With two recently approved chimeric antigen receptor T therapies targeting B-cell maturation antigen, this novel platform has altered the treatment paradigm for heavily-pretreated patients with multiple myeloma.
Ever since high-dose melphalan with autologous stem cell transplantation (ASCT) became standard-of-care for multiple myeloma (MM), many have sought a replacement. Part of the reason is the historical toxicity of ASCT; however, advances in supportive measures have significantly improved transplant-related morbidity and mortality, thereby allowing it to expand to wider populations and to be performed in the ambulatory setting.1-3 Perhaps, in part, the desire to find an alternative to ASCT stems from the perceived lack of refinement of the continued use of myeloablative chemotherapy for a disease in which clinicians have many highly effective novel agents and cellular/immunotherapies.
Nowhere is this circumstance more apparent than at the imminent collision of ASCT with chimeric antigen receptor (CAR) T-cell therapy. With two recently approved CAR T therapies targeting B-cell maturation antigen (BCMA), this novel platform has altered the treatment paradigm for heavily-pretreated patients with MM. The logical progression is to investigate if CAR T-cell therapy can challenge and supplant ASCT (with or without maintenance therapy) as a principal component of frontline MM therapy.
At the 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022), Amrita Krishnan, MD, Director of the Judy and Bernard Briskin Center for Multiple Myeloma Research, professor, Department of Hematology & Hematopoietic Cell Transplantation, and chief, Division of Multiple Myeloma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Cancer Center will debate this topic with Saad Z. Usmani, MD, MBA, FACP, chief, myeloma service, Memorial Sloan Kettering Cancer Center, New York, New York.
Krishnan is in favor of ASCT followed by maintenance therapy, but Usmani believes that CAR T-cell therapy will replace it. The hurdles that CAR T-cell therapy must overcome to replace ASCT are substantial, not only because of the proven efficacy of ASCT compared with other therapies but also because of ASCTs toxicity profile, the known effectiveness of subsequent therapies, and the favorable financial burden in comparison with CAR T-cell therapy. The debate will be September 29, 2022, at 1:58 pm during the meetings Multiple Myeloma session.
Evidence Supports Autologous Stem Cell Transplantation as the Current Standard for Frontline Consolidation
In the era predating novel MM therapies, the MRC Myeloma VII trial (NCT00002599) and an Intergroupe Francophone du Mylome (IFM; IFM2009) trial demonstrated an overall survival (OS) benefit of ASCT-based frontline therapy compared with prolonged nonmyeloablative conventional chemotherapy.4,5 The subsequent introduction of highly effective novel therapies led to similar studies comparing transplant and nontransplant frontline strategies (Table 16,7,8). The IFM 2009 study examined lenalidomide-bortezomib-dexamethasone (RVD) induction followed by ASCT vs RVD for 8 cycles without ASCT, with both arms receiving 1 year of lenalidomide maintenance.6,7 Although the primary end point of progression-free survival (PFS) was superior in the transplant arm, OS has remained statistically comparable. It results in part from the increased utilization of ASCT at first relapse among the nontransplant cohort (76.7%), but also the expansion of novel and immunotherapies available as salvage options. This study established that ASCT could be performed in the front line or at first relapse without sacrifice.
More recently, the phase 3 DETERMINATION study (NCT01208662) compared similar cohorts with those of IFM2009, with both arms receiving maintenance lenalidomide until progression or intolerance.8 Overall, the findings were similar to IFM2009 with superior PFS and comparable OS between cohorts. Notably, however, among patients with high-risk cytogenetics, ASCT yielded a particularly superior median PFS (55.5 months vs 17.1 months) and 5-year OS (63.4% vs 54.3%). To date, only a minority of patients at first relapse have received a subsequent ASCT (28%), although this proportion is expected to increase with longer follow-up.
Current State of CAR T as a Standard Therapy for Advanced Myeloma
CAR T therapy has revolutionized the treatment of advanced, relapsed/refractory MM, with the addition of 2 approved agents, idecabtagene vicleucel (ide-cel; Abecma) and ciltacabtagene autoleucel (cilta-cel; Carvykti); others are in clinical development.9 Ide-cel, in the pivotal phase II KarMMa trial (NCT03361748), yielded a median PFS of 8.6 months in a heavily pretreated patient population.10,11 At a median follow-up of 28 months in a similarly refractory cohort from CARTITUDE-1 (NCT03548207), the median PFS of cilta-cel had not yet been reached at the last analysis, with a 2-year PFS of 60.5% (Table 2).12,13 Responses with these cellular therapies are deep, especially with cilta-cel, for which recent highlights reported 55% sustained minimal residual disease (MRD) negativity (10-5) for 12 months or more, correlating with a 79% 2-year PFS.
Although ide-cel and cilta-cel are now established as a standard therapy option for eligible patients with triple-class refractory MM, data on earlier use are immature. CARTITUDE 2 (NCT04133636), a multiarm exploratory phase 2 trial, has reported early results from deploying cilta-cel in patients with 1 to 3 prior lines of therapy (cohort A) and patients with early relapse after 1 line of therapy (cohort B), both with complete response (CR) rates exceeding 80% and 6-month PFS rates exceeding 90%.14,15 However, the most provocative arm is exploring substitution of cilta-cel for ASCT as consolidation (Cohort E), which has yet to report findings. KarMMa-4 is similarly examining ide-cel for frontline consolidation in high-risk populations in lieu of ASCT.16 Although results of these studies will yield some insight into the feasibility of CAR T replacing ASCT, they are not powered to answer that question. The upcoming international phase III CARTITUDE-6/EMN trial (NCT05257083), however, will directly compare ASCT with cilta-cel, both following daratumumab plus RVD induction, in a study powered to assess coprimary end points of PFS and sustained MRD-negative CR (10-5 for 12 months).
The Imminent Collision between CAR T-cell Therapy and ASCT
CARTITUDE-6, and others pitting CAR T-cell therapy against ASCT as consolidation, will be required to answer questions beyond comparative efficacy. Whereas the cellular component of ASCT is solely for hematopoietic rescue, to date, the impact of intensive induction therapy on CAR T-cell therapy production, expansion, and function remains unclear, both from the standpoint of potential T-cell impairment and reduced in vivo antigenic stimulation.17
The toxicity profile of consolidative ASCT is well established and generally confined to the acute setting. Among 15,999 patients reported to the Center for International Blood and Marrow Transplant Research who received high-dose melphalan with ASCT between 2013 and 2017, 100-day nonrelapse mortality was 0% in those younger than 70 years and 1% among those 70 years or older.1 Among published studies, BCMA CAR T therapy has led to acute, life-threatening toxicities as well as delayed or prolonged adverse events such as cognitive and motor neurotoxicity, second primary malignancies, and delayed hematopoietic recovery.10,12 Although mitigation efforts have reduced immune-related toxicities, and fewer prior therapies will theoretically result in more resilient immune and hematopoietic systems, this residual robustness of the autologous CAR T-cell therapy cells could potentially raise the risk of immune-related toxicity in a relatively treatment-nave population.
Although ASCT with maintenance has long been the standard, substantial evidence exists demonstrating the efficacy of subsequent therapies after relapse.6 Frontline CAR T studies must also demonstrate that early use of CAR T-cell therapy does not impair therapies deployed after relapse, including stem cell collection and ASCT; therefore, PFS2 (time to second objective disease progression) and OS are imperative secondary end points.
High-dose melphalan with ASCT does have a transient negative impact on quality of life (QOL) metrics.18 Pivotal BCMA CAR T-cell therapy studies reported improvements in QOL, although many patients had advanced, symptomatic disease and the studies lacked control groups.19 Whether CAR T-cell therapy can meaningfully improve QOL among patients with controlled disease relative to standard of care remains to be seen.
Beyond PFS, all of the abovementioned end points (toxicity, QOL, OS, PFS2) are needed to gauge the relative efficacy and cost-effectiveness of these 2 modalities.20 With an established median PFS exceeding 5 years, a survival benefit among those with high-risk cytogenetics, manageable and predictable toxicity, and total treatment cost representing a fraction of that of CAR T-cell therapy, ASCT with maintenance is unlikely to be overtaken as frontline consolidation. Unless CAR T can effectively cure a substantial proportion of patients with MM, it would best serve patients as a complement to ASCT after relapse or potentially for those with suboptimal response to ASCT.
See more here:
In Multiple Myeloma, Will ASCT Survive Collision With CAR T-Cell Therapy? - Targeted Oncology
- Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $0 Thousand by 2027 - Yahoo Finance - October 13th, 2022
- Paris-based startup Gourmey uses the Big Idea Ventures accelerator program as a launch pad and goes on to raise the world's largest cultivated meat... - October 13th, 2022
- The New York Stem Cell Foundation Mourns the Loss of CEO Susan L. Solomon - October 4th, 2022
- The global live cell imaging market is expected to grow at a CAGR of 8.44% during 2022-2027 - Benzinga - October 4th, 2022
- Sernova to Participate in the Roth Inaugural Healthcare Opportunities Conference - Sernova (OTC:SEOVF) - Benzinga - October 4th, 2022
- New Study Finds Mouse Embryonic Stem Cells Have No Special - September 25th, 2022
- GMAs Robin Roberts replaced by Cecilia Vega as host is still absent from morning show following emotional... - The US Sun - September 25th, 2022
- Severe COVID-19 caused by senile interferon response in older patients, researchers suggest - EurekAlert - September 25th, 2022
- Money on the Move: Arsenal, ILiAD and a Hefty Gift to UCSD - BioSpace - September 8th, 2022
- How surviving cancer changed this 34-year-olds attitude toward work: The concept of checking email was laughable - CNBC - September 8th, 2022
- Garuda Therapeutics Announces Appointment of Roger Sawhney, M.D., as Chief Financial Officer - Benzinga - September 8th, 2022
- 6 Ingredients to Avoid Putting on Your Skin - Healthline - September 8th, 2022
- Scientists create 'synthetic' embryo with brain, beating heart in 'world first' - New York Post - August 30th, 2022
- Global Cell Banking Outsourcing Market to Grow at a CAGR of ~18% during 2022-2031; Market to Expand Owing to the Development of Advanced Cell... - August 30th, 2022
- Pelvic Reconstruction Market is projected to reach a valuation of US$ 366.9 million by 2032, at a CAGR of 2.8% during 2022-2032 Future Market... - August 30th, 2022
- Global Mesenchymal Stem Cell (MSC) Market to Grow at a CAGR of ~14% during 2022-2031; Market to Grow on the Back of Increasing Prevalence of Chronic... - August 5th, 2022
- Pigs died after heart attacks. Scientists brought their cells back to life. - Popular Science - August 5th, 2022
- Global Hematopoietic Stem Cell Transplant (HSCT) Market to be Driven by Increasing Prevalence of Blood Ca - Benzinga - August 5th, 2022
- Why Are There so Many Books and Shows About Cannibalism? - The New York Times - July 27th, 2022
- Cell Culture Media Market: Competitive Approach, Breakdown And Forecast by 2027 - Digital Journal - July 27th, 2022
- Herminia Pasantes revealed one of taurines big roles in the brain - Science News Magazine - July 27th, 2022
- Shai Efrati, MD, the World's Leading Research Scientist and Innovator in Hyperbaric Medicine, to Keynote at the Global Wellness Summit - PR Web - July 27th, 2022
- Journalist Benita Alexander reveals chilling clue that told her Miracle Man Paolo Macchiarini was a rom... - The US Sun - July 27th, 2022
- Melanoma Kills Nearly Twice The Number Of Men Than Women: Study - Kaiser Health News - July 19th, 2022
- Patients have turned to pricey 'blood washing' to treat long COVID - New York Post - July 19th, 2022
- Affimed Presents Preclinical Data of Novel Innate Cell Engager AFM28 at the Annual Meeting of the European Hematology Association (EHA) -... - July 11th, 2022
- Interferons Market is anticipated to reach US$ 13.8 Bn by 2032, at a CAGR of 3.9% from 2022 to 2032 - Digital Journal - July 11th, 2022
- 'World's Greatest Tuba-Playing Car Salesman' Bounces Back after Leukemia, Thanks to Wilmot Team - URMC - July 3rd, 2022
- Hadjiargyrou Is New York Tech's First Distinguished Professor | Box | New York Tech - New York Institute of Technology - July 3rd, 2022
- The global tissue engineering market is anticipated to reach US$ 13,236.87 million in 2022 and is project - Benzinga - July 3rd, 2022
- He Helped Cure the London Patient of H.I.V. Then He Turned to Covid. - The New York Times - June 13th, 2022
- Biden to Pause New Solar Tariffs as White House Aims to Boost Adoption - The New York Times - June 13th, 2022
- Gamida Cell to Present Corporate Highlights at the Jefferies Healthcare Conference - Business Wire - June 4th, 2022
- ReCode Therapeutics to Present at Jefferies Healthcare Conference - Benzinga - Benzinga - June 4th, 2022
- A Medical History of Transplant Surgery Thats Not for the Squeamish - The New York Times - May 15th, 2022
- Mesenchymal Stem Cells Market to Witness Growth Acceleration | Celprogen Inc., Thermo Fisher Scientific, Inc. Queen Anne and Mangolia News - Queen... - May 15th, 2022
- CORRECTING and REPLACING Paracrine Announces Appointment of Biotech Veteran David H. Crean, Ph.D. to the Board of Directors - Business Wire - May 15th, 2022
- William Blair Begins Coverage on Century Therapeutics (NASDAQ:IPSC) - Defense World - May 15th, 2022
- Aging Brain Initiative awards fund five new ideas to study, fight neurodegeneration - MIT News - May 2nd, 2022
- Treadwell Therapeutics Announces Fast Track Designation Granted by the FDA to CFI-400945 for the Treatment of Acute Myeloid Leukemia - PR Newswire - May 2nd, 2022
- What's Trending in the World of Hair Treatments - NewBeauty Magazine - May 2nd, 2022
- Demand in the US Animal Model Market is set to Increase at a 4.1% CAGR from 2022 to 2032 - Future Market Insights - PR Newswire - May 2nd, 2022
- Actinium Pharmaceuticals, Inc. and Immedica Announce Commercialization Agreement for Iomab-B (131I apamistamab) in Europe, the Middle East and North... - April 19th, 2022
- BioCardia Announces New Center for Medicare and Medicaid Services Reimbursement Code Applicable to the CardiAMP Cell Therapy Procedure - GlobeNewswire - March 25th, 2022
- Hoth Therapeutics Announces it Has Successfully Completed Manufacturing Feasibility of the HT-KIT Drug Substance - Yahoo Finance - March 25th, 2022
- Emendo Biotherapeutics and Seattle Children's Research Institute Announce Collaboration to Develop CRISPR-based Therapeutic Strategy for Severe... - December 24th, 2021
- 2021: The year in review | YaleNews - Yale News - December 24th, 2021
- 15 Truly Unbelievable Ways Science Changed the World in 2021 - Fatherly - December 24th, 2021
- Cargo Dragon Docks to Station with Brand New Science - NASA - December 24th, 2021
- Adaptation Is Key to Advancing Care for Adult Patients With Leukemia - OncLive - December 24th, 2021
- Cytovia Therapeutics' Scientific Leadership to Present at Upcoming Conferences - Business Wire - December 10th, 2021
- A New Stem-Cell Treatment Looks to Have Cured a Man of Type 1 Diabetes - Good News Network - December 10th, 2021
- BrainStorm Cell Therapeutics and Catalent Announce Completion of Technology Transfer for NurOwn Manufacturing - PRNewswire - December 10th, 2021
- Affimed to Host Virtual Investor Call Today to Discuss Treatment of CD30-positive Lymphoma ... - The Bakersfield Californian - December 10th, 2021
- No animals harmed in new chip drug tests that are faster and cheaper - ISRAEL21c - December 10th, 2021
- Stem Cell Therapy for Heart Failure Reduced Major Cardiac Events and Death - Diagnostic and Interventional Cardiology - November 22nd, 2021
- Global Cord Blood Stem Cells Market With An Annual Growth Rate, The Impact Of Covid-19: FAQ The UK Directory - The UK Directory - November 22nd, 2021
- The Beauty Products Violet Greys Cassandra Grey Uses to the Last Drop - The Cut - November 22nd, 2021
- Cellectis to Present Preclinical Data on UCARTMESO Supporting Anti-Tumor Activity at the Society for Immunotherapy of Cancer (SITC) 36th Annual... - October 16th, 2021
- Holy wars against vaccines and science People's World - People's World - October 16th, 2021
- Judge Rules to Uphold Religious Exemption to NY Vax Mandate - wnbf.com - October 16th, 2021
- Investigators Aim to Fill Unmet Need of Intermediate- to High-Risk MDS With ENHANCE Trial - OncLive - October 16th, 2021
- Healthcare Researchers Are Putting HUMAN Immune Systems In Pigs To Study Illnesses-Here's The Tech Behind It - Tech Times - October 5th, 2021
- Losing Your Hair? You Might Blame the Great Stem Cell Escape. - The New York Times - October 5th, 2021
- BrainStorm to Present at the 2021 Cell & Gene Meeting on the Mesa - KKTV 11 News - October 5th, 2021
- Coronavirus: What's happening in Canada and around the world on Tuesday - CBC.ca - October 5th, 2021
- Why Bezos, Musk, Page and other billionaires want to live forever - New York Post - October 5th, 2021
- Court hears dispute over N.Y. healthcare workers seeking COVID vaccine religious exemption - Washington Times - October 5th, 2021
- Glioma subtype may hold the secret to the success of immunotherapies - Michigan Medicine - October 5th, 2021
- Vera Nall: Misinformation will kill us in Southwest Missouri - Joplin Globe - October 5th, 2021
- Meet the Newest Group of Tenured, Tenure-Track Faculty at UT Dallas - University of Texas at Dallas - October 5th, 2021
- Global Stem Cell Banking Market to Reach US$11.3 Billion by the Year 2027 - Yahoo Finance - August 5th, 2021
- COVID-19 Antibody Therapy Now Available For Treatment and Post-Exposure Prophylaxis - PrecisionVaccinations - August 5th, 2021
- Primary Cells Market Research Report by Origin, by Cell Type, by End-user, by Region - Global Forecast to 2026 - Cumulative Impact of COVID-19 - Yahoo... - August 5th, 2021
- BeyondSpring Announces Positive Topline Results from its DUBLIN-3 Registrational Trial of Plinabulin in Combination with Docetaxel for the Treatment... - August 5th, 2021
- 5 days, 11 life science IPOs & more than $1.3B in new capital - MedCity News - August 5th, 2021
- What Its Like To Have Severe Iron Deficiency Anemia - Scary Mommy - August 5th, 2021
- 'Black fungus' infections on the rise in India: report - New York Post - June 23rd, 2021
- Global Cord Stem Cell Banking Market Status, Business Trends, Competitive Analysis, Growth Factors and Forecasts To 2028||Cryo-Cell International,... - June 23rd, 2021
- Turning to Books to Grasp the Most Ungraspable Disease - The New York Times - June 23rd, 2021