Search

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.

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.

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.

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.

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/m2on days −7 to −3; and melphalan, 140 mg/m2on 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.

Background

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.

Introduction. The outlook for myeloma patients who relapse after or become refractory to bortezomib and IMiDs is poor, with limited therapeutic options and a median survival (OS) of 9 months. In the phase 3 MM-003 study, pomalidomide plus low-dose dexamethasone resulted in a significant PFS (median 4 vs 1.9 months) and OS (median 13.1 vs 8.1 months) benefit, compared to high-dose dexamethasone. Information on real-world outcomes of pomalidomide therapy is limited. We carried out a retrospective analysis of patients receiving pomalidomide in the UK, to compare outcomes and tolerability with published clinical trial data, and focus on high risk subgroups.

A major challenge in modern myeloma management is the selection of the best initial treatment from a plethora of available therapies. PAD (bortezomib, doxorubicin, and dexamethasone) is a highly effective regimen which may obviate the need for an upfront high-dose melphalan stem cell transplant (HDSCT). However, it is not clear a prioriwhich patients will benefit from this treatment. In the phase 2 PADIMAC trial, patients with newly diagnosed myeloma were treated with six cycles of PAD and stratified to receive HDSCT in partial remission (PR) or watch and wait in very good partial remission (VGPR) or better. To identify predictive biomarkers, we extracted somatic RNA prior to treatment and performed massively parallel RNA sequencing (RNAseq).

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.

Schey: Celgene, Takeda: Honoraria; Celgene, Johnson & Johnson: Speakers Bureau; Celgene: Consultancy. Morris:Cogentia UK: Research Funding. Maguire:Cogentia UK: Research Funding. Dhanasiri:Celgene: Employment, Equity Ownership.

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.

Background: Multiple myeloma remains an incurable and relapsing haematological cancer. The FIRST study showed that lenalidomide, an immunomodulatory agent, plus dexamethasone improved overall survival of newly diagnosed multiple myeloma (ndMM) patients who are not eligible for transplants by 10.4 months when it was used continuously compared with fixed treatment duration (72 weeks) with melphalan, prednisone and thalidomide(Facon et al, EHA 2015). Compared with alternative intravenous agents, lenalidomide as an oral therapy has also been associated with fewer hospital visits(Gualtney et al, J Clin Pharm Ther, 2013; Armoiry et al, J Clin Pharm Ther, 2011; Arikian et al, Curr Med Res Opin, 2015). In an era of increasing cost conscious health systems, additional economic information is playing an important role in access decisions on innovative medicines. This analysis examines the cost impact of lenalidomide when used in the first-line setting for patients with ndMM in the EU5.

The NF-κB transcription factor pathway is aberrantly activated in multiple myeloma (MM) and many other cancers, where it promotes malignancy by upregulating survival genes, thus providing a compelling rationale for therapeutically targeting this pathway in MM. However, despite aggressive efforts to develop a specific NF-κB or IκB kinase (IKK)β inhibitor, no such inhibitor has been approved, due to the preclusive toxicities associated with the general suppression of NF-κB. As a key pathogenetic activity of NF-κB in MM is to block apoptosis through the induction of target genes, an attractive alternative to globally inhibiting NF-κB would be to therapeutically target the non-redundant, cancer-specific downstream effectors of the NF-κB survival pathway.

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.

Introduction:The role of autologous stem cell transplantation (ASCT) as first line treatment for newly diagnosed patients with myeloma is currently under evaluation given the high response rates to novel induction treatment. The outcomes for patients that do not proceed to ASCT following induction remain unclear and are likely to be determined by genetic risk and response to therapy. In order to evaluate this further, this single arm phase 2 clinical trial conducted at 13 sites in the UK was designed to determine the 2 year progression free survival for patients that achieved ≥ very good partial response (VGPR) following induction therapy without ASCT. Those achieving partial response (PR) were consolidated with ASCT according to routine practice. In this first analysis we report secondary endpoints: disease response and regimen-related toxicity in patients completing induction, including minimal residual disease (MRD) negativity by multiparameter flow cytometry.

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.

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 oneis a randomised phase II selection trial assessing the activity & tolerability of two doses of bendamustine (B), 60mg/m2vs 100mg/m2, in combination with thalidomide (T) & dexamethasone (D) in patients with relapsed/refractory MM.

Despite of newly developed and more efficacious therapies, multiple myeloma (MM) remains incurable as most patient will eventually relapse and become refractory. The bone marrow (BM) microenvironment provides niches that are advantageous for drug resistance. Effective therapies against MM should ideally target the various protective BM niches that promote MM cell survival and relapse. In addition to stromal mesenchymal/myofibroblastic cells, osteoclasts play a key supportive role in MM cell viability. Additionally, 80% of patients develop osteolytic lesions, which is a major cause of morbidity. Increased osteoclast activity is characteristic in these patients and targeting osteoclast function is desirable to improve therapies against MM.

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.

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.

Abstract 3979

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.

Abstract 1835

Abstract 326

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.

Abstract 4718

Abstract 4181

Abstract 1809

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 1931