Basic and translational Myeloma Research:
Recent literature- Editors’ picks

Compiled by Mariateresa Fulciniti, PhD
Dana-Farber Cancer Institute

Myeloma Genomics

• Whole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities.  Oben B, Froyen G, Maclachlan KH, Leongamornlert D, Abascal F, Zheng-Lin B, Yellapantula V, Derkach A, Geerdens E, Diamond BT, Arijs I, Maes B, Vanhees K, Hultcrantz M, Manasanch EE, Kazandjian D, Lesokhin A, Dogan A, Zhang Y, Mikulasova A, Walker B, Morgan G, Campbell PJ, Landgren O, Rummens JL, Bolli N, Maura F. Nat Commun. 2021 Mar 25;12(1):1861. doi: 10.1038/s41467-021-22140-0.
• del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma. Corre J, Perrot A, Caillot D, Belhadj K, Hulin C, Leleu X, Mohty M, Facon T, Buisson L, Do Souto L, Lannes R, Dufrechou S, Prade N, Orsini-Piocelle F, Voillat L, Jaccard A, Karlin L, Macro M, Brechignac S, Dib M, Sanhes L, Fontan J, Clement-Filliatre L, Marolleau JP, Minvielle S, Moreau P, Avet-Loiseau H. Blood. 2021 Mar 4;137(9):1192-1195. doi: 10.1182/blood.2020008346.

The Myeloma microenvironment

• The multiple myeloma microenvironment is defined by an inflammatory stromal cell landscape.
  de Jong MME, Kellermayer Z, Papazian N, Tahri S, Hofste Op Bruinink D, Hoogenboezem R, Sanders MA, van de Woestijne PC, Bos PK, Khandanpour C, Vermeulen J, Moreau P, van Duin M, Broijl A, Sonneveld P, Cupedo T. Nat Immunol. 2021 Jun;22(6):769-780. doi: 10.1038/s41590-021-00931-3. Epub 2021 May 20.
• Co-evolution of tumor and immune cells during progression of multiple myeloma. Liu R, Gao Q, Foltz SM, Fowles JS, Yao L, Wang JT, Cao S, Sun H, Wendl MC, Sethuraman S, Weerasinghe A, Rettig MP, Storrs EP, Yoon CJ, Wyczalkowski MA, McMichael JF, Kohnen DR, King J, Goldsmith SR, O’Neal J, Fulton RS, Fronick CC, Ley TJ, Jayasinghe RG, Fiala MA, Oh ST, DiPersio JF, Vij R, Ding L. Nat Commun. 2021 May 7;12(1):2559. doi: 10.1038/s41467-021-22804-x.

Myeloma Bone Disease

• Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease. Garcia-Gomez A, Li T, de la Calle-Fabregat C, Rodríguez-Ubreva J, Ciudad L, Català-Moll F, Godoy-Tena G, Martín-Sánchez M, San-Segundo L, Muntión S, Morales X, Ortiz-de-Solórzano C, Oyarzabal J, San José-Enériz E, Esteller M, Agirre X, Prosper F, Garayoa M, Ballestar E. Nat Commun. 2021 Jan 18;12(1):421. doi: 10.1038/s41467-020-20715-x.

Myeloma Cell Metabolism

• Acetyl-CoA Synthetase 2: A Critical Linkage in Obesity-Induced Tumorigenesis in Myeloma. Li Z, Liu H, He J, Wang Z, Yin Z, You G, Wang Z, Davis RE, Lin P, Bergsagel PL, Manasanch EE, Wong STC, Esnaola NF, Chang JC, Orlowski RZ, Yi Q, Yang J. Cell Metab. 2021 Jan 5;33(1):78-93.e7. doi: 10.1016/j.cmet.2020.12.011.

Multiple Myeloma Mouse Models

• Progression signature underlies clonal evolution and dissemination of multiple myeloma. Shen YJ, Mishima Y, Shi J, Sklavenitis-Pistofidis R, Redd RA, Moschetta M, Manier S, Roccaro AM, Sacco A, Tai YT, Mercier F, Kawano Y, Su NK, Berrios B, Doench JG, Root DE, Michor F, Scadden DT, Ghobrial IM. Blood. 2021 Apr 29;137(17):2360-2372. doi: 10.1182/blood.2020005885.
• Expression of NrasQ61R and MYC transgene in germinal center B cells induces a highly malignant multiple myeloma in mice. Wen Z, Rajagopalan A, Flietner ED, Yun G, Chesi M, Furumo Q, Burns RT, Papadas A, Ranheim EA, Pagenkopf AC, Morrow ZT, Finn R, Zhou Y, Li S, You X, Jensen J, Yu M, Cicala A, Menting J, Mitsiades CS, Callander NS, Bergsagel PL, Wang D, Asimakopoulos F, Zhang J. Blood. 2021 Jan 7;137(1):61-74. doi: 10.1182/blood.2020007156.

Novel targets & therapeutics

• Targeting NSD2-mediated SRC-3 liquid-liquid phase separation sensitizes bortezomib treatment in multiple myeloma. Liu J, Xie Y, Guo J, Li X, Wang J, Jiang H, Peng Z, Wang J, Wang S, Li Q, Ye L, Zhong Y, Zhang Q, Liu X, Lonard DM, Wang J, O’Malley BW, Liu Z. Nat Commun. 2021 Feb 15;12(1):1022. doi: 10.1038/s41467-021-21386-y.
• Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Jan M, Scarfò I, Larson RC, Walker A, Schmidts A, Guirguis AA, Gasser JA, Słabicki M, Bouffard AA, Castano AP, Kann MC, Cabral ML, Tepper A, Grinshpun DE, Sperling AS, Kyung T, Sievers QL, Birnbaum ME, Maus MV, Ebert BL. Sci Transl Med. 2021 Jan 6;13(575):eabb6295. doi: 10.1126/scitranslmed.abb6295.
• The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma. Longo J, Smirnov P, Li Z, Branchard E, van Leeuwen JE, Licht JD, Haibe-Kains B, Andrews DW, Keats JJ, Pugh TJ, Trudel S, Penn LZ. Leukemia. 2021 Mar;35(3):796-808. doi: 10.1038/s41375-020-0962-2. Epub 2020 Jul 14.
• Targeting the GCK pathway: a novel and selective therapeutic strategy against RAS-mutated multiple myeloma. Li S, Fu J, Yang J, Ma H, Bhutani D, Mapara MY, Marcireau C, Lentzsch S. Blood. 2021 Apr 1;137(13):1754-1764. doi: 10.1182/blood.2020006334.
• Targeting the Otub1/c-Maf axis for the treatment of multiple myeloma. Xu Y, Xu M, Tong J, Tang X, Chen J, Chen X, Zhang Z, Cao B, Stewart AK, Moran MF, Wu D, Mao X. Blood. 2021 Mar 18;137(11):1478-1490. doi: 10.1182/blood.2020005199.PMID: 32842143

Molecular mechanisms of Drug Resistance and/or Sensitivity

• Identification of resistance pathways and therapeutic targets in  relapsed multiple myeloma patients through single-cell sequencing. Cohen YC, Zada M, Wang SY, Bornstein C, David E, Moshe A, Li B, Shlomi-Loubaton S, Gatt ME, Gur C, Lavi N, Ganzel C, Luttwak E, Chubar E, Rouvio O, Vaxman I, Pasvolsky O, Ballan M, Tadmor T, Nemets A, Jarchowcky-Dolberg O, Shvetz O, Laiba M, Shpilberg O, Dally N, Avivi I, Weiner A, Amit I. Nat Med. 2021 Mar;27(3):491-503. doi: 10.1038/s41591-021-01232-w. Epub 2021 Feb 22.
• Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma. Samur MK, Fulciniti M, Aktas Samur A, Bazarbachi AH, Tai YT, Prabhala R, Alonso A, Sperling AS, Campbell T, Petrocca F, Hege K, Kaiser S, Loiseau HA, Anderson KC, Munshi NC. Nat Commun. 2021 Feb 8;12(1):868. doi: 10.1038/s41467-021-21177-5.
• Homozygous BCMA gene deletion in response to anti-BCMA CAR T cells in a patient with multiple myeloma. Da Vià MC, Dietrich O, Truger M, Arampatzi P, Duell J, Heidemeier A, Zhou X, Danhof S, Kraus S, Chatterjee M, Meggendorfer M, Twardziok S, Goebeler ME, Topp MS, Hudecek M, Prommersberger S, Hege K, Kaiser S, Fuhr V, Weinhold N, Rosenwald A, Erhard F, Haferlach C, Einsele H, Kortüm KM, Saliba AE, Rasche L. Nat Med. 2021 Apr;27(4):616-619. doi: 10.1038/s41591-021-01245-5. Epub 2021 Feb 22
• Multiple cereblon genetic changes are associated with acquired resistance to lenalidomide or pomalidomide in multiple myeloma. Gooding S, Ansari-Pour N, Towfic F, Ortiz Estévez M, Chamberlain PP, Tsai KT, Flynt E, Hirst M, Rozelle D, Dhiman P, Neri P, Ramasamy K, Bahlis N, Vyas P, Thakurta A. Blood. 2021 Jan 14;137(2):232-237. doi: 10.1182/blood.2020007081.
• The IMiD target CRBN determines HSP90 activity toward transmembrane proteins essential in multiple myeloma. Heider M, Eichner R, Stroh J, Morath V, Kuisl A, Zecha J, Lawatscheck J, Baek K, Garz AK, Rudelius M, Deuschle FC, Keller U, Lemeer S, Verbeek M, Götze KS, Skerra A, Weber WA, Buchner J, Schulman BA, Kuster B, Fernández-Sáiz V, Bassermann F. Mol Cell. 2021 Mar 18;81(6):1170-1186.e10. doi: 10.1016/j.molcel.2020.12.046. Epub 2021 Feb 10.
• Venetoclax sensitivity in multiple myeloma is associated with B-cell gene expression. Gupta VA, Barwick BG, Matulis SM, Shirasaki R, Jaye DL, Keats JJ, Oberlton B, Joseph NS, Hofmeister CC, Heffner LT, Dhodapkar MV, Nooka AK, Lonial S, Mitsiades CS, Kaufman JL, Boise LH. Blood. 2021 Jul 1;137(26):3604-3615. doi: 10.1182/blood.2020007899.
• Tumor Burden Limits Bispecific Antibody Efficacy through T-cell Exhaustion Averted by Concurrent Cytotoxic Therapy. Erin W. Meermeier, Seth J. Welsh, Meaghen E. Sharik, Megan T. Du, Victoria M. Garbitt, Daniel L. Riggs, Chang-Xin Shi, Caleb K. Stein, Marco Bergsagel, Bryant Chau, Matthew L. Wheeler, Natalie Bezman, Feng Wang, Pavel Strop, P. Leif Bergsagel and Marta Chesi. Blood Cancer Discov July 1 2021 2 (4) 354-369; DOI:10.1158/2643-3230.BCD-21-0038