Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development.

BACKGROUND: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. CONCLUSIONS: Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted.

PD-1 blockade for relapsed lymphoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD.

Given the limited treatment options for relapsed lymphoma post-allogeneic hematopoietic cell transplantation (post-allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post-allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post-allo-HCT and prior to anti-PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti-PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post-allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.

Hematopoietic Progenitor Cell Mobilization with Ifosfamide, Carboplatin, and Etoposide Chemotherapy versus Plerixafor-Based Strategies in Patients with Hodgkin and Non-Hodgkin Lymphoma.

Studies comparing the efficacy and safety of chemo-mobilization with ifosfamide, carboplatin, and etoposide (ICE) ± rituximab with plerixafor-based approaches in lymphoma patients have not been performed. We analyzed hematopoietic progenitor cell mobilization outcomes in lymphoma patients undergoing chemo-mobilization with ICE (n = 35) compared with either routine plerixafor (n = 30) or "just in time" (JIT) plerixafor-based mobilization (n = 33). Chemo-mobilization provided a significantly higher total CD34(+) cell yield (median collection, 5.35 × 10(6) cells/kg for ICE versus 3.15 × 10(6) cells/kg for routine plerixafor and 3.6 × 10(6) cells/kg for JIT plerixafor, P < .001). The median day 1 yield of CD34(+) cells was not significantly different (median, 2.2 × 10(6) cells/kg in ICE versus 1.9 × 10(6) cells/kg in upfront plerixafor versus 1.7 × 10(6) cells/kg in JIT plerixafor, P = .20). There was no significant difference in the 3 groups in terms of total number of apheresis sessions performed (median, 2 in each group; P = .78). There were no mobilization failures (inability to collect at least 2 × 10(6) cells/kg) in the chemo-mobilization group, whereas 5 patients (16.7%) in the routine plerixafor and 3 patients (9.1%) in JIT group had mobilization failure (P = .04). Mean time to neutrophil engraftment was faster in the chemo-mobilization group, 10.3 days (±1.2) compared with 12.1 days (±3.6) in the routine plerixafor group and 11.6 days (±3.0) in the JIT group (P < .001) and mean time to platelet engraftment was 13.7 days (±.7) in ICE versus 20.3 days (±1.6) in routine plerixafor versus 17.1 days (± .9) in JIT group (P < .001). Red blood cell transfusions were significantly higher in the chemo-mobilization group (34.3% versus 0 versus 3.2% versus 1, P < .001) and so were the platelet transfusions (22.9% versus 0 versus 0, P < .001). Excluding the cost of chemotherapy administration, chemo-mobilization was associated with significantly less mobilization cost (average cost $17,601.76 in ICE versus $28,963.05 in routine and $25,679.81 in JIT, P < .001). Our data suggests that chemo-mobilization with ICE provides a higher total CD34(+) cell yield, lower rates of mobilization failure, faster engraftment, and lower cost compared to plerixafor-based approaches with comparable toxicity profile between the groups, except for higher transfusion requirements with chemo-mobilization.

Higher infused CD34+ cell dose and overall survival in patients undergoing in vivo T-cell depleted, but not t-cell repleted, allogeneic peripheral blood hematopoietic cell transplantation.

BACKGROUND AND OBJECTIVES: Understanding the effect of cellular graft composition on allogeneic hematopoietic cell transplantation (AHCT) outcomes is an area of great interest. The objective of the study was to analyze the correlation between transplant-related outcomes and administered CD34+, CD3+, CD4+ and CD8+ cell doses in patients who had undergone peripheral blood, AHCT and received either in vivo T-cell depleted or T-cell replete allografts. DESIGN AND SETTING: Comparison of consecutive patients who underwent peripheral blood AHCT in our institution between January 2003 and December 2009. PATIENTS AND METHODS: The cohort of 149 patients was divided into two groups; non T-cell depleted (NTCD) (n=54) and T-cell depleted (TCD) (n=95). Study endpoints were overall survival (OS), progression free survival (PFS), engraftment kinetics (neutrophil and platelet recovery), incidence of acute graft versus host disease (acute GVHD), chronic GVHD, nonrelapse mortality (NRM) and disease relapse. RESULTS: Multivariate analysis showed that higher infused CD34+ cell dose improved OS (relative risk 0.58, 95% CI 0.34-0.98, P=.04), PFS (relative risk 0.59, 95% CI 0.35-1.00, P=.05) and NRM (relative risk 0.49, 95% CI 0.24-0.99, P=.048) in the TCD group. By multivariate analysis, there was no difference in engraftment, grades II-IV acute GVHD, extensive chronic GVHD and relapse in the two groups relative to the infused cell doses. There was a trend towards improved OS (relative risk 0.54, 95% CI 0.29-1.01, P=.05) with higher CD3+ cell dose in the TCD group. CONCLUSION: Our findings suggest that higher CD34+ cell dose imparts survival benefit only to in vivo TCD peripheral blood AHCT recipients.