Blood Cancer Talks Rajshekhar Chakraborty, Ashwin Kishtagari, and Edward Cliff

In this episode, we dive into updates in Minimal Residual Disease (MRD) in multiple myeloma, along with the FDA ODAC meeting in April 2024 to decide on MRD as a surrogate endpoint for accelerated approval. Our guests are Dr. Benjamin Derman and Dr. Manni Mohyuddin. Here are the key papers we discussed:
1.      Recording of FDA ODAC meeting: https://www.youtube.com/watch?v=pooME9gMaL0
2.     EVIDENCE meta-analysis on individual-level and trial-level correlation between MRD and PFS/OS in multiple myeloma: https://pubmed.ncbi.nlm.nih.gov/38768337/
3.     Predictors of un-sustained MRD-negativity in multiple myeloma: 
a)     Secondary analysis of FORTE trial: https://pubmed.ncbi.nlm.nih.gov/38048557/
b)     Secondary analysis of GEM2012MENOS65 and GEM2014MAIN trials: https://pubmed.ncbi.nlm.nih.gov/38048552/
4.     Kinetics of MRD resurgence and subsequent relapse in multiple myeloma: https://pubmed.ncbi.nlm.nih.gov/34807986/
5.     MRD2STOP trial (MRD-guided maintenance discontinuation): https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.106
6.     MRD-guided maintenance discontinuation in myeloma (Secondary analysis of GEM2012MENOS65 trial): https://pubmed.ncbi.nlm.nih.gov/37506339/
 

In this episode, we discuss updates in primary myelofibrosis with Dr. Ayalew Tefferi from the Mayo Clinic. The key studies and trials discussed are as follows:
 
·       GIPSS: Genetically inspired prognostic scoring system that is exclusively based on genetic markers.
 
§  https://www.nature.com/articles/s41375-018-0107-z
 
·       MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis
 
§  https://ascopubs.org/doi/10.1200/JCO.2018.78.9867?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
 
·       TRANSFORM-1: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Phase 3 Study of Navitoclax in Combination with Ruxolitinib Versus Ruxolitinib Plus Placebo in Patients with Untreated Myelofibrosis
 
§  https://ashpublications.org/blood/article/142/Supplement%201/620/502738/Transform-1-A-Randomized-Double-Blind-Placebo
 
·       MANIFEST-2: Pelabresib in Combination with Ruxolitinib for Janus Kinase Inhibitor Treatment-Naïve Patients with Myelofibrosis: Results of the MANIFEST-2 Randomized, Double-Blind, Phase 3 Study
 
§  https://ashpublications.org/blood/article/142/Supplement%201/628/502728/Pelabresib-in-Combination-with-Ruxolitinib-for
 
·       XPORT-MF-034: Selinexor Plus Ruxolitinib in JAK Inhibitor (JAKi)-Naïve Patients with Myelofibrosis: Long Term Follow up from XPORT-MF-034 Suggestive of Disease Modification
 

In this episode, we dive into the data on maintenance therapy in multiple myeloma with Dr. Hira Mian and Dr. Manni Mohyuddin. Here are the key studies we discussed:
1. Meta-analysis of individual patient-level data from CALGB, IFM, and Italian maintenance RCTs (lenalidomide vs placebo or observation): 
https://pubmed.ncbi.nlm.nih.gov/28742454/
 
2. Myeloma XI RCT (lenalidomide vs observation): https://pubmed.ncbi.nlm.nih.gov/30559051/
 
3. Outcomes of lenalidomide maintenance stratified by cytogenetic subgroups (Secondary analysis of Myeloma XI): https://pubmed.ncbi.nlm.nih.gov/36564045/
 
4. Canadian real-world data on lenalidomide maintenance: https://pubmed.ncbi.nlm.nih.gov/33054120/
 
5. FORTE trial (Carfilzomib-Lenalidomide vs Lenalidomide): https://pubmed.ncbi.nlm.nih.gov/34774221/
 
6. ATLAS trial (Carfilzomib-Lenalidomide-Dexamethasone vs Lenalidomide): https://pubmed.ncbi.nlm.nih.gov/36642080/
 
7. Differential censoring and potential impact on PFS in ATLAS trial: https://pubmed.ncbi.nlm.nih.gov/37433885/
 
8. GEM2014 (Ixazomib-Lenalidomide-Dexamethasone vs Lenalidomide-Dexamethasone): https://ashpublications.org/blood/article-abstract/142/18/1518/497188
 
9. MASTER trial (MRD-guided treatment de-escalation): https://pubmed.ncbi.nlm.nih.gov/37776872/
 
10. Outcomes after MRD-guided treatment discontinuation (Secondary analysis of GEM2014MAIN trial): https://pubmed.ncbi.nlm.nih.gov/37506339/

In this episode, we discuss the diagnosis and management of Essential Thrombocythemia with Dr. Raajit Rampal. Here are the shownotes:1.     IPSET (revised) system, risk categories are defined by the presence of a prior thrombosis, age, and JAK2 mutation status:
·        Very low risk: No prior thrombosis, age ≤60 years, JAK2-unmutated
·        Low risk: No prior thrombosis, age ≤60 years, JAK2-mutated
·        Intermediate risk: No thrombosis, age >60 years, JAK2-unmutated
·        High risk: History of thrombosis (any age/genotype), or age >60 years with JAK2 mutation
https://ashpublications.org/blood/article/120/26/5128/30914/Development-and-validation-of-an-International
                      
2.    The MIPSS-ET provides points for:
·        Age > 60 years (3 points)
·        Adverse mutation (SF3B1/SRSF2/U2AF1/TP53) (2 points)
·        Male sex (1 point)
·        White blood cell count ≥11 × 10^9/L (1 point)
·        https://onlinelibrary.wiley.com/doi/abs/10.1111/bjh.16380?sid=nlm%3Apubmed
 
3.    Aspirin
 
o   Is there a benefit of twice-daily aspirin dosing, especially in high-risk or JAK2-mutant disease?
https://ashpublications.org/blood/article/136/2/171/454293/A-randomized-double-blind-trial-of-3-aspirin
 
4.     Cytoreduction in High-risk ET 
Hydroxyurea: https://www.nejm.org/doi/full/10.1056/NEJM199504273321704
 
Pegylated interferon alfa
 
MPD-RC 112 Mascarenhas J et al. A randomized phase 3 trial of interferon- α vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood . 2022) 
https://ashpublications.org/blood/article/139/19/2931/483404/A-randomized-phase-3-trial-of-interferon-vs
 
Anagrelide in ET
https://ashpublications.org/blood/article/121/10/1720/31186/Anagrelide-compared-with-hydroxyurea-in-WHO
 
5.    Ruxolitinib  
In a randomized study phase 2 study (MAJIC-ET), ruxolitinib treatment did not deliver better rates of hematological response than best-available therapy, although symptoms did improve. 
 
·        MAJIC-ET study which is a randomized phase 2 trial 
·        ET patients resistant/intolerant to HU were randomized to receive RUX or standard treatment (HU 71%, anagrelide 48%, IFN 40%). The primary study outcome was CR, defined by normal platelet and white cell counts and normal spleen size.  
·        At 1 year, response was achieved in 46% of patients in the RUX group and in 44% in the standard arm, without statistically significant difference between the two groups.  
·        In addition, no difference was observed in the rates of thrombosis, hemorrhage, and disease transformation after 2 years of follow-up.  
·        MRs were also uncommon. RUX was superior, however, in symptom control. 
https://ashpublications.org/blood/article/130/17/1889/36509/Ruxolitinib-vs-best-available-therapy-for-ET

In this episode, we talked about overall survival data from CARTITUDE-4 and KarMMa-3 that was presented at FDA ODAC meeting with Dr. Samer Al Hadidi from University of Arkansas Myeloma Center. 
RCTs of BCMA CAR T-cell Therapy in Early Relapsed Multiple Myeloma:
a) KarMMa-3 (ide-cel): https://pubmed.ncbi.nlm.nih.gov/36762851/
b) CARTITUDE-4 (cilta-cel): https://pubmed.ncbi.nlm.nih.gov/37272512/
FDA ODAC on overall survival data from KarMMa-3 and CARTITUDE-4:https://www.youtube.com/watch?v=VSjdGeeXb40

In this episode, we discuss mentorship and career development as a clinician-investigator with Dr. Ayalew Tefferi from the Mayo Clinic.