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Research
The Black Swan Team discusses the progress of the ongoing “Cure” Trials. [From Left:] María-Victoria Mateos, MD, Phd (University of Salamanca — Spain); IMF Chairman of the Board Brian G.M. Durie, MD; Bruno Paiva, PhD (University of Navarro — Pamplona, Spain); Shaji Kumar, MD (Mayo Clinic — Rochester, MN); and S. Vincent Rajkumar, MD (Mayo Clinic — Rochester, MN).
The International Myeloma Foundation’s signature research project, the Black Swan Research Initiative® (BSRI®), fueled by a team of multinational myeloma researchers, continues to make strides. Below is a follow-up on BSRI projects that have been ongoing since 2016.
• Recent minimal residual disease (MRD) research focuses on Next
Generation Flow testing in the blood (versus in the bone marrow) for disease monitoring. Early published results demonstrate the value of serial blood monitoring. New data emerging in the future will possibly validate the approach of combining NGF testing with mass spectrometry testing. This combined testing approach may reduce the need for frequent bone marrow testing. • The ASCENT trial (Aggressive Smoldering Curative Approach
Evaluating Novel Therapies) continues to evaluate the efficacy and safety of the combination of Darzalex® (daratumumab), Kyprolis® (carfilzomib), Revlimid® (lenalidomide), and dexamethasone in high-risk smoldering multiple myeloma (HRSMM). Its goal: to learn whether starting treatment early substantially improves outcomes, leads to a higher level of undetected MRD, to sustained remissions, and to a potential cure. The trial continues to accrue participants, and its early results are very promising. • The CESAR trial is ongoing in Spain with Professor María-Victoria
Mateos as the Principal Investigator. CESAR (Curativo Estrategia
Smouldering Alto Riesgo, or Curative Strategy for High-Risk
Smoldering) uses the combination of Kyprolis, Revlimid, and dexamethasone (KRd) with autologous stem cell transplant in the same setting as ASCENT. With a three-year follow-up reported at the American Society of Hematology annual conference in
December 2019, 62% of patients have achieved deep responses and are MRD-negative at 10-6 level, or zero out of one million bone marrow cells. • Finally, for patients not achieving MRD-negative status, many BSRI projects focus on characterizing the disease as residual and/or relapsing. Dr. Andrew Spencer in Australia leads a BSRI-supported team to evaluate DNA in the blood—so-called cell free or cfDNA.
The team has observed a range of mutations that can serve as a basis for possible new treatment strategies for patients with residual disease.
ISTOPMM FORGES AHEAD IN 2020
In November 2016, the Iceland-based iStopMM (Iceland Screens, Treats, Or Prevents Multiple Myeloma) project was launched in Reykjavík. The project’s ambitious screening process to identify new patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma (MM) has been successful beyond all expectations, with more than 80,000 individuals screened and tested to date. The hard work continued as the team worked to understand as much as possible.
Topline Questions from the Study: What clues might point to possible causes for MGUS/SMM/MM?
A major reason for conducting this project in Iceland is that full DNA sequencing is available through deCODE Genetics for all participants. Because of this, genetic predisposing factors can be accurately assessed. In addition, participants’ full medical histories are available, including family history, occupations, and details of all medical interventions (such as surgeries) and medications used. Diet has already been closely studied. The possible triggering role of infections will now be explored in a new collaboration with investigators in another Black Swan project in France. These French investigators are studying if myeloma is being driven by infections such as hepatitis C or the Epstein-Barr virus. Initial results will be available soon.
iStopMM’s Principal Investigator Dr. Sigurdur Kristinsson presents to his team in Reykjavík, Iceland.
How early does MGUS begin?
Initial screening in the iStopMM project has been for individuals over 40 because the median age of onset for myeloma is approximately 67 years of age. The study uses mass spectrometry, a very sensitive technique for detecting the serum M-component. It shows that MGUS is occurring at a much younger age than expected, even below the age of 40. Studies of such younger patients, including detailed immune monitoring, are now ongoing to help understand the immune evolution of early disease. Initial results will soon be available.
What is the risk status of patients screened in the iStopMM project?
Initial results indicate that a majority of MGUS patients are “low risk” and can be followed safely. Conversely, the SMM patients are more frequently “higher risk” and need to be assessed for potential early intervention, with the goal of cure. Dr. Sigurdur Kristinsson, the iStopMM Principal Investigator, is to be congratulated. He pulled together a talented team of approximately 20 members. This team conducted testing, including baseline bone marrow evaluation, and psychological assessments to ensure that no undue stresses occur as a result of the screening process.
BSRI PUBLICATIONS FROM FISCAL YEAR 2020
Measurable Residual Disease by Next-Generation Flow Cytometry in Multiple Myeloma
Bruno Paiva, Noemi Puig, Maria-Teresa Cedena, Laura Rosiñol, Lourdes Cordón, María-Belén Vidriales, Leire Burgos, Juan Flores-Montero, Luzalba Sanoja-Flores, Lucia Lopez-Anglada, Roberto Maldonado, Javier de la Cruz, Norma C Gutierrez, Maria-Jose Calasanz, Maria-Luisa Martin-Ramos, Ramón Garcia-Sanz, Joaquin Martinez-Lopez, Albert Oriol, María-Jesús Blanchard, Rafael Rios, Jesus Martin, Rafael MartinezMartinez, Anna Sureda, Miguel-Teodoro Hernandez, Javier de la Rubia, Isabel Krsnik, Jose-Maria Moraleda, Luis Palomera, Joan Bargay, Jacques J M Van Dongen, Alberto Orfao, María-Victoria Mateos, Joan Blade, Jesús F San-Miguel, Juan-José Lahuerta, GEM (Grupo Español de Mieloma)/PETHEMA (Programa Para el Estudio de la Terapéutica en Hemopatías Malignas) Cooperative Study Group. J Clin Oncol. 2020 Mar 10; 38(8): 784-792.
Transcriptional profiling of circulating tumor cells in multiple myeloma: a new model to understand disease dissemination
Juan-Jose Garcés, Michal Simicek, Marco Vicari, Lucie Brozova, Leire Burgos, Renata Bezdekova, Diego Alignani, Maria-Jose Calasanz, Katerina Growkova, Ibai Goicoechea, Xabier Agirre, Ludek Pour, Felipe Prosper, Rafael Rios, Joaquin Martinez-Lopez, Pamela Millacoy, Luis Palomera, Rafael Del Orbe, Albert Perez-Montaña, Sonia Garate, Laura Blanco, Marta Lasa, Patricia Maiso, Juan Flores-Montero, Luzalba Sanoja-Flores, Zuzana Chyra, Alexander Vdovin, Tereza Sevcikova, Tomas Jelinek, Cirino Botta, Halima El Omri, Jonathan Keats, Alberto Orfao, Roman Hajek, Jesús F. San-Miguel & Bruno Paiva. Leukemia. 2020 Feb; 34(2): 589-603.
Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy
Luzalba Sanoja-Flores, Juan Flores-Montero, Noemi Puig, Teresa Contreras-Sanfeliciano, Roberia Pontes, Alba Corral-Mateos, Omar García-Sánchez, María Díez-Campelo, Roberto José Pessoa de Magalhães, Luis García-Martín, José María Alonso-Alonso, Aranzazú García-Mateo, Carlos Aguilar-Franco, Jorge Labrador, Abelardo Barez-García, Angelo Maiolino, Bruno Paiva, Jesús San Miguel, Elaine Sobral da Costa, Marcos González, María Victoria Mateos, Brian Durie, Jacques J. M. van Dongen, Alberto Orfao on behalf of the EuroFlow Consortium. Blood. 2019 Dec 12; 134(24): 2218-2222.
Pictured is the moderator for the International Myeloma Working Group Summit, which brought together dozens of myeloma experts online during August 2020.
The IMF hosted the 11th Annual International Myeloma Working Group (IMWG) Summit virtually on August 25-26, 2020. Even though it was held online, the Summit convened the world’s top myeloma experts to review works in progress, set the agenda for future myeloma research projects, and learn from those who are exploring new frontiers in the biology and/or treatment of this disease.
Professor Kàri Stefànsson, Founder and CEO of deCODE Genetics in Reykjavík, Iceland, gave the keynote address—a lecture on population genetics. Prof. Stefànsson helped the audience understand the origin and impact of individual gene mutations on disease predisposition. Many other leading myeloma experts presented plenary lectures, covering such topics as frontline therapy, the role of minimal residual disease as an endpoint, immune therapies, and more.
Other highlights from the Summit included the presentation of the IMF’s 19th Annual Robert A. Kyle Lifetime Achievement Award to Prof. Thierry Facon (University of Lille — France). This award honors an individual whose body of work has made significant contributions to myeloma research and patient care. The Brian G.M. Durie Outstanding Achievement Award, recognizing excellence in myeloma research, was awarded to Dr. Wee Joo Chng (Yong Loo Lin School of Medicine, NUS and National University Cancer Institute, NUHS — Singapore).
As is tradition with the Summit, the myeloma experts break out into working group committees. Highlights from the IMWG Summit Working Group reports included: • The role of mass spectrometry, a very sensitive blood-test technology, was summarized. Mass spectrometry will hopefully revolutionize both diagnostic testing and response monitoring in the future. • The new criteria for identification of high-risk smoldering myeloma, or the 2/20/20 model, was discussed. • Planned projects and studies by the Immune Therapy
Committee were endorsed. • Plans and accomplishments of the Bone Committee were recognized as well.
IMWG PUBLICATIONS
In 2020
Mateos MV, et al. International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM). Blood Cancer J. 2020 Oct; 10(10): 102.
Upcoming in 2021
Moreau P, et al. Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group.
Murray D, et al. Mass spectrometry for the evaluation of monoclonal proteins in multiple myeloma and related disorders: an International Myeloma Working Group Mass Spectrometry Committee Report.
Terpos E, et al. Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group.
The Asian Myeloma Network team came together for their annual summit in Bangkok, Thailand, in late October 2019.
ASIAN MYELOMA NETWORK ANNUAL SUMMIT IS A SUCCESS
Asia is home to the greatest number of myeloma patients in the world. Unfortunately, despite some recent advances, access to the newest myeloma treatments continues to be limited in the Asian region. Delays in government approval processes as well as insufficient insurance and healthcare contribute to these access limitations. The mission of IMF’s Asian Myeloma Network (AMN) is to provide a platform for Asian experts to discuss shared challenges and to work together to enhance patient support in the Asian region.
The third annual Asian Myeloma Network Summit was held in Bangkok from October 25-27, 2019, focusing on priorities for action in the region. The meeting, by-invitation-only, limited participants to allow for discussions in a workshop setting. At the Summit, 120 myeloma experts from China, Hong Kong, Taiwan, Japan, Korea, Malaysia, Singapore, and Thailand took part. They discussed developments in myeloma science and its impact on diagnosis and treatment in Asia. IMF Chairman of the Board Dr. Brian G.M. Durie and many international experts led beneficial presentations and workshops for all.
The five subjects of the AMN Summit were:
• 1) Developments in CAR T-cell therapy, led by Juan Du, MD (Shanghai Changzheng Hospital — Shanghai) and Thomas G.
Martin, MD (University of California —San Francisco)
• 2) MRD Assessment, led by Wenming Chen, PhD (University of Melbourne — Melbourne), Jae Hoon Lee, MD (Gachon
University — Incheon, South Korea), and Alberto Orfao, MD (University of Salamanca — Salamanca, Spain) • 3) Treatment of High-Risk Patients, led by Kihyun Kim, MD, PhD (Sungkyunkwan University — Seoul, South Korea); and IMF
Chairman of the Board Brian G.M. Durie, MD
• 4) Asian Tissue Bank led by Wee Joo Chng, MD (National
University Cancer Institute — Singapore), and Jean-Luc
Harousseau, MD (University of Nantes — Nantes, France).
• 5) Patient Support in Asia, led by Daryl Tan, MD (Mount
Elizabeth Hospital — Singapore) and Kazuyuki Shimizu, MD,
PhD (East Nagoya Hospital — Nagoya, Japan).
IMF’s Asian-wide clinical trial initiative, led by Dr. Wee Joo Chng, was a major focus of AMN. Dr. Chng reported to the Summit on successful AMN trials. These trials have been useful in getting novel agents to Asian patients while providing valuable research. Discussions during the Summit raised proposals for new AMN clinical trial projects, including potential studies involving CAR T-cell therapy.
Participants also discussed the expansion of the AMN database and increasing physician education, including developing an Asian “IMF Master Class.” The Summit also benefited from partner support including Amgen, Celgene, Janssen, and Sanofi (platinum sponsors); Binding Site (gold sponsor); and AbbVie, BeiGene, CARSgen, and Takeda (silver sponsors).
UPDATE ON AMN CLINICAL TRIALS
• AMN001 concluded this year. It was an access program that enrolled 136 relapsed myeloma patients who had previous exposure to bortezomib and lenalidomide, and were later
AMN Article Continued
Asian Myeloma Network members Drs. Wee Joo Chng and Wen-ming Chen.
treated with pomalidomide (pom) and dexamethasone (dex).
The data demonstrated high response rates. Its findings were published in Blood Cancer Journal. • AMN002, a randomized phase II study, was also completed this year. It used different doses of carfilzomib with cyclophosphamide and dex for relapsed/refractory myeloma patients who had prior exposure to bortezomib. The project involved 41 patients in Asia and 50 patients in Australia and
New Zealand. • AMN003 is an ongoing randomized phase III study comparing the combination of pomalidomide (pom), cyclophosphamide, and dex to the combination of pom and dex in relapsed or refractory myeloma patients. The project is ongoing and will involve up to 120 patients in Asia. • AMN004 is a phase II study examining the use of daratumumab (dara) in combination with thalidomide and dex in patients with relapsed and/or refractory myeloma. This study is ongoing and involves 70 patients in Asia. • AMN006 is a phase II study initiated in 2019 that will consider the use of daratumumab in combination with bortezomib and dex in newly diagnosed, transplant-ineligible patients. This study will involve 63 patients in Asia. • Additional AMN clinical trial projects are currently being negotiated with implementation scheduled to begin in early 2021.
MORE AMN ACTIVITIES
• AMN Treatment Guidelines for Asia were updated and published in Oncology. • Physician training seminars were held in Shanghai and Beijing,
China. • The Black Swan Research Initiative® minimal residual disease projects continued in China and Japan. • AMN held member Patient Seminars in China, Hong Kong,
Taiwan, Korea, and Singapore.
2020 BRIAN D. NOVIS RESEARCH GRANT AWARDS
The International Myeloma Foundation (IMF) presented its 2020 Research Grant awards in December 2019 in Orlando, Florida.
Senior Grant Recipients
Senior Research Grant projects are funded at $80,000.
Sylvie Hermouet, MD, PhD
Mikhail Nikiforov, PhD
Sylvie Hermouet, MD, PhD
CRCINA Inserm U1232 | Centre de Recherche en Cancérologie et Immunologie | NantesAngers | Nantes, France Functional characterization of monoclonal immunoglobulins from antigen-driven MGUS and myeloma Funded by the 7th Annual Miracles for Myeloma 5K
Mikhail Nikiforov, PhD
Wake Forest University Health Services | Cancer Biology | Winston-Salem, NC, USA Leveraging polyamine dependency for treatment of drug-resistant multiple myelomas Funded by Laughs 4 Life
Junior Grant Recipients
Junior Research Grant projects are funded at $50,000.
Francesco Maura, MD
Francesco Maura, MD
Memorial Sloan Kettering Cancer Center | Medicine | New York, NY, USA Deciphering the impact of melphalan on secondary malignancy in multiple myeloma Funded by the 12th Annual Miles for Myeloma 5K
Kim De Veirman, PhD
Kim De Veirman, PhD
Vrije Universiteit Brussel | Hematology and Immunology, Myeloma Center Brussels | Brussels, Belgium Targeting AXL, a putative dormancy regulator in multiple myeloma Funded by the 12th Annual Miles for Myeloma 5K
Alexandre Detappe, PhD
Centre Paul Strauss / Université de Strasbourg Medical Oncology | Strasbourg, France A ‘click-ready’ cereblon E3 ligase modulation drug library for fast in vivo evaluation in multiple myeloma mouse evaluations Funded by Dr. Christopher Meier — Flying Pig Marathon
