Current developments in immunotherapy in the treatment of multiple myeloma

Köhler, M.; Greil, Christine; Hudecek, Michael; Lonial, Sagar; Raje, Noopur; Wäsch, Ralph; Engelhardt, Monika

doi:10.1002/cncr.31243

Cited by 54 publications

(39 citation statements)

References 83 publications

(126 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple myeloma (MM) is the second most frequent hematologic malignancy that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment . Despite increasingly new methods and agents have been validated, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, and CAR‐T cell therapy, MM remains incurable for a majority of patients. Liposomal nanomedicines such as Doxil and Oncocort IV are also used for the treatment of MM patients, though their therapeutic benefits are limited as a result of poor MM selectivity.…”

Section: Methodsmentioning

confidence: 99%

CD44‐Specific A6 Short Peptide Boosts Targetability and Anticancer Efficacy of Polymersomal Epirubicin to Orthotopic Human Multiple Myeloma

Meng

et al. 2019

Advanced Materials

View full text Add to dashboard Cite

Chemotherapy is widely used in the clinic though its benefits are controversial owing to low cancer specificity. Nanovehicles capable of selectively transporting drugs to cancer cells have been energetically pursued to remodel cancer treatment. However, no active targeting nanomedicines have succeeded in clinical translation to date, partly due to either modest targetability or complex fabrication. CD44‐specific A6 short peptide (KPSSPPEE) functionalized polymersomal epirubicin (A6‐PS‐EPI), which boosts targetability and anticancer efficacy toward human multiple myeloma (MM) in vivo, is described. A6‐PS‐EPI encapsulating 11 wt% EPI is small (≈55 nm), robust, reduction‐responsive, and easy to fabricate. Of note, A6 decoration markedly augments the uptake and anticancer activity of PS‐EPI in CD44‐overexpressing LP‐1 MM cells. A6‐PS‐EPI displays remarkable targeting ability to orthotopic LP‐1 MM, causing depleted bone damage and striking survival benefits compared to nontargeted PS‐EPI. Overall, A6‐PS‐EPI, as a simple and intelligent nanotherapeutic, demonstrates high potential for clinical translation.

show abstract

Section: Methodsmentioning

confidence: 99%

CD44‐Specific A6 Short Peptide Boosts Targetability and Anticancer Efficacy of Polymersomal Epirubicin to Orthotopic Human Multiple Myeloma

Meng

et al. 2019

Advanced Materials

View full text Add to dashboard Cite

show abstract

“…However, since not all patients may profit from IO and relapse remains inescapable, a better understanding of resistance continues to be a crucial research interest and novel treatment strategies for RRMM are needed. 14,22 Results from this phase I/II VBDD/VERUMM trial demonstrated encouraging efficacy and tolerability. Due to the favorable responses in previously treated and untreated MM patients with renal impairment (RI) and due to the synergy of vorinostat and BDD-backbone, this was chosen for our quadruplet.…”

mentioning

confidence: 97%

Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma)

et al. 2018

Self Cite

View full text Add to dashboard Cite

Engelhardt. Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma). Haematologica. 2018; 103:xxx doi:10.3324/haematol.2018.189969 Publisher's Disclaimer. Vorinostat is an oral class I/II HDACi and has been investigated with bortezomib in a randomized phase III trial for RRMM patients: this VANTAGE088 study reported a median PFS of 7.6 vs. 6.8 months for (Table 1A). The synergism of vorinostat and bortezomib is depicted in Fig.S1A. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.All patients suffered from relapsed (n=23) or RRMM (n=10). The median age was 62 years, which was comparable or more advanced to others (Table 1B). In line with our earlier description of age and stage migration, 8 we here observed more elderly, unfit and advanced MM stages. [8][9][10] The Revised Myeloma Comorbidity Index (R-MCI) was 4, thus patients were by definition intermediate-fit. In line, their Charlson Comorbidity Index (CCI) was 2 vs. 1 in our control patients (Table 1C). For comparison, Palumbo et al.described their elderly clinical trial cohort with a CCI of 0. 11Our pretreatment with PIs, IMiDs and autologous stem cell transplantation (ASCT) was similar to others. 5,12,13 The number of prior lines was 3: virtually all (91%) had received ASCT, bortezomib (88%) and IMiDs (42%). The median bone marrow (BM) infiltration was 40%, iFISH showed HR in 18% and unfavorable cytogenetics (CG) in 52% (Table 1A+B). The VBDD data were presented as of 12/2016 with at least one year follow-up of the last patient being treated. NA being approved in Europe since 2016, 3 such as daratumumab (Dara), elotuzumab, carfilzomib or ixazomib, had not been available for RRMM patients outside clinical trials at that time.14 With three patients having been treated in each dose level (DL) 0 and +1, without any DLT during the first cycle, the remaining 27 proceeded to DL+2. Common hematologic side effects (AEs) included anemia and thrombocytopenia. Non-hematological AEs included infections, amongst others three cases of sepsis, three with pneumonia, and one each with esophageal candidiasis, colitis and herpes zoster reactivation.Others included one case of syncope and cerebral seizure in a patient with seizure history (Table 2).Cardiotoxicity was not observ...

show abstract

“…Also, they reveal new opportunities for combinatorial therapeutic interventions in MM and/or other haematological malignancies by employing inhibitors of STATs and/or secretory cytokines/chemokines. Consistently with the notion that the dynamic milieu generated by the cytokines/chemokines as a whole may dictate treatment response and disease outcome, recent studies have revealed that combinatorial therapies with PIs plus anticytokine/chemokine (eg anti‐IL6) treatment could have beneficial effect on MM therapy and on MM‐related bone disease …”

Section: Discussionmentioning

confidence: 79%

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Skorda

Sklirou

Sakellaropoulos

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Multiple myeloma (MM) is a haematological malignancy being characterized by clonal plasma cell proliferation in the bone marrow. Targeting the proteasome with specific inhibitors (PIs) has been proven a promising therapeutic strategy and PIs have been approved for the treatment of MM and mantle‐cell lymphoma; yet, while outcome has improved, most patients inevitably relapse. As relapse refers to MM cells that survive therapy, we sought to identify the molecular responses induced in MM cells after non‐lethal proteasome inhibition. By using bortezomib (BTZ), epoxomicin (EPOX; a carfilzomib‐like PI) and three PIs, namely Rub999, PR671A and Rub1024 that target each of the three proteasome peptidases, we found that only BTZ and EPOX are toxic in MM cells at low concentrations. Phosphoproteomic profiling after treatment of MM cells with non‐lethal (IC10) doses of the PIs revealed inhibitor‐ and cell type‐specific readouts, being marked by the activation of tumorigenic STAT3 and STAT6. Consistently, cytokine/chemokine profiling revealed the increased secretion of immunosuppressive pro‐tumorigenic cytokines (IL6 and IL8), along with the inhibition of potent T cell chemoattractant chemokines (CXCL10). These findings indicate that MM cells that survive treatment with therapeutic PIs shape a pro‐tumorigenic immunosuppressive cellular and secretory bone marrow microenvironment that enables malignancy to relapse.

show abstract

Current developments in immunotherapy in the treatment of multiple myeloma

Cited by 54 publications

References 83 publications

CD44‐Specific A6 Short Peptide Boosts Targetability and Anticancer Efficacy of Polymersomal Epirubicin to Orthotopic Human Multiple Myeloma

CD44‐Specific A6 Short Peptide Boosts Targetability and Anticancer Efficacy of Polymersomal Epirubicin to Orthotopic Human Multiple Myeloma

Safety and efficacy of vorinostat, bortezomib, doxorubicin and dexamethasone in a phase I/II study for relapsed or refractory multiple myeloma (VERUMM study: vorinostat in elderly, relapsed and unfit multiple myeloma)

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

Contact Info

Product

Resources

About