Immunotherapy in multiple myeloma

Introduction

Immune dysregulation has a powerful role in the pathogenesis of multiple myeloma (MM). A multitude of abnormalities in the immune microenvironment have been implicated, including an excess of inflammatory cytokines, imbalance of regulatory T cells and T helper cells, impaired differentiation of natural killer (NK) cells, dendritic cell dysfunction, and expansion of myeloid-derived suppressor cells (1). Novel therapies are focused on activating the immune response against myeloma cells and overcoming the tumor’s immune escape mechanisms. In this review, we discuss the immunotherapies which have been recently approved for the management of MM, as well as some promising therapeutic approaches in the earlier phases of clinical development.

Immunomodulatory drugs (IMiDs)

IMiDs such as thalidomide, lenalidomide, and pomalidomide, are frequently integrated into multidrug regimens for MM. In addition to their direct antimyeloma effect, IMiDs have several proposed mechanisms, including modulation of cytokine signaling, inhibition of angiogenesis, inhibition of regulatory T cell proliferation, and augmentation of cytotoxic T lymphocyte and NK cell activity (2,3). IMiDs also interact with cereblon, resulting in cereblon-dependent destruction of Ikaros proteins, which function as B-cell transcription factors (4,5). Cereblon-binding protein levels after IMiD therapy have shown correlation with clinical outcomes (6). IMiDs significantly improve response rates when combined with other myeloma immunotherapies, and in some cases evoke response to antibodies that have little or no single-agent activity (7,8).

Monoclonal antibodies

Antibodies targeting surface molecules

Daratumumab was the first monoclonal antibody approved by the United States Food and Drug Administration (FDA) in 2015 for relapsed or refractory multiple myeloma (RRMM). Daratumumab targets CD38, a transmembrane receptor glycoprotein highly expressed on malignant plasma cells. Several mechanisms of antimyeloma activity have been described, including promotion of complement-mediated and cell-mediated cytotoxicity, macrophage-mediated phagocytosis, direct apoptosis, and depletion of CD38 positive immune-regulatory cells (9,10).

In a phase I/II study of single agent daratumumab in a heavily pretreated population, no maximum tolerated dose was identified. Overall response rate (ORR) was 36% among patients receiving daratumumab 16 mg/kg dosed weekly for 8 doses, biweekly for the next 8 doses, then monthly for up to 24 months. The majority of responders remained progression-free at 12 months (11). Another phase II multicenter trial of single agent daratumumab in patients with a median of five prior lines of therapy showed comparable results: ORR was 29%, with 2.8% stringent complete responses, 9.4% very good partial responses, and 17% partial responses. Median time to first response was one month, progression free survival was 3.7 months, and median overall survival was 17.5 months. Infusion reactions were common (42%), although mostly grade 1 or 2, and typically occurring only during the first infusion. The most common grade 3 or 4 adverse events were anemia (24%), thrombocytopenia (19%), and neutropenia (12%), however no drug related adverse events resulted in treatment discontinuation (12).

The favorable safety and efficacy data for daratumumab have led to multiple subsequent trials investigating the drug in combination with other therapies. Daratumumab in combination with bortezomib and dexamethasone in RRMM showed an ORR of 83%, compared to 63% with bortezomib and dexamethasone alone. One-year progression free survival (PFS) was 61% in the daratumumab group, versus 27% in the control group. The addition of daratumumab was associated with slightly higher rates of thrombocytopenia and neutropenia (13).

In a phase III randomized trial of 569 patients with RRMM, the combination of daratumumab with lenalidomide and dexamethasone demonstrated an ORR of 93%, compared to 78% with lenalidomide and dexamethasone alone. CR rate was 43% in the daratumumab group, versus 19% in the control group. 22% of patients achieved remission below the threshold for minimal residual disease, compared with 4.6% of those in the control group. PFS at one year was significantly higher in the daratumumab group compared to controls (83% versus 60%). There was a slightly higher rate of neutropenia in the daratumumab group. Of note, patients who were refractory to lenalidomide were excluded from the trial (14). In November 2016, the FDA approved daratumumab for use in combination with bortezomib/dexamethasone or lenalidomide/dexamethasone for patients with MM who have received at least one prior line of therapy.

Other anti-CD38 antibodies currently being investigated include isatuximab and MOR202. Isatuximab in combination with lenalidomide and dexamethasone showed 50% ORR in a heavily pretreated population. Of note, responses were seen even among patients who were previously lenalidomide refractory (15). MOR202 is currently being studied alone or in combination with lenalidomide or pomalidomide, with promising preliminary efficacy data (16).

Elotuzumab was approved by the FDA in 2015 for use in combination with lenalidomide and dexamethasone for the treatment of patients with myeloma who have received one to three prior therapies. Elotuzumab is a monoclonal antibody targeting the signaling lymphocytic activation molecule F7 (SLAMF7), a transmembrane glycoprotein selectively expressed on plasma cell and NK cell membranes, and present on a majority of MM cells. Elotuzumab enhances NK cytotoxicity by upregulating the adaptor protein, Ewing’s sarcoma associated transcript 2 (EAT-2), leading to antibody dependent cell-mediated cytotoxicity (17,18).

A phase I single agent dose escalation trial showed no objective responses to elotuzumab in RRMM; stable disease was noted in 26% (19). A phase III trial of elotuzumab with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone showed ORRs of 79% versus 66%, PFS 68% versus 57% at one year, and PFS 41% versus 27% at two years. The benefit of elotuzumab was preserved in patients with high risk features such as t(Jeny4:14), del(Jeny17p), and +1q21. The most common grade 3 or 4 adverse events were cytopenias, fatigue, and pneumonia (7). In a phase II trial, elotuzumab with bortezomib and dexamethasone showed PFS of 9.9 months compared to 6.8 months with bortezomib and dexamethasone alone (20). Elotuzumab showed no added toxicity when combined with lenalidomide, bortezomib, and dexamethasone in a 4-drug regimen for newly diagnosed MM; efficacy data are pending (21).

Antibody-drug conjugates

CD138 functions as a growth factor receptor on malignant plasma cells, and represents one of the most specific target antigens for MM therapy. CD138 exists as a membrane-bound protein, but is also converted to soluble forms via proteinase-mediated shedding (22). The presence of soluble CD138 limits the use of free antibody against this target. Indatuximab ravtansine (BT062) is an antibody-drug conjugate comprised of an anti-CD138 antibody fused to the cytotoxic maytansinoid DM4. The drug is stable and non-toxic in circulation, but upon binding to CD138 on the cell surface, it is internalized by the cell leading to cell cycle arrest and apoptosis. Preliminary phase I/II data indicate that indatuximab ravtansine is well tolerated in combination with lenalidomide and dexamethasone, with an overall response rate of 78% in RRMM, including patients previously treated with lenalidomide and bortezomib (23).

Neural cell adhesion molecule (NCAM), also known as CD56, is expressed in NK cells, glia, skeletal muscle, and is found in approximately 75% of MM cells (24). Lorvotuzumab mertansine is a humanized monoclonal antibody to CD56, conjugated to the cytotoxic maytansinoid derivative DM1. In phase I studies, Lorvotuzumab demonstrated a 7% ORR in as a single agent in RRMM (25), and 59% ORR in combination with lenalidomide and dexamethasone (26).

B cell maturation antigen (BCMA) is universally expressed on the surface of myeloma cells. The antibody-drug conjugate J6M0-mcMMAF targeting BCMA has been shown to rapidly eliminate myeloma cells in mouse models (27). A phase I dose-escalation study is currently in progress [National Clinical Trial identifier number (NCT) 02064387] (28).

Checkpoint inhibitors

The interaction of the T cell with its target is regulated by molecular signals that help maintain self-tolerance, however these regulatory checkpoints may also interfere with immune activation against malignancy. Checkpoint inhibitors are monoclonal antibodies that bind to coinhibitory molecules, allowing T cell activation in response to antigens on malignant cells.

In a phase Ib study, the programmed cell death protein 1 (PD-1) inhibitor nivolumab as a single agent showed no objective responses in 27 patients with RRMM, however 63% of patients had stable disease at a median follow up of 66 weeks (29). Several trials using treatment combinations with nivolumab are ongoing (NCT02726581, NCT02903381, NCT01592370).

Pembrolizumab in combination with lenalidomide and dexamethasone in RRMM yielded responses in 20 of 40 patients (50%), including 11 of 29 patients (38%) with lenalidomide-refractory disease. Disease control, defined as stable disease or better, was reported in 39 of 40 patients (98%) (30). Preliminary data for pembrolizumab with pomalidomide and dexamethasone showed a 50% ORR in heavily pretreated RRMM. The most common grade 3 or 4 toxicities were neutropenia, lymphopenia, thrombocytopenia, and infection (31). A phase III randomized controlled trial of pembrolizumab with lenalidomide and dexamethasone in the frontline setting is in progress (NCT02579863) (8).

Overexpression of CTLA-4, a coinhibitory molecule expressed on regulatory T cells, has been demonstrated in the bone marrow of MM patients, making CTLA-4 an attractive target for checkpoint inhibition in these patients (32). A role for anti-CTLA-4 agents in treating MM has not yet been established, but is currently being investigated, with particular interest in combination with PD-1 blockade (NCT01592370, NCT02681302, NCT01822509).

Vaccines

Several antimyeloma vaccines are being evaluated in clinical trials. Idiotype vaccines, derived from the variable region of the patient-specific clonal immunoglobulin, were among the first to be studied in MM (33). While idiotype vaccines have been shown to induce major histocompatibility complex (MHC) restricted T cell responses and reduction in peripheral blood tumor mass, clinical benefit has been difficult to achieve (34,35). Attempts have been made to augment immunogenicity by incubating autologous dendritic cells with the idiotype protein. When patients were vaccinated with the idiotype-pulsed dendritic cell product after autologous stem cell transplant (ASCT), a significant overall survival benefit was reported (5.3 versus 3.4 years), although there was no difference in PFS (36).

A dendritic cell/tumor cell fusion vaccine has been developed in order to generate antigen presenting cells with a patient-specific repertoire of MM antigens. The administration of the dendritic cell/tumor cell fusion vaccine in the post-ASCT period resulted in expansion of myeloma specific CD4 and CD8 T cells. Late responses were observed several months after ASCT, suggesting a durable vaccine effect (37). A multicenter randomized trial utilizing dendritic cell/tumor cell fusion vaccination is ongoing (NCT02728102).

MAGE-A3, a cancer-testis antigen expressed in MM, inhibits apoptosis of malignant cells, and has been associated with more aggressive disease. A recombinant MAGE-A3 protein has been developed for use as a vaccine. When given prior to ASCT, the MAGE-A3 vaccine has demonstrated acceptable safety and elicits a strong anti-MAGE IgG response (38). In a phase II trial, a MAGE-A3 peptide vaccine was combined with a toll-like-receptor 3 agonist before and after ASCT, followed by infusion of ex-vivo expanded costimulated autologous T cells, resulting in vaccine-specific humoral and CD4 responses in more than 3/4 of patients. Further studies are needed to determine whether MAGE-A3 antibodies have clinical benefit in myeloma (39).

The use of commercially available allogenic MM cell lines to formulate vaccines has several advantages, including the potential to create an unlimited supply of vaccine, and the possibility for use in patients from whom autologous tumor cells cannot be collected (e.g., patients with minimal residual disease). Myeloma GVAX is a granulocyte-macrophage colony stimulating factor (GM-CSF) based vaccine comprised of two allogeneic MM cell lines (H929 and U266) conjugated to a GM-CSF secreting bystander cell line (K562/GM). Among 17 patients in remission who received the myeloma GVAX in conjunction with maintenance lenalidomide, PFS was not reached at 34 months, compared to PFS 18 months among patients who continued on a lenalidomide-containing regimen without receiving the vaccine (40). This study suggests that the immune response evoked by myeloma GVAX may help prolong the duration of remission.

Adoptive T cell therapy

Allogeneic stem cell transplantation

Allogeneic stem cell transplantation as an immunotherapy approach in myeloma remains an area of active research. Myeloablative allogeneic transplantation was associated with a high treatment-related mortality, however subsequent studies using reduced intensity conditioning (RIC) have resulted in more favorable outcomes. In an Italian randomized controlled trial of tandem autologous transplant (tandem auto) versus autologous transplant followed by a RIC allogeneic transplant (auto-allo), treatment-related mortality was similar in both groups. However, disease-related mortality was much higher in the tandem auto group compared to auto-allo group (43% versus 7%, median follow-up 45 months) (41). Another phase III multicenter randomized controlled trial of tandem auto compared to auto-allo transplant with RIC demonstrated no improvement in 3-year PFS or OS with the auto-allo strategy in standard risk myeloma (42). A meta-analysis of similar trials showed a higher CR rate among patients who underwent auto-allo compared to those who underwent tandem auto transplant, however there was no significant difference in PFS or OS (43). With the reduction in transplant-related mortality using a RIC strategy as opposed to myeloablative conditioning, ongoing clinical trials are helping to better define which patients are most likely to benefit from allogeneic transplant, the appropriate timing of allogeneic transplant, and measures to further reduce graft versus host disease while maintaining the graft versus tumor effect (NCT02440464).

Marrow infiltrating lymphocytes

Expansion and reinfusion of marrow-infiltrating T lymphocytes (MILs) may confer antitumor immunity in hematologic malignancies. Since the T cells are obtained from the site of disease, they have enhanced endogenous tumor specificity in marrow-derived malignancies (44,45). Compared to peripheral blood lymphocytes (PBLs), MILs possess greater cytotoxicity and express CXCR4, which promotes trafficking to the bone marrow (45). Unlike PBLs, ex vivo expanded MILs do not cause significant lymphocytosis after reinfusion, and therefore do not tend to cause cytokine release syndrome (CRS) (46). In the first clinical trial using MILs in MM, the tumor specificity of the ex vivo expanded product correlated with clinical outcomes after MIL reinfusion. Additionally, patients whose pre-expansion MILs had a higher percentage of CD8 memory T cells and lower interferon gamma production were more likely to achieve CR (46). A randomized phase II trial of ASCT with or without MILs in high risk myeloma is currently ongoing (NCT01858558).

T cell receptor modified T cells (TCRts)

TCRts are engineered to recognize targets presented in an HLA-restricted manner. One such target is the NY-ESO-1 antigen, which is expressed in over 60% of high-risk MM (47). Twenty heavily pretreated patients receiving NY-ESO-1 TCRts showed median PFS of 19 months and OS 32 months. NY-ESO-1 TCRts were detected in the blood up to two years after infusion. Patients who relapsed were found to have developed NY-ESO-1 antigen negative clones, indicating the evolution of antigen escape variants (48).

CAR T therapy

CAR T cells are created by transducing autologous T cells, most commonly with a lentivirus, to express chimeric antigen receptors (CARs) that allow the T cells to recognize a specific tumor antigen. The CAR is typically comprised of a single chain variable fragment of a monoclonal antibody fused with a T cell intracellular signaling domain, resulting in MHC-independent tumor recognition, in vivo T cell expansion, and memory cell generation.

The most successful so far is the CD19 targeted CAR T, which has produced durable remissions in patients with advanced CLL and ALL (49,50). Malignant plasma cells have very low-level or absent CD19 expression, however the use of CD19 CAR T therapy in MM interestingly demonstrated a dramatic clinical response in one case despite the absence of CD19 expression in 99.95% of the patient’s neoplastic plasma cells (51). MM precursors are post-germinal B cells with CD19 expression, which may play a role in the antimyeloma effect of CD19 targeted CAR T (52). This approach is currently being evaluated in a phase II trial (NCT02794246).

BCMA is strongly expressed on malignant plasma cells, and has low-level expression on normal B cells, making it an attractive target for CAR T therapy (53). Dose-dependent response to BCMA-targeted CAR T cells has been demonstrated in advanced MM, although with significant toxicities due to CRS (54). Other CAR T targets under investigation include CD38 (55), CS1 (56), CD138 (57), and kappa light chain (58).

Therapeutic efficacy of CAR T is associated with potentially life-threatening IL-6 mediated CRS, which is related to the overall tumor burden. Manifestations of CRS include fever, hypotension, and pulmonary edema. The interleukin-6 receptor antibody tocilizumab has been implemented in the management of CRS with some success (59). CD19 targeted CAR T can result in persistent B cell aplasia and hypogammaglobulinemia due to on-target effects on nonmalignant cells. CAR T induced hypogammaglobulinemia is managed with intravenous immunoglobulin (49). Ongoing efforts directed at improving tolerability of CAR T therapy will expand the application of this approach.

Conclusions

Immunotherapy is an integral component of the management of patients with MM. Immunomodulators are currently incorporated into regimens in the frontline and beyond. Monoclonal antibodies have demonstrated remarkable efficacy in the relapsed/refractory setting, leading to accelerated approvals by the FDA for daratumumab and elotuzumab. Further studies will help better define the appropriate sequencing of these agents, including use in the frontline setting. Vaccines may be useful in maintaining remission and prolonging survival. Adoptive T-cell therapy shows very promising antimyeloma activity, however use is currently limited by toxicities. Ongoing research efforts are directed at improving the specificity of targeted agents, managing toxicities, and utilizing novel therapies in strategic combinations to optimize response. We anticipate significant improvement in the long-term outcomes for patients with MM as our treatment approach continues to evolve.

Acknowledgments

Marin Xavier for her ongoing mentorship and encouragement of scholarly pursuits in the field of hematology.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Marin Feldman Xavier) for the series “Advances on Clinical Immunotherapy” published in Translational Cancer Research. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2017.01.34). The series “Advances on Clinical Immunotherapy” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Noonan K, Borrello I. The immune microenvironment of myeloma. Cancer Microenviron 2011;4:313-23. [Crossref] [PubMed]
2. Görgün G, Calabrese E, Soydan E, et al. Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma. Blood 2010;116:3227-37. [Crossref] [PubMed]
3. Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood 2001;98:210-6. [Crossref] [PubMed]
4. Lu G, Middleton RE, Sun H, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science 2014;343:305-9. [Crossref] [PubMed]
5. Krönke J, Udeshi ND, Narla A, et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 2014;343:301-5. [Crossref] [PubMed]
6. Zhu YX, Braggio E, Shi CX, et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood 2014;124:536-45. [Crossref] [PubMed]
7. Lonial S, Dimopoulos M, Palumbo A, et al. Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. N Engl J Med 2015;373:621-31. [Crossref] [PubMed]
8. Palumbo A, Mateos MV, Miguel JS, et al. KEYNOTE-185: a randomized, open-label phase 3 study of pembrolizumab in combination with lenalidomide and low-dose dexamethasone in newly diagnosed and treatment-naive multiple myeloma (MM). J Clin Oncol 2016;34:abstr TPS8069.
9. Overdijk MB, Verploegen S, Bögels M, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs 2015;7:311-21. [Crossref] [PubMed]
10. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 2016;128:384-94. [Crossref] [PubMed]
11. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med 2015;373:1207-19. [Crossref] [PubMed]
12. Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 2016;387:1551-60. [Crossref] [PubMed]
13. Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;375:754-66. [Crossref] [PubMed]
14. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2016;375:1319-31. [Crossref] [PubMed]
15. Vij R, Lendvai N, Martin TG, et al.A phase Ib dose escalation trial of isatuximab (SAR650984, anti-CD38 mAb) plus lenalidomide and dexamethasone (Len/Dex) in relapsed/refractory multiple myeloma (RRMM): Interim results from two new dose cohorts. J Clin Oncol 2016;34:abstr 8009.
16. Raab MS, Chatterjee M, Goldschmidt H, et al. MOR202 alone and in combination with pomalidomide or lenalidomide in relapsed or refractory multiple myeloma: Data from clinically relevant cohorts from a phase I/IIa study. J Clin Oncol 2016;34:abstr 8012.
17. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother 2013;62:1841-9. [Crossref] [PubMed]
18. Guo H, Cruz-Munoz ME, Wu N, et al. Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. Mol Cell Biol 2015;35:41-51. [Crossref] [PubMed]
19. Zonder JA, Mohrbacher AF, Singhal S, et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 2012;120:552-9. [Crossref] [PubMed]
20. Jakubowiak A, Offidani M, Pegourie B, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. Blood 2016;127:2833-40. [Crossref] [PubMed]
21. Usmani SZ, Sexton R, Ailawadhi S, et al. Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211. Blood Cancer J 2015;5:e334 [Crossref] [PubMed]
22. Nikolova V, Koo CY, Ibrahim SA, et al. Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression. Carcinogenesis. 2009;30:397-407. [Crossref] [PubMed]
23. Kelly KR, Chanan-Khan A, Heffner LT, et al. Indatuximab Ravtansine (BT062) in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma: Clinical Activity in Patients Already Exposed to Lenalidomide and Bortezomib. Blood 2014;124:4736.
24. Leite LA, Kerbauy DM, Kimura E, et al. Multiples aberrant phenotypes in multiple myeloma patient expressing CD56(-), CD28(+),CD19 Rev Bras Hematol Hemoter 2012;34:66-7. [Crossref] [PubMed]
25. Chanan-Khan A, Wolf JL, Garcia J, et al. Efficacy Analysis From Phase I Study of Lorvotuzumab Mertansine (IMGN901), Used as Monotherapy, In Patients with Heavily Pre-Treated CD56-Positive Multiple Myeloma - A Preliminary Efficacy Analysis. Blood 2010;116:1962.
26. Berdeja JG, Hernandez-Ilizaliturri F, Chanan-Khan A, et al. Phase I Study of Lorvotuzumab Mertansine (LM, IMGN901) in Combination with Lenalidomide (Len) and Dexamethasone (Dex) in Patients with CD56-Positive Relapsed or Relapsed/Refractory Multiple Myeloma (MM). Blood 2012;120:728. [PubMed]
27. Tai YT, Mayes PA, Acharya C, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood 2014;123:3128-38. [Crossref] [PubMed]
28. Cohen AD, Popat R, Trudel S, et al. First in Human Study with GSK2857916, an Antibody Drug Conjugated to Microtubule-Disrupting Agent Directed Against B-Cell Maturation Antigen (BCMA) in Patients with Relapsed/Refractory Multiple Myeloma (MM): Results from Study BMA117159 Part 1 Dose Escalation. Blood 2016;128:1148.
29. Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol 2016;34:2698-704. [Crossref] [PubMed]
30. Mateos MV, Orlowski RZ, Siegel DS, et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): Final efficacy and safety analysis. J Clin Oncol 2016;34:abstr 8010.
31. Badros AZ, Kocoglu MH, Ma N, et al. A Phase II Study of Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM). Blood 2015;126:506.
32. Braga WM, da Silva BR, de Carvalho AC, et al. FOXP3 and CTLA4 overexpression in multiple myeloma bone marrow as a sign of accumulation of CD4(+) T regulatory cells. Cancer Immunol Immunother 2014;63:1189-97. [Crossref] [PubMed]
33. Hart DN, Hill GR. Dendritic cell immunotherapy for cancer: application to low-grade lymphoma and multiple myeloma. Immunol Cell Biol 1999;77:451-9. [Crossref] [PubMed]
34. Rasmussen T, Hansson L, Osterborg A, et al. Idiotype vaccination in multiple myeloma induced a reduction of circulating clonal tumor B cells. Blood 2003;101:4607-10. [Crossref] [PubMed]
35. Osterborg A, Yi Q, Henriksson L, et al. Idiotype immunization combined with granulocyte-macrophage colony-stimulating factor in myeloma patients induced type I, major histocompatibility complex-restricted, CD8- and CD4-specific T-cell responses. Blood 1998;91:2459-66. [PubMed]
36. Lacy MQ, Mandrekar S, Dispenzieri A, et al. Idiotype-pulsed antigen-presenting cells following autologous transplantation for multiple myeloma may be associated with prolonged survival. Am J Hematol 2009;84:799-802. [Crossref] [PubMed]
37. Rosenblatt J, Avivi I, Vasir B, et al. Vaccination with dendritic cell/tumor fusions following autologous stem cell transplant induces immunologic and clinical responses in multiple myeloma patients. Clin Cancer Res 2013;19:3640-8. [Crossref] [PubMed]
38. Cohen AD, Lendvai N, Gnjatic S, et al. MAGE-A3 Recombinant Protein (recMAGE-A3) Immunotherapy and Autologous Peripheral Blood Lymphocyte (PBL) Infusion Is Safe and Induces Robust Humoral Immune Responses In Multiple Myeloma (MM) Patients Undergoing Autologous Stem Cell Transplantation (autoSCT). Blood 2013;122:154.
39. Rapoport AP, Aqui NA, Stadtmauer EA, et al. Combination immunotherapy after ASCT for multiple myeloma using MAGE-A3/Poly-ICLC immunizations followed by adoptive transfer of vaccine-primed and costimulated autologous T cells. Clin Cancer Res 2014;20:1355-65. [Crossref] [PubMed]
40. Borrello IM, Noonan K, Huff CA, et al. Allogeneic Myeloma GVAX with Lenalidomide Enhances Progression Free Survival through the Generation of Tumor Specific Immunity in Patients in Near Complete Remission. Blood 2015;126:4238.
41. Bruno B, Rotta M, Patriarca F, et al. A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med 2007;356:1110-20. [Crossref] [PubMed]
42. Krishnan A, Pasquini MC, Logan B, et al. Autologous haemopoietic stem-cell transplantation followed by allogeneic or autologous haemopoietic stem-cell transplantation in patients with multiple myeloma (BMT CTN 0102): a phase 3 biological assignment trial. The Lancet Oncology 2011;12:1195-203. [Crossref] [PubMed]
43. Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: meta-analysis of trials with biological assignment. Bone Marrow Transplant 2013;48:562-7. [Crossref] [PubMed]
44. Borrello I, Noonan KA. Marrow-Infiltrating Lymphocytes - Role in Biology and Cancer Therapy. Front Immunol 2016;7:112. [Crossref] [PubMed]
45. Noonan K, Matsui W, Serafini P, et al. Activated marrow-infiltrating lymphocytes effectively target plasma cells and their clonogenic precursors. Cancer Res 2005;65:2026-34. [Crossref] [PubMed]
46. Noonan KA, Borrello IM. Marrow Infiltrating Lymphocytes: Their Role in Adoptive Immunotherapy. Cancer J 2015;21:501-5. [Crossref] [PubMed]
47. Szmania S, Tricot G, van Rhee F. NY-ESO-1 immunotherapy for multiple myeloma. Leuk Lymphoma 2006;47:2037-48. [Crossref] [PubMed]
48. Rapoport AP, Stadtmauer EA, Binder-Scholl GK, et al. NY-ESO-1-specific TCR-engineered T cells mediate sustained antigen-specific antitumor effects in myeloma. Nat Med 2015;21:914-21. [Crossref] [PubMed]
49. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365:725-33. [Crossref] [PubMed]
50. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507-17. [Crossref] [PubMed]
51. Garfall AL, Maus MV, Hwang WT, et al. Chimeric Antigen Receptor T Cells against CD19 for Multiple Myeloma. N Engl J Med 2015;373:1040-7. [Crossref] [PubMed]
52. Matsui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008;68:190-7. [Crossref] [PubMed]
53. Carpenter RO, Evbuomwan MO, Pittaluga S, et al. B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma. Clin Cancer Res 2013;19:2048-60. [Crossref] [PubMed]
54. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 2016;128:1688-700. [Crossref] [PubMed]
55. Drent E, Groen RW, Noort WA, et al. Pre-clinical evaluation of CD38 chimeric antigen receptor engineered T cells for the treatment of multiple myeloma. Haematologica 2016;101:616-25. [Crossref] [PubMed]
56. Chu J, He S, Deng Y, et al. Genetic modification of T cells redirected toward CS1 enhances eradication of myeloma cells. Clin Cancer Res 2014;20:3989-4000. [Crossref] [PubMed]
57. Jiang H, Zhang W, Shang P, et al. Transfection of chimeric anti-CD138 gene enhances natural killer cell activation and killing of multiple myeloma cells. Mol Oncol 2014;8:297-310. [Crossref] [PubMed]
58. Vera J, Savoldo B, Vigouroux S, et al. T lymphocytes redirected against the kappa light chain of human immunoglobulin efficiently kill mature B lymphocyte-derived malignant cells. Blood 2006;108:3890-7. [Crossref] [PubMed]
59. Maude SL, Barrett D, Teachey DT, et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J 2014;20:119-22. [Crossref] [PubMed]