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The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma is controversial. Between 2008 and 2014 a total of 217 multiple myeloma patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multicenter clinical trial to compare alloTSCT to autologous tandem transplantation (autoTSCT) followed by 2 years of maintenance therapy with thalidomide (100 mg/day) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent a second transplant (132 allogeneic, 46 autologous). PFS at 4 years after the second transplant was 47% (95% CI: 38-55%) for alloTSCT and 35% (95% CI: 21-49%) for autoTSCT (P=0.26). This difference increased to 22% at 8 years (P=0.10). The cumulative incidences of non-relapse mortality and of relapse at 4 years were 13% (95% CI: 8-20%) and 2% (95% CI: 0.3-2%) (P=0.044) and 40% (95% CI: 33-50%) and 63% (95% CI: 50-79%) (P=0.04) for alloTSCT and autoTSCT, respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (P=0.002). Four-year overall survival was 66% (95% CI: 57-73%) for alloTSCT and 66% (95% CI: 50-78%) for autoTSCT (P=0.91) and 8-year overall survival was 52% and 50% (P=0.87), respectively. In conclusion, alloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly. This study was registered with ClinicalTrials.gov (NCT00777998).

Rationale : CD38 is a target for the therapy of multiple myeloma (MM) with monoclonal antibodies such as daratumumab and isatuximab. Since MM patients exhibit a high rate of relapse, the development of new biologics targeting alternative CD38 epitopes is desirable. The discovery of single-domain antibodies (nanobodies) has opened the way for a new generation of antitumor therapeutics. We report the generation of nanobody-based humanized IgG1 heavy chain antibodies (hcAbs) with a high specificity and affinity that recognize three different and non-overlapping epitopes of CD38 and compare their cytotoxicity against CD38-expressing hematological cancer cells in vitro , ex vivo and in vivo . Methods : We generated three humanized hcAbs (WF211-hcAb, MU1067-hcAb, JK36-hcAb) that recognize three different non-overlapping epitopes (E1, E2, E3) of CD38 by fusion of llama-derived nanobodies to the hinge- and Fc-domains of human IgG1. WF211-hcAb shares the binding epitope E1 with daratumumab. We compared the capacity of these CD38-specific hcAbs and daratumumab to induce CDC and ADCC in CD38-expressing tumor cell lines in vitro and in patient MM cells ex vivo as well as effects on xenograft tumor growth and survival in vivo . Results : CD38-specific heavy chain antibodies (WF211-hcAb, MU1067-hcAb, JK36-hcAb) potently induced antibody-dependent cellular cytotoxicity (ADCC) in CD38-expressing tumor cell lines and in primary patient MM cells, but only little if any complement-dependent cytotoxicity (CDC). In vivo, CD38-specific heavy chain antibodies significantly reduced the growth of systemic lymphomas and prolonged survival of tumor bearing SCID mice. Conclusions : CD38-specific nanobody-based humanized IgG1 heavy chain antibodies mediate cytotoxicity against CD38-expressing hematological cancer cells in vitro , ex vivo and in vivo . These promising results of our study indicate that CD38-specific hcAbs warrant further clinical development as therapeutics for multiple myeloma and other hematological malignancies., Competing Interests: Competing Interests: K.S., W.F., L.S., S.M., P.B., and F.K.-N. are co-inventors on a patent application on CD38-specific nanobodies. F.H. and F.K.-N. receive a share of antibody and protein sales via MediGate GmbH, a wholly owned subsidiary of the University Medical Center Hamburg-Eppendorf., (© The author(s).)

The major reason for treatment failure after allografting in multiple myeloma (MM) is relapse. Donor lymphocyte infusions (DLIs) are considered a valuable post-transplant strategy mainly for relapsed patients but using them to prevent relapse in MM has been reported rarely. In the present study, we examined the efficacy of prophylactic DLIs after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in myeloma patients with a long-term follow-up of more than 5 years. A total of 61 patients with MM who did not relapse or develop disease progression after allo-HSCT were treated with prophylactic DLI in an escalating fashion (overall 132 DLI procedures) to deepen remission status and prevent relapse. Overall response rate to DLI was 77%. Thirty-three patients (54%) upgraded their remission status, 41 patients (67%) achieved or maintained complete remission, and 26% achieved a molecular remission. Incidence of acute graft-versus-host disease (GVHD) grade II to IV was 33% and no DLI-related mortality was noted. After a median follow-up of 68.7 months from first DLI the estimated 8-year progression-free survival (PFS), and overall survival (OS) in a landmark analysis was 43% (95% confidence interval [CI], 28% to 57%) and 67% (95% CI, 53% to 82%), respectively, with best outcome for patients who acquired molecular remission (8-year PFS was 62% and 8-year OS was 83%). Prophylactic escalating DLI in a selected cohort of MM patients to prevent relapse after allograft resulted in a low incidence of severe GVHD and encouraging long-term results, especially if molecular remission is achieved., (Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction: Multiple myeloma is still incurable in most cases. Polyclonal anti T lymphocyte globulins (ATG) have been reported to kill human myeloma cells in vitro and in mouse models., Methods: Anti-human-myeloma globulins (AMG) were produced by immunizing rabbits with human myeloma cell lines RPMI-8226 (AMG-8226) or KMS-12-BM (AMG-12-BM). Cytotoxicity of the polyclonal antibodies was analyzed in vitro and in a xenograft NOD-SCID mouse model., Results: Both AMG had stronger cytotoxicity against myeloma cells compared to ATG. In primary T cells, AMG-8226 showed greater complement-dependent cytotoxicity (CDC) than ATG, whereas complement-independent cytotoxicity did not differ. Effects on non-hematopoietic cell lines were also similar. Competitive blocking assays revealed fourfold more antibodies against CD38 in AMG-8226 compared to ATG. Low concentrations of AMG-8226 and ATG increased ADCC. At higher concentrations, ATG inhibited ADCC more potently than AMG-8226. Combinations of ATG and AMG-8226 with melphalan or bortezomib showed additive to synergistic cytotoxicity on myeloma cells. The cytotoxic effects of AMG and ATG were confirmed in the xenograft NOD-SCID mouse model., Conclusion: Our data show more potent antimyeloma effects of AMG compared to ATG. These results lay the ground for the development of polyclonal antibodies for the treatment of multiple myeloma.

Within a prospective protocol, the incidence and impact of achievement of molecular remission (mCR) and high-risk cytogenetics was investigated in 73 patients with multiple myeloma (MM) after autologous (auto)-allogeneic (allo) tandem stem cell transplantation (SCT). After induction chemotherapy, patients received melphalan 200 mg/m(2) before undergoing auto-SCT, followed 3 months later by melphalan 140 mg/m(2) and fludarabine 180 mg/m(2) before allo-SCT. Sixteen patients had high-risk cytogenetic features, defined by positive FISH for del(17p13) and/or t(4;14). Overall, 66% of the patients achieved CR or near-CR, and 41% achieved mCR, which was sustained negative (at least 4 consecutive samples negative) in 15 patients (21%), with no significant difference in incidence between the patients with high-risk cytogenetics and others (P = .70). After a median follow-up of 6 years, overall 5-year progression-free survival was 29%, with no significant difference between del 17p13/t(4;14)-harboring patients and others (24% versus 30%; P = .70). The 5-year progression-free survival differed substantially according to the achieved remission: 17% for partial remission, 41% for CR, 57% for mCR, and 85% for sustained mCR. These results suggest that auto-allo tandem SCT may overcome the negative prognostic effect of del(17p13) and/or t(4;14) and that achievement of molecular remission resulted in long-term freedom from disease., (Copyright © 2013. Published by Elsevier Inc.)

Lenalidomide may prevent relapses after allogeneic stem cell transplantation by promoting the immune-mediated graft-versus-tumor effect. We performed a prospective phase I/II study to define the dose-limiting toxicity and the immunologic effects of lenalidomide given early (day 100-180) after allograft for four cycles in patients with multiple myeloma. According to the Fibonacci design, 24 patients with a median age of 53 years were included. Dose-limiting toxicity was organ toxicity owing to graft-versus-host disease, and the maximum tolerable dose was 5 mg. The incidence of graft-versus-host disease after lenalidomide was 38%, occurring after a median of 22 days, and was beside organ toxicity, a leading cause to discontinue the study in 29% of the patients. Immune monitoring revealed a significant increase in peripheral γ-interferon-secreting CD4(+) and CD8(+) T cells within the first week of lenalidomide treatment followed by a delayed increase in T regulatory cells. Furthermore, natural killer (NK) cells isolated from the peripheral blood of patients evidenced a significantly improved antimyeloma activity after lenalidomide treatment. The immune effect might have contributed to the increased CR rate from 24-42% after lenalidomide treatment because nonresponding patients showed significantly less natural killer and T cell activation. (Study registered under: NCT 00778752.)., (Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate post-transplant immunotherapy with escalating donor-lymphocyte infusions (DLI) and novel agents (thalidomide, bortezomib, and lenalidomide) to target complete remission (CR)., Materials and Methods: Thirty-two patients with multiple myeloma who achieved only partial remission after allogeneic stem cell transplantation were treated with DLI. If no CR was achieved, one of the novel agents was added to target CR., Results: CR defined either by European Group for Blood and Marrow Transplantation criteria, flow cytometry, or molecular methods as assessed by patient-specific immunoglobulin H-polymerase chain reaction or plasma cell chimerism polymerase chain reaction was accomplished in 59%, 63%, and 50% of patients, respectively. Achievement of CR resulted in improved 5-year progressive-free and overall survival, according to European Group for Blood and Marrow Transplantation criteria (53% vs 35%; p=0.03 and 90% vs 62%; p=0.06), flow cytometry (74% vs 15%; p=0.001 and 100% vs 52%; p=0.1), or molecular methods (84% vs 38%; p=0.001 and 100% vs 71%; p=0.03)., Conclusions: Our finding demonstrates the clinical relevance of posttransplantation therapies to upgrade remission, and of remission's depth for long-term survival in myeloma patients.

Background: Antithymocyte globulin or human Jurkat T-cell-line-derived antilymphocyte globulin is used in allogeneic stem cell transplantation to induce in vivo T-cell depletion to facilitate engraftment and lower graft-versus-host disease. In vitro studies suggest that antithymocyte globulin, besides causing T-cell depletion, has strong anti-myeloma activity., Design and Methods: We evaluated the anti-myeloma activity of antilymphocyte globulin in a melphalan/fludarabine-based reduced intensity conditioning regimen as well as the incidence of graft-versus-host disease in 138 multiple myeloma patients who underwent allogeneic stem cell transplantation with (n=79) or without (n=59) antilymphocyte globulin., Results: Leukocyte and platelet engraftment were faster in the group not receiving antilymphocyte globulin (13 vs. 16 days, p<0.001 and 11 vs. 19 days, p< 0.001, respectively). Inclusion of antithymocyte globulin led to a better day 100 overall response rate (93% vs. 78%, p=0.03) and complete response rate (59% vs. 39%, p=0.04), to a lower incidence of both acute grade III/IV graft-versus-host-disease (11% vs. 22%, p=0.10) and chronic graft-versus-host disease (23% vs. 65%, p<0.001) and to a trend to improved event-free survival at 3 years (39% vs. 27%, p=0.5). There was no difference in the estimated cumulative incidence of treatment-related mortality at 1 year between the groups receiving or not antilymphocyte globulin (25% vs. 26%). In a multivariate analysis treatment with antilymphocyte globulin was the only significant factor for achievement of a complete remission (RR:2.57, p=0.02)., Conclusions: Inclusion of antithymocyte globulin in allogeneic stem cell transplantation protocols for patients with multiple myeloma may increase remission rates and at the same time prevent graft-versus-host disease with no increase of relapses.

Objective: We investigated the effect of at least two cycles of bortezomib (1.3 mg/m(2) intravenously, days 1, 4, 8, and 11) after dose-reduced allogeneic stem cell transplantation (SCT) on toxicity, CD3(+) cells, graft-versus-host disease (GvHD), and response in patients with multiple myeloma., Methods: Eighteen patients with multiple myeloma without progressive disease were included. The proteasome inhibitor was given at median of 8 months after allografting to enhance or maintain remission status., Results: Fourteen patients (78%) completed the proposed two cycles. Four patients had to discontinue therapy due to neurotoxicity (n = 3) or gastrointestinal toxicity (n = 1). Severe grade III/IV toxicity was seen for thrombocytopenia (50%), leukopenia (17%), or neuropathy (17%), which was more often seen in patients treated concomitantly with cyclosporine (p = 0.06). The median circulating CD3(+) cells decreased during treatment from 550 muL to 438 muL (p = 0.03), resulting in herpes zoster infection in three patients (17%). In three patients, a mild aggravation of existing acute or chronic GvHD of the skin, and in one patient de novo skin grade I acute GvHD was noted. In patients with measurable disease, complete remission, partial remission, and minor response was seen in 3 (30%), 5 (50%), and 2 (20%) patients, respective., Conclusion: Bortezomib after allogeneic SCT is effective but further studies are needed to balance the efficacy with potential hazards such as infectious complications, aggravation of GvHD, and neurotoxicity.

Objective: To investigate lineage-specific chimerism of plasma cells after allogeneic transplantation by real-time PCR based on bi-allelic sequence polymorphism or, in case of female-to-male transplantation, on the detection of the DFFRY gene and to determine its value to quantify minimal residual disease in myeloma patients., Methods: Forty-eight samples from bone marrow samples and peripheral blood from 34 nonmyeloma patients were analyzed at different times after transplantation. Sixty-two samples from 22 myeloma patients were analyzed at different times after allogeneic stem cell transplantation, and results were compared with immunofixation and, in some cases, with PCR data using patient-specific primers., Results: The median chimerism for T cells at day +100 was greater than 99.9% and remained stable on day +180 and 1 year after transplantation. In contrast, the median donor plasma cell chimerism at day +100 was 95.5%, at day +180 98.6%, at day +360 99.8%, and 2 or more years after transplantation greater than 99.9%. Sensitivity of real-time PCR using human short insertion/deletion polymorphisms (SIDP) was 10(-4) and in case of Y-PCR 10(-5). Sequential monitoring of donor plasma cell chimerism showed that increasing and stable chimerism were associated with ongoing remission in 15 out of 16 samples (93%), and decreases in chimerism predicted relapse in 5 out of 6 patients., Conclusion: We conclude that plasma cell chimerism after allogeneic stem cell transplantation is delayed in comparison to T-cell chimerism. Sequential quantitative measurement of plasma cells after allogeneic stem cell transplantation with highly sensitive real-time PCR allows monitoring of residual host-tumor cells in patients with multiple myeloma and allows guiding adoptive immunotherapy strategies to enhance remission status and to prevent clinical relapse.

Objective: Allogeneic stem cell transplantation is a potentially curative therapy for patients with multiple myeloma. Polyclonal antithymocyte globulins (ATG) or monoclonal anti-CD52 (Alemtuzumab) are included in conditioning regimens to enhance engraftment and reduce risk of severe graft-vs-host disease. Because both agents have been reported to induce depletion of B cells, we sought to investigate their cytotoxic activity on myeloma cells., Materials and Methods: Complement-mediated and complement-independent activity of ATG-Fresenius and Alemtuzumab was investigated on four myeloma cell lines (RPMI-8226, U266, KMS-12-BM, and EJM) and bone marrow samples from six myeloma patients. Cytotoxicity was determined by staining with annexin V-fluorescein isothiocyanate and 7-amino-actinomycin D followed by flow cytometry., Results: ATG at a concentration of 500 microg mL(-1) induced up to 100% and 85% complement-dependent killing of myeloma cell lines and primary myeloma samples respectively. In the absence of complement ATG still could induce up to 50% and 80% apoptosis in myeloma cell lines and primary myeloma samples, respectively. Preincubation of myeloma cells with a general caspase inhibitor abrogated ATG-induced complement-independent cell death. Alemtuzumab-mediated myeloma cytotoxicity was only observed in KMS-12-BM cells, and in none of the patient samples., Conclusion: ATG induces marked cytotoxic activity both in myeloma cell lines and in primary myeloma samples. Further elucidation of antibodies and antigens involved may pave the way for antibody-based myeloma therapy.

To improve the antimyeloma effect of donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation in multiple myeloma, we investigated in a phase 1/2 study the effect of low-dose thalidomide (100 mg) followed by DLI in 18 patients with progressive disease or residual disease and prior ineffective DLI after allografting. The overall response rate was 67%, including 22% complete remission. Major toxicity of thalidomide was weakness grade I/II (68%) and peripheral neuropathy grade I/II (28%). Only 2 patients experienced mild grade I acute graft versus host disease (aGvHD) of the skin, while no grades II to IV aGvHD was seen. De novo limited chronic GvHD (cGvHD) was seen in 2 patients (11%). The 2-year estimated overall and progression-free survival were 100% and 84%, respectively. Adoptive immunotherapy with low-dose thalidomide and DLI induces a strong antimyeloma effect with low incidence of graft versus host disease.

We evaluated prognostic factors of melphalan/fludarabine-based dose-reduced allografts in patients with multiple myeloma. From 1998 to 2002, 120 patients with multiple myeloma were treated with melphalan/fludarabine followed by allogeneic stem cell transplantation. The cumulative risk at 1 year for treatment-related mortality (TRM) was 18% (95% confidence interval [CI], 12%-28%). In a multivariate analysis, relapse after prior high-dose chemotherapy was the most significant risk factor for TRM (hazard ratio [HR], 2.80; 95% CI, 1.16-6.74; P =.02), relapse (HR, 4.14; 95% CI, 2.04-8.38; P <.001), event-free survival (HR, 3.11; 95% CI, 1.77-5.46; P <.001), and overall survival (HR, 2.69; 95% CI, 1.35-5.35; P =.005). In addition, relapse was also significantly diminished by chronic graft-versus-host disease (GVHD) in a time-dependent Cox model (HR, 0.37; 95% CI, 0.16-0.87; P =.02). At transplantation, 8% of the patients were in complete remission, whereas 27% had progressive disease. After allografting, 49% achieved complete remission, and 38% achieved partial remission. In a subgroup of patients with chemosensitivity at transplantation and no relapse after prior high-dose chemotherapy who underwent transplantation with peripheral blood stem cells (n = 46), the cumulative risk of TRM at 1 year was only 8% (95% CI, 1%-54%). The 2-year estimated event-free and overall survival was 60% (95% CI, 42%-78%) and 75% (95% CI, 59%-91%), respectively, for related donors (n = 34) and was 81% (95% CI, 59%-100%) and 92% (95% CI, 76%-100%), respectively, for unrelated donors (n = 12).

We investigated the feasibility of unrelated stem cell transplantation in 21 patients with advanced stage II/III multiple myeloma after a reduced-intensity conditioning regimen consisting of fludarabine (150 mg/m(2)), melphalan (100-140 mg/m(2)), and antithymocyte globulin (ATG; 10 mg/kg on 3 days). The median patient age was 50 years (range, 32-61 years). All patients had received at least one prior autologous transplantation, in 9 cases as part of an autologous-allogeneic tandem protocol. No graft failure was observed. At day 40 complete donor chimerism was detected in all patients. Grade II to IV acute graft-versus-host disease (GVHD) was seen in 8 patients (38%), and severe grade III/IV GVHD was observed in 4 patients (19%). Six patients (37%) developed chronic GVHD, but only 2 patients (12%) experienced extensive chronic GVHD. The estimated probability of nonrelapse mortality at day 100 was 10% and at 1 year was 26%. After allografting, 40% of the patients achieved a complete remission, and 50% achieved a partial remission, resulting in an overall response rate of 90%. After a median follow-up of 13 months, the 2-year estimated overall and progression-free survival rates are 74% (95% CI, 54%-94%) and 53% (95% CI, 29%-87%), respectively. A shorter progression-free survival was seen in patients who already experienced relapse to prior autograft (26% versus 86%, P =.04). Dose-reduced conditioning with pretransplantation ATG followed by unrelated stem cell transplantation provides durable engraftment and donor chimerism, reduces substantially the risk of transplant-related organ toxicity, and induces high remission rates.

Acute kidney injury and chronic kidney disease is common in multiple myeloma. Fludarabine which is part of lymphodepletion before CAR-T cell therapy is renally eliminated and its use is not recommended for patients with severe renal impairment defined as a glomerular filtration rate below 30ml/min/1.73m². We administered fludarabine to a 58-year-old female patient with myeloma-associated severe renal impairment as part of lymphodepletion before Idecabtagen vicleucel infusion. Fludarabine was administered in reduced dose (15mg/m² ) and cyclophosphamide with a dose of 300mg/m² followed by hemodialysis over six hours using a larger filter (FX-100). The therapy was well tolerated with excellent CAR-T cell expansion and complete remission which is ongoing now beyond 12 months. [ABSTRACT FROM AUTHOR]