Allogeneic Transplantation In Multiple Myeloma Research Articles

Allogeneic Transplantation in Multiple Myeloma-Does It Still Have a Place?

Novel drugs have improved survival for patients with multiple myeloma in recent years. However, the disease is still fatal. Allogeneic stem cell transplantation (Allo) has proven to cure some patients with the disease, but its role is controversial due to relatively high transplant-related toxicity and mortality (nonrelapse mortality, NRM). Using nonmyeloablative reduced-intensity conditioning (RIC), both toxicity and NRM can be reduced, and RICAllo is, therefore, an option for subgroups of patients. Upfront tandem autologous/RICAllo (Auto/RICAllo) was shown to be superior to single Auto or tandem Auto/Auto in both progression-free (PFS) and overall survival (OS) in two prospective studies with long-term follow-up, while three similarly designed studies did not detect a difference. A recent update of pooled patient data from four of these studies showed significantly superior PFS and OS with Auto/RICAllo. Importantly, none of these studies showed inferior results with Auto/RICAllo in patients less than 70 years of age. Auto/RICAllo appears to overcome some poor risk cytogenetic markers. Encouraging results have also been seen in treatment of relapsed patients. Combining Allo with new proteasome inhibitors and immunomodulatory drugs may further improve results. Other encouraging new cell therapies such as with CAR T-cells, NK- and CAR NK-cells may well have a place in combination with RICAllo. Such studies are warranted.

Treosulfan Conditioning for Allogeneic Transplantation in Multiple Myeloma – Improved Overall Survival in first line Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a potentially curative treatment for multiple myeloma (MM) utilizing the graft versus myeloma effect. However, the treatment remains controversial mainly due to a high non-relapse mortality (NRM), partly due to the type of conditioning. Treosulfan is a prodrug of a bifunctional alkylating agent which has both myelotoxic and immunosuppressive properties. Previous small studies on the use of treosulfan conditioning (Treo) in Allo-HSCT for MM have indicated feasibility, stable engraftment and low NRM.

Allogeneic Transplantation in Multiple Myeloma: Long-Term Follow-Up and Cytogenetic Subgroup Analysis

Background: Allogeneic (allo) following autologous (auto) stem-cell transplantation (SCT) has yielded conflicting results in newly diagnosed multiple myeloma (MM). In alloSCT, information is lacking regarding the impact of cytogenetic features except chromosome 13q deletion (del13q). Methods: This phase 3 trial compared tandem autoSCT versus autoSCT followed by reduced-intensity conditioning alloSCT (auto/alloSCT) in del13q MM. The availability/absence of a human leukocyte antigen-matched related or matched unrelated donor (MUD) determined the nature of the second SCT. The primary endpoint was progression-free survival (PFS) in the intent-to-treat population (n=199). Findings: Auto/alloSCT was performed in 126 patients; 74 received MUD allografts. After 91 months' median follow-up (range 2-143 months), median PFS with auto/allo versus tandem autoSCT was 34·5 versus 21.8 months (p=0·003; adjusted hazard ratio 0·55, 95% confidence interval [CI] 0·36-0·84). Median overall survival (OS) was 70.2 versus 71.8 months (p=0.856). Two-year non-relapse mortality (NRM) with auto/allo versus tandem autoSCT was 14·3% versus 4·1% (p=0·008). In patients harbouring both del13q and deletion of chromosome 17p, median PFS and OS were 37·5 and 61·5 months with auto/allo (n=19) versus 6·1 and 23·4 months with tandem autoSCT (n=6) (p=0·0002 and 0·032). Interpretation: Auto/alloSCT significantly extends PFS versus tandem autoSCT in patients with del13q MM. We believe this to be the first MM study demonstrating that MUD alloSCT can be performed with reasonable NRM. Furthermore, our data suggest some survival benefit for first-line alloSCT in high-risk MM. Funding: The trial was sponsored by Wurzburg University, Wurzburg, Germany. Declaration of Interest: MH reports personal fees from Amgen, Celgene, Janssen, Bristol-Myers Squibb, and Takeda. GH reports personal fees from Janssen, Roche, AbbVie, Gilead, Novartis, MorphoSys, and Celgene; and grants from Roche, Pfizer, and Celgene. SM reports non-financial support from EBMT/EHA, IACH, Celgene, Miltenyi, KIADIS, Bellicum, DGHO, Jazz Pharma, and ISCT; and personal fees from Celgene, Miltenyi, KIADIS, Bellicum, and Jazz Pharma. GM reports personal fees from Gilead, Pfizer, Boehringer Ingelheim, Bristol-Myers Squibb, and Merck-Serono; and non-financial support from Janssen-Cilag. LK reports honoraria for presentation at “MedIpdate” (OnkoUpdate, IntemistenUpdate, PraxisUpdate) and at “Medizin Aktuell”. Amgen and Celgene are sponsors of the “Biannual International Stem Cell Conference, Tubingen, Germany): Scientific chairman: LK. HE reports grants, personal fees, and other (advisory board) from Janssen, Celgene, Amgen, BristolMyers Squibb, Novartis, and Takeda. All other authors declare no competing interests. Ethical Approval: The trial protocol was approved by the Wurzburg University ethics committee. All patients provided written informed consent prior to trial entry, and all procedures were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Guidelines for Good Clinical Practice.

Treosulfan Conditioning for Allogeneic Transplantation in Multiple Myeloma Improved Overall Survival in Upfront Hematopoietic Stem Cell Transplantation — a Large Retrospective Study By the Chronic Malignancies Working Party of the EBMT

BackgroundAllogeneic hematopoietic stem cell transplantation (AlloSCT) for treatment of multiple myeloma (MM) is controversial mainly due to high non-relapse mortality (NRM) with myeloablative conditioning. However, AlloSCT is probably the only treatment that result in cure of a small fraction of patients. Treosulfan is a prodrug of a bifunctional alkylating agent which has both myelotoxic and immunosuppressive properties. Conditioning regimes with treosulfan have been tried in various hematologic neoplasia such as AML and MDS indicating low NRM and increased progression free survival (PFS). Previous studies on use of treosulfan condition in AlloSCT for MM indicated feasibility, stable engraftment and low NRM. In the present study we have analysed the results of low and high dose treosulfan respectively on OS, RFS, relapse incidence and NRM as well as results of Treosulfan conditioning compared to non-Treosulfan reduced intensity conditioning (RIC) and non-Treosulfan myeloablative conditioning (MAC).Patients and MethodsWe conducted a retrospective analysis of 4544 patients with MM undergoing AlloSCT 2008-2016 reported to the EBMT data registry. Out of 537 patients receiving Treosulfan based conditioning the impact of dose could be analysed in 441. Three hundred and twenty-seven patients received a total dose of >36g/m2 and 114 <=36g/m2.These patients were compared to 2830 patients receiving RIC, and 1177 receiving MAC. 1103 patients were transplanted upfront and 3441 patients in later lines following relapse/progression. Patient characteristics shown in table 1.ResultsThe 5-year OS in upfront Treosulfan conditioned patients was 62%, which was significantly superior to both non-Treo RIC and MAC patients respectively, apparently due to a tendency for lower NRM (10%) albeit a higher relapse rate (Table 2). Patients in later lines of conditioning had either low NRM (3rd line) or no significant difference (2nd line) (Table 2). Heterogeneity in the material makes it difficult to interpret results in the patients transplanted late in the course of the disease.A higher total treosulfan dose, >36g/m2, showed a tendency for improved OS and RFS compared to the lower dose treosulfan as well as RIC and MAC (table 2) respectively.In multivariate analysis of upfront transplanted patients, with a model adjusted for ISS score at diagnosis, age, Karnofsky score, response at AlloSCT, interval between diagnosis and transplant, donor type and donor - patient sex match, treosulfan and RIC retained significance for OS, HR 0.57 (P=0.006) and RFS, HR 0.65 (P=<0.005). For 2nd line Treosulfan RFS was significantly worse, HR 1.46 (P=<0.005) while there was no significant difference for OS between conditioning regimes in 2nd or for OS and RFS in 3rd line (table 2). The factors associated with most inferior OS in upfront line of conditioning was Karnofsky <90 and ISS score III at diagnosis. ISS score III at diagnosis was also associated with inferior OS also in 2nd and 3rd line (Table 2) A less then partial response at AlloSCT was consistently a factor associated with inferior RFS regardless of line of treatment with HR 1.67 (P=<0.005) in upfront, HR 1,63 (P=<0.005) in 2nd line and HR 1,66 (P=<0.005) for 3rd line or later (Table 2)In multivariate analysis of treosulfan based conditioning regimes, upfront line of conditioning was superior for OS, PFS and relapse as expected (Table 3). Notably was an increased hazard ratio for donor-patient sex match other than female to male in OS, PFS as well as relapse, HR 1.64 (P=0.02), HR 1.66 (P=0.004) and HR 1.83 (P=0.003) respectively (Table 3).ConclusionsConditioning upfront with Treosulfan containing regimens for AlloSCT in multiple myeloma, is associated with a superior overall survival and a low NRM, however with a slightly higher relapse rate compared to other regimens. A higher dose > 36g/m2 tends to further improve OS, RFS and relapse rate without increasing NRM. The better results of Treo conditioning in female to male transplants as compared to other sex combinations and in contrast to MAC transplants may be due to the overall lower NRM with treosulfan, thus utilizing the GVM more effectively as indicated by the trend for lower relapse rate. In conclusion, Treosulfan containing regimens appear to be of value in upfront AlloSCT. Prospective studies on Treosulfan conditioning are warranted to further define the best dosing in MM AlloSCT. [Display omitted] DisclosuresNiederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding. Beelen:Medac: Consultancy, Other: Travel Support. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Finke:Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Garderet:Amgen: Consultancy; Celgene: Consultancy; Takeda: Consultancy. Kroeger:Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding.

The Role of Allogeneic Transplantation for Multiple Myeloma in the Era of Novel Agents: A Study from the Japanese Society of Myeloma

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered a potentially curative therapy for patients with multiple myeloma, the role of allo-HSCT remains unclear in the novel agent era. We conducted a retrospective study of 65 patients with multiple myeloma who underwent allo-HSCT at 19 institutions from 2009 to 2016. Patients received a median of 3 (range, 1 to 7) lines of prior therapy, including at least 1 novel agent, except for autologous HSCT. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 18.8% (95% confidence interval [CI], 9.6% to 30.3%) and 47.2% (95% CI, 33.9% to 59.4%), respectively. In a multivariate analysis, an age ≥50 years and less than a very good partial response (VGPR) before allo-HSCT were independent significant adverse factors for PFS (hazard ratio [HR], 2.30, P = .0063; HR, 2.86; P = .0059) and OS (HR, 2.37, P = .013; and HR, 2.74; P = .040). In contrast, the 3-year PFS and OS rates in patients <50 years of age who achieved a VGPR or better before allo-HSCT were 64.3% (95% CI, 29.8% to 85.1%) and 80.2% (95% CI, 40.3% to 94.8%), respectively. The overall response rate was 86.4% (95% CI, 75.0% to 94.0%). The proportion of VGPR or better increased from 29% before allo-HSCT to 71% after allo-HSCT. The nonrelapse mortality at 3 years was 23.4% (95% CI, 13.8% to 34.4%). Only an age ≥50 years was associated with higher nonrelapse mortality (HR, 4.71; P = .015). We showed that allo-HSCT is feasible for heavily pretreated patients with multiple myeloma, even in the novel agent era. Allo-HSCT in particular is a promising therapy for young and chemosensitive patients.

Allogeneic transplantation for multiple myeloma: yes, no or maybe?

Allogeneic transplantation for multiple myeloma: yes, no or maybe?

Reduced relapse rate in upfront tandem autologous/reduced-intensity allogeneic transplantation in multiple myeloma only results in borderline non-significant prolongation of progression-free but not overall survival

Reduced relapse rate in upfront tandem autologous/reduced-intensity allogeneic transplantation in multiple myeloma only results in borderline non-significant prolongation of progression-free but not overall survival

Mini-Allogeneic Transplantation in Multiple Myeloma: A Single-Center Ten-Year Experience

Allogeneic stem-cell transplantation is a potential curative option in multiple myeloma (MM). Reduced-intensity conditioning regimens (allo-RIC) result in a lower transplant related mortality (TRM) compared to conventional conditioning, despite of a higher relapse rate. Several prospective studies compared single or tandem autologous stem cell transplantation (SCT) with planned tandem autologous-reduced intensity allogeneic SCT, with discordant results in overall and progression-free survival (OS and PFS). Many studies were conducted using a “mini-allo-SCT”, a regimen containing a low-dose total body irradiation (TBI) and Fludarabine (Flu). Moreover, introduction of new drugs (bortezomib, thalidomide or lenalidomide) in the first decade of 2000 changed the biological history of MM.We analyzed the results of ten-year experience with mini-allo-SCT in patients with MM in our institution.Patients, materials and methods: Between June 2000 and December 2010, 21 patients (9 M, 12 F, median age 54 – range 36-66) received a mini-allo-SCT, 17 from an HLA identical sibling donor, 4 from a MUD full-matched. The source of stem cell was the peripheral blood in all patients. All grafts were not manipulated. At the time of diagnosis, Durie-Salmon (DS) stage was I in 5 patients (23.8%), II in 3 patients and III in 13 patients (61.9%). Disease status at the time of transplant was partial response (PR) in 17 patients (81%), 13 of them in first PR, 4 in second or more PR; 4 patients received allo-SCT as salvage therapy in active ore refractory disease. Eleven patients (52.4%) underwent to transplant after one line of treatment, 5 patients after 2 lines, 5 patients after 3 or more lines. Five patients (23.8%) were treated with new drugs. Auto-SCT is included in previous lines. Nine patients received one auto-SCT before the mini-allo-SCT; ten patients (47.6%) underwent transplantation after two auto-SCT. Two patients were allo-grafted frontline. Conditioning regimen was Flu-TBI in all patients. Graft versus Host Disease (GvHD) prophylaxis consisted on cyclosporine and MMF in all.Results: Overall response rate was 76%, 5 PR and 11 complete remission (CR). One patient developed progression next allo-SCT. Four patients died in the first 100 days after allo-SCT, and they are censored for OS and PFS analyses. Of 17 pre-transplant PR, 11 achieved CR (64%), 4 maintained PR, 2 died before response evaluation. Of 4 patients who underwent allo-SCT in active disease, only 1 obtained a PR, whereas the other 3 patients developed progression or were not-valuable. Six patients (28.6%) developed acute GvHD, but no one died for complicated acute GvHD. Eleven patients (52.4%) had chronic GvHD.Follow up range was from 4 to 96 months. The median time was 19 months. The relapse/progression rate in course of follow up was 29%. Two patients progressed after PR (40%), 3 after CR (5.9%). At the time of the last follow-up 8 patients died (47%), 3 of them for progression of MM.Survival analyses: TRM at 1 and 3 years was respectively 24% and 31%. OS at five years was 51%, with a plateau trend after 3 years (Fig. 1). In univariate statistical analysis, early DS stage at diagnosis (I-II), double auto-transplant, development of chronic GvHD have a significant impact (p value <.05) on OS. PFS at 3 years was 39%, at 6 years was near 20% (Fig 1). Early DS stage at diagnosis (I-II), double auto-transplant, and development of chronic GvHD have a significant impact (p value <.05) on PFS. Both in OS than in PFS, the previous treatment with new drugs did not result in statistical significant improvement, but the curves are spaced (Fig. 3 a and b), with a better performance for patients treated with new drugs.Conclusions: Use of allogeneic transplantation in MM is limited because of high TRM. Mini-allo reduces the TRM. We observed 50% of long term survivors. DS stage at diagnosis, double auto-SCT and development of chronic GvHD impact on survival. New drugs demonstrate better trend in OS and PFS, despite the number of patients is too small to obtain a clear conclusion. This finding suggests the execution of further studies in this regard. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Transplantation in Multiple Myeloma: A Potential Renaissance in the Era of Novel Therapies?

Allogeneic Transplantation in Multiple Myeloma: A Potential Renaissance in the Era of Novel Therapies?

The Graft-Versus-Myeloma Effect: Chronic Graft-Versus-Host Disease but Not Acute Graft-Versus-Host Disease Prolongs Survival in Patients with Multiple Myeloma Receiving Allogeneic Transplantation

We conducted a study of patients with multiple myeloma (MM) undergoing allogeneic transplantation to evaluate outcome parameters. Fifty-seven consecutive patients with MM received an allogeneic transplantation between 2004 and 2011 at our institution. Patients who had received at least 1 prior autologous transplantation were included. Twenty-six patients underwent allogeneic transplantation for consolidation after a response to their first autograft, and 30 patients received an allogeneic transplantation as salvage therapy. Donor source was evenly distributed between related and unrelated. The median follow-up was 52 months. Thirty-two (57.1%) patients achieved a complete response (CR). At 5 years, 49.2% of all patients were in CR. Sixteen patients received either donor lymphocyte infusions or immune suppression withdrawal for disease progression, with a 62.5% response rate. The 5-year overall survival (OS) for all patients was 59%. The 5-year OS for the 30 patients in the consolidation group was 82% compared with 38% for those in the salvage group. In multivariate analysis, 3 factors remained significantly associated with OS. These include being in the salvage group (hazard ratio [HR], 4.05; P = .0196), acute graft-versus-host disease (aGVHD) (HR, 2.99; P = .034), and chronic graft-versus-host disease (cGVHD), which was highly protective, with a 5-year OS of 78.8% for patients with cGVHD versus 42.6% for patients without cGVHD (HR .17, P = .008). Our data show that allogeneic transplantation for MM can lead to sustained remissions. aGVHD is significantly deleterious to OS and progression-free survival, whereas cGVHD is strongly favorable, supporting an important role for the graft-versus-myeloma effect.

Allogeneic Stem-Sell Transplantation In Multiple Myeloma In Real Practice: Long-Term Results From a Single Institution

BackgroundAllogeneic stem-cell transplantation with myeloablative conditioning (MAC) in multiple myeloma (MM) is associated with a high transplant-related mortality (TRM) with a 15% of long-term survivors. Allogeneic transplantation with reduced-intensity conditioning (alloRIC) results in a lower TRM with a higher relapse rate. When used in first line in a tandem transplant approach (auto/alloRIC), the incidence of acute graft-versus host disease (aGvHD) grade II-IV reported ranges between 20-43%, chronic GvHD between 50-75% and the TRM between 10-15%. The reported PFS was 25% beyond 7 years. Because of this high morbimortality and the higher rate of relapse, the role of allogeneic transplantation in MM remains controversial, especially as part of the front-lline therapy. Aimto analyze the results of allogeneic transplantation in patients with MM outside clinical trials at our institution over a period of 27 years. Patients and MethodsBetween Feb 1986 and April 2009, 23 patients (17 M, 6 F, median age 41 –range 21-52 -) received a MAC from an HLA identical sibling donor. Disease status at the time of transplant was first response in 12 patients (53%) (3 CR, 9 PR), sensitive relapse in 3 (13%) (all PR) and refractory disease in 8 (35%). Conditioning regimen was heterogeneous (6 Cyclo/TBI, 2 Bu/Cyclo, 3 BCNU/Mel/Cyclo/TBI, 4 Cyclo/Mel/TBI, 5 Mel/TBI, 2 Bu/Mel). GvHD prophylaxis consisted on cyclosporine/MTX (10), cyclosporine/PDN (8), cyclosporine (2) or other (3).Between April 2001 and Aug 2012, 31 patients (18 M, 13F, median age 48 –range 25-64) received an alloRIC: 25 of them (80%) from an identical sibling donor and 6 (20%) from an unrelated donor. Seven patients (13%) who did not achieve a CR after front-line autologous transplant received an alloRIC in a tandem strategy. 17 (31%) were in sensitive relapse (first relapse 14, second relapse 3). Seven patients (13%) had refractory disease at the time of alloRIC. Conditioning regimen consisted on Fluda/Mel (26 patients), Flu/TBI (3) and Fluda/Mel/bortezomib (2). GVHD prophylaxis consisted on cyclosporine/MTX (6) or cyclosporine/MMF (25). All patients in the alloRIC group had received a prior single autologous transplant. ResultsOn an intention-to-treat analysis, the CR rate after MAC was 35%. The incidence of aGvHD grade II-IV and III-IV were 48% and 39%, respectively. The TRM at any time was 56%. The causes of death were GvHD in 7 patients, infection not related to GvHD in 5 patients and VOD in 1 patient. The relapse rate was 30%.There are 3 patients who remain in continued CR at 13, 23 and 27 years beyond transplantation.With alloRIC the CR rate was 45%. The incidence of aGvHD grade II-IV and III-IV were 55% and 22%, respectively. Nine patients develop chronic GvHD. The TRM at any time was 29% and the causes of death were GVHD in 7 patients and pulmonary hemorrhage and postransplant lymphoma one patient each. Nine patients remain alive in continued CR from 5 months to 9 years of follow-up.After a median follow-up of 36.4 months, the median PFS was not significantly different between MAC and alloRIC and there was a trend towards a longer overall survival in the alloRIC group (4.6 vs 35 months, p=0.05). ConclusionsAlthough a small fraction of patients with MM can be cured with MAC allogeneic transplantation, this procedure is associated with an extremely high TRM. Unfortunately, alloRIC was also associated with a high incidence of severe aGVHD resulting in a high TRM leading to a short PFS. New approaches aimed at decreasing the incidence of aGVHD are crucial. Disclosures:Jiménez:Janssen: Honoraria. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria.

Long-Term Follow-up of Patients With Multiple Myeloma Who Received Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic transplantation for multiple myeloma (mm), although seen as potentially curative, has inherent treatment-related mortality and long-term implications. Important questions remain such as the expectation for long-term survival and the role, if any, of the graft versus tumor effect.The study cohort included 56 consecutive patients (pts) with mm who received an allogeneic hematopoietic stem cell transplant (HSCT) between November 9, 2004 and June 1st 2011. Only pts who had received at least one prior autologous transplant were included in this retrospective analysis. Patients received either a non-myeloablative (NMA), a reduced intensity (RIC) or an ablative (MA) regimen. The NMA regimen consisted of low dose TBI for siblings and low dose TBI with fludarabine for unrelated donors. The RIC regimen was fludarabine melphalan, with the addition of low dose thymoglobulin for unrelated donors. The MA regimen was busulfan and melphalan, with thymoglobulin for unrelated donors. A favorable group of 26 pts received their allogeneic transplantation for consolidation after demonstrating a response (PR, VGPR, CR) to their prior autograft and without evidence of progression, leaving 30 pts in the salvage transplant group defined as pts unresponsive (less than PR) or with relapse after their prior autograft. The median age was 52.4 years (SD = 6.9 years). Twenty six (46%) pts were female. The hematopoietic cell donors were 35 siblings and 21 unrelated (URD). In the URD group, 10 (47.6%) pts had a mismatched donor. In our cohort 10 (17.9%) pts received a MA, 22 (39.3%) received a RIC and 24 (42.9%) received a NMA regimen. The median follow-up was 52 months. The related and unrelated donor cohorts were similar except for age (53.9 years versus 49.8 years p = 0.03).Overall, 32 (57.1%) pts achieved a CR. Seven (12.5%) pts had a VGPR, 13 (23.2%) had a PR and 2 (3.6%) had stable disease. At the time of analysis, 49.2% of pts were in CR. Twenty one (37.5%) pts relapsed post transplantation of whom 16 received donor lymphocytes (DLI 15 pts) or immune suppression withdrawal (1 pt), with 10 (62.5%) pts responding to this intervention. The cumulative incidence of acute GVHD (aGVHD) grade II-IV was 35.4%, 28.6% for related donors and 47.6% for URD (p = 0.16). The cumulative incidence of chronic GVHD (cGVHD) was 50%, 52% for related donors and 43% for URD (p=NS). The number of non-relapse deaths (NRM) was 13 (23.2%). The cumulative incidence of NRM at 1 year was 18.2%, and 25.5% at 5 years. In the multivariate model, number of prior autologous HSCT (1 vs >1) and grade III-IV aGVHD were significantly associated with an increased NRM. The overall survival (OS) for all 56 pts was 59% at 5 years. The OS at 5 years for the 30 pts who received transplantation as salvage (refractory to the prior autograft or relapsed after the prior autograft), was 38% compared to 82% for the consolidation group. The univariate analysis indicates that pts receiving their allogeneic transplantation as salvage, disease status prior to allogeneic HSCT, number of prior auto HSCT, aGVHD, response post allo HSCT and cGVHD were significantly associated with the risk of all cause mortality, with cGVHD being protective. Donor type (URD versus related), adverse cytogenetics, preparative regimen and age were not significant predictors of risk for all cause mortality by univariate analysis. [Display omitted] [Display omitted] Multivariate analysis shows OS significance for being in the salvage group (HR 4.05, p=0.0196), a GVHD (HR 2.99, p=0.034) and cGVHD (HR 0.26, p=0.012), the latter being protective. The PFS for all 56 pts was 38% at 5 years, 57% for the consolidation group and 21% for the salvage group.In conclusion, patients with multiple myeloma can have an excellent overall survival following allogeneic transplantation even in the setting of relapsed or refractory disease to a prior auto HSCT. Unrelated donors performed just as well as matched siblings. Acute GVHD was deleterious to OS, whereas chronic GVHD was significantly associated with improvement in OS supporting the role of a graft versus tumor effect in multiple myeloma. Disclosures:No relevant conflicts of interest to declare.

Digging Deeper with Allogeneic Transplantation in Multiple Myeloma

Digging Deeper with Allogeneic Transplantation in Multiple Myeloma

A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma

AbstractNatural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose–escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient–derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396.

Allogeneic Transplantation for Multiple Myeloma – the Swiss Experience

Abstract 3112While the introduction of novel drugs has significantly improved the prognosis of multiple myeloma, cure remains rare. Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to induce long-term remission, but controlled studies have shown conflicting results and the role of allogeneic HSCT remains unclear. While in trials showing a survival advantage of allogeneic HSCT, the procedure was performed upfront as part of first-line therapy, in daily practice this modality is mainly used in patients with primary refractory disease, in patients with high-risk features or after multiple relapses.To assess the effect of allogeneic HSCT, we performed a retrospective analysis of patients with multiple myeloma who received an allogeneic HSCT in Switzerland. At the time of writing, outcome data was available from 2 of the 3 national transplant centers. In these 2 centers, 76 allogeneic transplants were performed in 74 patients between 1991 and 2010 at a median of 21 (range 2–156) months after diagnosis. Of these, 41% (n=31) were performed upfront as part of first line therapy, while 59% (n=45) were performed after one or more relapses, or for refractory disease. Patients had received a median of 2 (range 0–7) lines of therapy and 1 (range 0–3) autologous transplant before allogeneic HSCT. Before transplant, 67% (n=51) of patients had reached at least a partial remission, 13% (n=10) were in complete remission.The median age at transplant was 52 (range 32–68) years. Conditioning was myeloablative in 24% (n=18), and non-myeloablative in 76% (n=58). 66% (n=50) had a related sibling donor, while 34% (n=25) had an unrelated donor and one patient received a cord blood graft. The majority of patients (n=68) received peripheral stem cells. In 3 patients, the graft was T-cell depleted.53% (n=40) of patients experienced acute graft-versus-host disease (GvHD) grade II-IV, 16% (n=12) had grade III-IV. Chronic GvHD occurred in 49% (n=37) of the 67 of patients surviving beyond day 100, extensive in 30 patients. 14 patients received donor lymphocyte infusion (DLI) either due to progressive disease (n=11) or per protocol following T-cell depleted transplant (n=3).At the time of analysis, 37 patients are alive, with a median follow up of survivors of 3.9 years. While 23 deaths were caused by the underlying disease, the cumulative incidence of transplant related mortality at 2 years post-transplant was 17% (95% CI: 8%-26%).Following transplant 43% (n=33) of patients reached a complete remission, 13% (n=10) attained a partial remission and 18% (n=14) a very good partial remission. The median progression free survival (PFS) was 343 days, with a 2 and 5 year PFS of 40% (95% CI: 29%-51%) and 34% (95% CI: 22%-46%), respectively. Median overall survival (OS) was 3.4 years, with a 2 and 5 year OS of 57% (95% CI: 36%-68%) and 46% (95% CI: 34%-58%) respectively.When comparing patients who received a planned allogeneic transplantation upfront rather than later in the disease course, the former had a significantly better 2 year OS and PFS: 77% versus 43% (p<0.001) and 57% versus 28% (p=0.022) respectively (Figure 1). Patients in partial remission or better at the time of transplant also had a superior 2 year PFS (49% versus 24%, p=0.04), with no significant difference in OS. Patients who developed chronic GvHD had an improved OS (HR 0.65, 95% CI 0.29–1.44) and PFS (HR 0.77, 95% CI 0.34–1.71), however this did not reach statistical significance. Finally, while PFS was not influenced by type of donor, we observed an improved 2 year OS for patients with a related donor (64% versus 45%, p=0.02).While long term remission following allogeneic HSCT can be achieved in a subset of patients, morbidity and mortality remain substantial. Clinical benefit is highest when used early in the disease course. Clinical studies evaluating the benefit of allogeneic HSCT as part of salvage strategies are needed. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Patterns of Serum Free Light Chain (FLC) Recovery After Reduced Intensity Conditioning (RIC) Allogeneic Transplant for Multiple Myeloma (MM) Predict Long Term Outcomes

AbstractAbstract 1301 Introduction:Allogeneic transplantation in MM is pursued in the hope of establishing an immune mediated graft vs. MM effect (allogeneic effect) in order to prevent relapse. After RIC allogeneic transplantation, donor immune function (donor chimerism) is established over time in the recipient. Long term B lymphocyte recovery may be delayed by graft vs. host disease (GVHD). GVHD may also be associated with the beneficial graft vs. MM effect. The recovery pattern of the original light chain associated with MM clone (involved free light chain) and the alternate light chain (uninvolved in MM and donor derived after allotransplant) serve as markers for MM progression vs. establishment of donor derived B cell function respectively after allotransplant. The serum FLC assay is a marker for both the progression of the recipient's original MM clone (rising involved FLC) as well as establishment of donor derived immune recovery (restoration of uninvolved FLC to normal).We hypothesized that the FLC assay is influenced by the competing effects of progression of the MM clone vs. the beneficial impact of alloimmunity/GVHD on relapse. Methods:Forty seven RIC allogeneic peripheral blood hematopoietic stem cell transplant recipients (45 matched sibling donors) for MM at the Medical College of Wisconsin (2005-2009) were studied. Conditioning regimen was,(200 cGY TBI +/− fludarabine). Median follow up was 2 years. Baseline and follow-up serum free light chain assay results at 3 monthly intervals were correlated with outcomes. The light chain associated with MM clone was designated as “involved” (IFLC) and the complementary light chain designated as the “uninvolved” (UFLC). Results:Overall (OS) and progression free (PFS) survival of cohort at 4.5 years was 54% (CI 36 – 72%) and 38% (CI 15– 61%) respectively. Treatment related mortality was 14.5%. All patients, except those with rapidly progressive MM (group 1 below), had suppression of both IFLC and UFLC immediately after RIC. Based on pattern of recovery of UFLC we identified 3 distinct groups. Group 1(n=12) – those who did not have any UFLC recovery, Group 2(n=10) those UFLC returned to normal levels within 6 months of RIC (early recovery) and a group 3 (n=25) where the UFLC recovery was delayed beyond 6 months (late recovery). Outcomes for all the three groups are shown in the table 1. The incidence of clinical GVHD was similar across the groups. Median PFS was significantly superior in the late recovery group (not reached at 5 years, vs. 4.6 mo and 11.8 mo in the other groups) (p=0.0001). In order to eliminate “survival by response” bias, we performed a landmark analysis, restricting the analysis to those alive at 6 mo after RIC and confirmed these findings (Fig 1.).Table:Outcomes and UFLC recovery after RIC allografts for MMGroupUFLC Response GroupAny GVHDMedian PFSPFSRelapsed DeathRelapsed AliveN47231071No Recovery (12)9 (75%)4.6 mo0602Early Recovery (10)8 (80%)11.8 mo4323Late Recovery (25)18 (72%)NR @ 5 yrs1915P=NSP=0.0001 [Display omitted] Conclusion:Our data suggest that after RIC, with immunosuppressive conditioning, late recovery of UFLC is a marker of the efficacy of the allogeneic effect. The antineoplastic effect of donor alloimmunity likely explains the delayed recovery of UFLC (mediated by clinical/subclinical GVH activity) and paradoxically, better anti-MM effect in the late UFLC recovery group. Rapid progression of MM clone and non-establishment of a donor anti-MM effect explains the rapid relapse in those with no UFLC recovery. In the early recovery group, a higher risk of relapse is likely mediated by the absence of an alloimmune effect sufficient enough to delay B cell recovery and also insufficient for beneficial graft vs. MM effect. Since GVHD rates were similar across groups, the beneficial “allo immune effect” is likely independent of clinical GVHD. The FLC assay may be a sensitive marker of donor B cell recovery after allotransplant and needs further validation as a measure of donor derived antineoplastic effect in MM and other malignancies. Disclosures:No relevant conflicts of interest to declare.

Non‐myeloablative conditioning and allogeneic transplantation for multiple myeloma

In multiple myeloma (MM), allogeneic stem cell transplantation (alloHCT) carries a lower relapse risk than autologous transplantation but a greater transplant-related mortality. Nonmyeloablative conditioning for allogeneic transplantation (NST) reduces transplant-related toxicity. Results are encouraging when used during first remission in low-risk patients, but less-so in relapsed or refractory disease. This is a single-center retrospective analysis of 20 previously treated MM patients who underwent NST from matched-related or matched-unrelated donors from 2000-2006. Median age was 52.7 years (37.2-68.0). Twenty-five percent had advanced or high-risk disease. Eleven still had active disease prior to NST. Conditioning was total body irradiation 200 cGy on a single fraction on day -5, followed by antithymocyte globulin (ATG) 1.5 mg/kg/day and fludarabine 30 mg/m(2)/day on days -4 to -2. All received immunosuppression, most commonly with oral mycofenylate mofetil and cyclosporine beginning on day -5. At day 100, 50% had achieved complete remission. Transplant-related mortality was 25%. Median overall survival (OS) was 21.2 months (0.6-90+) and progression-free survival (PFS) 6.6 months (0.6-90+). Both OS and PFS were 24% at 3 years. OS was significantly greater for patients with age <52 years (median 27 months vs. 7.9 months, P = 0.031), and there was a trend toward greater OS for those with beta2 microglobulin <2.5 mg/l (median 27 months vs. 7.7 months, P = 0.08). Donor characteristics and Ig type had no significant effect on survival. These data suggest a benefit of NST in relapsed/refractory MM. Randomized trials must be performed to confirm and further qualify this benefit.

Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect

Long-term outcomes following myeloablative allogeneic transplantation for multiple myeloma compared to autologous transplantation and the impact of graft-versus-myeloma effect

A621 Nonmyeloablative Conditioning and Allogeneic Transplantation for Multiple Myeloma

A621 Nonmyeloablative Conditioning and Allogeneic Transplantation for Multiple Myeloma

Non-Myeloablative Conditioning and Allogeneic Transplantation for Multiple Myeloma

Autologous stem cell transplantation (ASCT) increases survival in multiple myeloma (MM) but is not curative. Allogeneic transplantation (alloSCT) carries a lower relapse risk, attributed to a graft-versus-myeloma effect, but a greater transplant-related mortality (TRM). Nonmyeloablative (NMA) conditioning reduces transplant-related toxicity. Our group previously reported on 90 patients conditioned with total body irradiation (TBI), fludarabine, and antithymocyte globulin (ATG). Results were encouraging when used during first remission in low-risk patients, but less-so in advanced or resistant disease.