF-1 associated activation of Akt. The effect of GCS-100 on cell cycle regulatory proteins revealed downregulation of cyclin D1, p16INK4A and CDK6 at 24hrs, however, there was no change in expression of CDK4 and p15INK4B. The p21CIP1 was upregulated with a corresponding decrease in protein levels of cyclin E2 and CDK2 but there was no change in p27KIP1. GCS-100 clearly inhibits progression through G1 / S phase of cell cycle. Studies are currently ongoing for primary cells. In conclusion GCS-100 is a novel complex carbohydrate that is effective for the induction of myeloma cell death. It has multi faceted effects in reducing proliferation and induces apoptosis by down regulating crucial anti-apoptotic proteins, cell cycle regulators and signalling proteins and may also act by interfering with the myeloma cell microenvironment. Phase I studies in myeloma have been commenced.