MSK ASH 2024 Research Roundup: Practice-Changing Advances in Leukemia, Lymphoma, and Multiple Myeloma

Memorial Sloan Kettering Cancer Center (MSK) researchers presented results of their latest research at the 66^th American Society of Hematology (ASH) Annual Meeting and Exposition held in San Diego from December 7 to 10, 2024.

Highlights of practice-changing insights for patients with multiple myeloma, chronic lymphocytic leukemia, and acute myeloid leukemia were as follows:

Multiple Myeloma: A High-Fiber Dietary Intervention May Delay Smoldering Myeloma from Progressing

For patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), an elevated body-mass index (BMI) over 25 kg/m² in confers a two-fold higher risk of progression to multiple myeloma (MM). 

MSK myeloma specialist Urvi Shah, MD, presented findings of the Nutrition Prevention (NUTRIVENTION) Study, the first investigator-initiated pilot study (NCT04920084) investigating the feasibility of a high-fiber, plant-based dietary intervention in patients with MGUS or SMM and an elevated BMI. 

A total of 20 MSK patients received self-selected frozen lunches and dinners provided weekly for three months, along with guidance for breakfast and snacks and nutrition coaching for six months. Patients had no calorie restriction. 

Overall, the high-fiber, plant-based diet met its primary endpoint with high adherence to minimally processed plant foods (mean increase from 25% at baseline to 89% at 12 weeks) and sustained BMI reduction (mean reduction of 8% at 12 weeks).

The intervention was safe, improved the quality of life, and addressed several modifiable factors that increase the risk of progression to MM. Specifically, it improved the metabolic profile (BMI, insulin resistance, adiponectin-leptin ratio), the fecal microbiome profile (increased alpha-diversity and butyrate producers), and immune markers (decreased inflammation and increased anti-inflammatory classical monocytes). The trajectory of long-term disease progression improved in two patients. 

Human bone marrow and peripheral blood analyses indicated that the dietary intervention reduced inflammatory biomarkers, such as c-reactive protein, neutrophil count, and increased anti-inflammatory classical monocytes. Bone marrow immune cell interaction between myeloid cells (including monocytes) showed interaction with exhausted CD8 T cells at baseline and with cytotoxic CD8 T cells and CD56^dim natural killer cells at one year, suggesting enhanced anti-tumor immunity.

These findings were confirmed in a smoldering myeloma mouse model in the Bellone Lab at IRCCS Ospedale San Raffaele in Milan: for mice fed a high-fiber diet, 44% did not progress to myeloma and progression-free survival (PFS) was 30 weeks, whereas all mice in the standard diet group did progress to myeloma and PFS was 12 weeks. These benefits were independent of calorie restriction-induced weight loss. The microbiome and immune changes in mice after the intervention were consistent with the human trial. 

Dr. Shah is also principal investigator of the NUTRIVENTION-3 study, a large, randomized trial (NCT0560843) comparing a high-fiber, plant-based diet with curcumin and algae omega-3 supplements with placebo in patients with MGUS or SMM. The trial is ongoing and actively recruiting at seven MSK locations.  

Read ASH 2024 Abstract 671. Review a preprint of the study. The study was funded by the Allen Foundation Inc, the Paula and Rodger Riney Foundation, the National Cancer Institute, the American Society of Hematology, the Solomon Fund, the AIRC Foundation for Cancer Research, and the Leukemia and Lymphoma Society. Explore MSK clinical trials for patients with multiple myeloma. Access disclosures for Dr. Shah.

Chronic Lymphocytic Leukemia: A Shorter Duration of Front-Line Venetoclax and Obinutuzumab for Fit Patients using Measurable Residual Disease

Venetoclax and obinutuzumab is an effective, one-year, fixed-duration treatment for patients with chronic lymphoblastic leukemia (CLL). Extended follow up of the CLL14 study (NCT02242942) showed that undetectable minimal residual disease (uMRD) at the end of treatment predicts longer progression-free survival (PFS).

MSK leukemia specialist Meghan Thompson, MD, presented results from a phase 2, investigator-initiated study (NCT04447768) that tested whether the duration of venetoclax plus obinutuzumab treatment could be tailored according to individual patients’ depth of response as measured by peripheral blood MRD testing. Patients received either 9, 12 or 24 cycles of venetoclax based on MRD status in the peripheral blood at planned timepoints during treatment.

The study has accrued 100 patients with CLL requiring first-line treatment. At a median follow-up of 27 months, the estimated two-year PFS was 92% and OS was 95% for the entire cohort. As of the data cut off, 50 patients were confirmed to have uMRD at a sensitivity of 10^-6 (uMRD6) in the peripheral blood at cycle 7 and 9 and discontinued venetoclax after 9 cycles of treatment, and 30 patients were confirmed to have uMRD at a sensitivity of 10^-5 (uMRD5) at cycle 12 and discontinued venetoclax after 12 cycles of treatment. Early discontinuation of venetoclax plus obinutuzumab after 9 cycles for patients with uMRD6 achieved a similar PFS as patients who completed 12 cycles and had uMRD5 status before entering a period of treatment-free observation.

Dr. Thompson anticipates that longer follow-up from this study will provide more insights into the durability of responses for patients who discontinued venetoclax after 9 cycles of therapy and more information regarding the impact of additional treatment with venetoclax and obinutuzumab beyond 12 cycles for patients with detectable MRD at cycle 12 (10^-5 sensitivity).

Read ASH 2024 Abstract 1010. Explore MSK clinical trials for patients with CLL. Access disclosures for Dr. Thompson.

Acute Myeloid Leukemia: Similar Outcomes for Outpatient versus Inpatient Consolidation

Standard management for non-adverse risk acute myeloid leukemia (AML) in fit patients is intensive induction chemotherapy followed by consolidation with post-remission high-dose cytarabine (HiDAC). Historically, HiDAC has been administered in the inpatient setting given associated prolonged cytopenias, infection risk, transfusion and supportive care needs, as well as logistical challenges of outpatient chemotherapy.

However, improvements in antimicrobial prophylaxis plus the increased risks of nosocomial infection and financial burden associated with prolonged hospitalizations have highlighted the potential role for outpatient chemotherapy. To date, there are limited data supporting the use of inpatient versus outpatient HiDAC administration.

MSK medical oncology/hematology fellow Leora Boussi, MD presented results from a study that investigated differences in outcomes for outpatient versus inpatient HiDAC for patients who received the treatment at MSK between January 2014 and June 2023. Among 198 patients in total, 70% received outpatient HiDAC and 30% received inpatient HiDAC.

The study found that outpatient HiDAC administration is safe and cost-effective without an increased risk of major treatment-related complications, and that inpatient HiDAC administration is associated with increased hospitalization days per cycle and higher total treatment cost. The incidence of admission for febrile neutropenia and rates of major bleeding, ICU admission, and death during treatment were comparable between the inpatient and outpatient groups.

Read ASH 2024 Abstract 445. Explore MSK clinical trials for patients with AML. Refer to the abstract for disclosures.

Other Notable MSK Research News from ASH 2024:

• Multiple Myeloma: Immune-MRD Status Informs Tumor-MRD Outcome Prognosis in Patients on Lenalidomide Maintenance. MSK hematology-oncology fellow Ross Firestone, MD, PhD, presented a translational study using samples from 108 MSK patients with MM followed prospectively in a phase 2, five-year study of continuous lenalidomide (Len) maintenance. Using high-dimensional T cell profiling, the investigators identified an immune signature of functional high-risk disease that was independent of dynamic tumor MRD status. This immune signature, defined by an activated T cell landscape enriched in differentiated effector cells, was associated with early relapse even in patients with low or undetectable levels of disease, and may represent a novel predictive biomarker in MRD-negative patients on Len maintenance. Read ASH 2024 Abstract 672. Explore MSK multiple myeloma clinical trials.
   
• Multiple Myeloma: Whole Genome Sequencing Reveals Lower Mutational Activity in Patients with African American Ancestry Versus European Ancestry. MSK myeloma specialist Kylee Maclachlan, MBBCh, PhD, presented whole genome sequencing results from a large series of 340 samples from patients with MM or precursor disease. The study investigated differences in mutational activity in patients with African ancestry compared to those with European ancestry. In collaboration with the New York Genome Center and the Polyethnic-1000 consortium, Dr. Maclachlan and colleagues integrated somatic and germline ancestry data. Most biological disease features were the same between patient groups. However, while African ancestry patients had a higher polygenic risk score, European patients had a more complex genomic classification, higher pre-chromosomal-gain SBS9, reflecting higher early germinal cancer activity, more apolipoprotein B mRNA editing catalytic polypeptide-like (APOEBEC) activity, and more localized hypermutations associated with APOEBEC. The data indicated that germinal center interaction may be more intense for patients of European versus African ancestry. The overall lower genomic complexity in patients with African ancestry suggests that, with comparable treatment, these patients would be expected to have better clinical outcomes than a comparable group with European ancestry. Read ASH 2024 Abstract 766. Explore MSK multiple myeloma clinical trials. Access disclosures for Dr. Maclachlan.
   
• Chronic Lymphocytic Leukemia: Preliminary Phase 1 Trial Results for Novel BTK Degrader. MSK leukemia specialist Meghan Thompson, MD, presented preliminary data from the ongoing, open-label, phase 1 study of the novel Bruton tyrosine kinase (BTK) inhibitor BGB-16673 in heavily pre-treated patients with relapsed/remitting CLL (NCT05006716). The drug is a bivalent small molecule that degrades BTK by binding to BTK and the E3 ligase. Pre-clinical data has demonstrated the ability of BGB-16673 to degrade both wild-type and mutant BTK, including BTK mutants that may arise as mechanisms of resistance to covalent and non-covalent BTK inhibitors. Among 60 patients treated as of September 2024, the novel drug demonstrated a tolerable safety profile and showed promising and deep responses, including in patients treated with a prior BTK inhibitor and those with BTK resistance mutations. The overall response rate, defined as partial response with lymphocytosis or better, was 78%, with a median time to first response of 2.8 months. Read ASH 2024 Abstract 885. The study was sponsored by BeiGene. A phase 2 study in CLL patients is currently enrolling. Explore MSK clinical trials for patients with CLL. Access disclosures for Dr. Thompson.