March 11, 2019

Myeloma Center Staff Share Recent Discoveries at 2018 American Society of Hematology Conference

More than 30,000 clinicians and researchers gathered at the American Society of Hematology Conference in San Diego, California, this past December. Several representatives from the UAMS Myeloma Center presented a total of 24 abstracts on our recent discoveries, including three prestigious oral presentations. Here are lay summaries of those presentations:

 Personalized Therapy in Multicentric Castleman Disease Produces Excellent Outcomes in a Tertiary Referral Center

1Katie Stone, 1Francisco Socola, 1Amy Greenway, 1Samina Waheed, 1Kristen Carter, 1Diane Glendinning, 2Daisy Alapat, 1Frits van Rhee

The Myeloma Center is a center of excellence for research and treatment of Castleman Disease (CD), a rare inflammatory disorder that is characterized by enlarged lymph nodes. CD exists as a spectrum of related clinical entities sharing a similar pathology; some patients experience lymph node enlargement in a single lymph node or sometimes multiple nodes in a single area, while other patients present with enlarged lymph nodes in multiple anatomical sites such as the neck, armpits, or groin. These “multicentric” CD (MCD) patients experience variable disease severity, ranging from mild, easily managed symptoms, to multi-organ failure and risk of death. Statistical assessment of the clinical presentation, treatment, and outcome of CD has been difficult to perform due to the rarity of the disease. However, the UAMS Myeloma Center has treated a large number of CD patients, allowing us the ability to evaluate these data and share our clinical experience with other CD clinicians and researchers. Our data was presented at the 2018 meeting of the American Society of Hematology held December 1-4, 2018 in San Diego, CA, and a full-length peer-reviewed journal article is in preparation.

We reported on 76 MCD patients, the largest series from a single institution. Data was collected from our institution and outside records via systematic chart review and standardized survey for self-reported symptoms. These patients were sorted into groups based on their particular subtype of MCD, and groups were compared. Notable results include differences in symptoms, laboratory values, and disease severity score among subgroups, with a particular variety called TAFRO-iMCD (characterized by low platelet counts, large amounts of fluid retention, fever, bone marrow changes, and enlargement of the liver and/or spleen) exhibiting the most severe disease symptoms. We also studied the kinds of therapy that have been used to treat MCD patients and outcomes for each. We found that the largest numbers of patients have been treated with antibodies that block the effects of a growth factor called interleukin-6, followed by patients treated with rituximab (an antibody that targets B cells), and steroids. Most patients responded well to their treatment, with our longest patient follow up being nearly 25 years. The goal of this work is to better understand which therapies are best for different groups of CD patients based on their clinical presentation, which will ultimately help clinicians to assign therapy in a manner that is tailored to each patient’s disease.

 The Mutational Landscape of Primary Plasma Cell Leukemia

By Carolina Schinke, M.D.

Primary Plasma Cell Leukemia (pPCL) is a rare form of multiple myeloma (MM) that is characterized by an aggressive disease course with >20% peripherally circulating plasma cells (PCs) and poor clinical outcome. Despite the advances of modern anti-MM therapy, pPCL patients continue to experience low median overall survival (OS) suggesting a distinct biological background. Due to its low incidence of 1-2% of all MM patients, studies on physiopathology remain challenging and are limited.  The aim of this study was to elucidate the differences in biology and outcome between non-pPCL MM and pPCL, to determine the genetic landscape of pPCL and to identify distinct signatures and pathways that potentially could be used as therapeutic targets. In order to achieve this goal, we performed whole exome sequencing (WES) of 19 pPCL patients, which presents the largest pPCL patient cohort reported on to date. We show that pPCL is a highly complex disease that is enriched for adverse risk translocations, such as MAF and MYC translocations. High risk mutations are also more prevalent compared to non-pPCL MM, in particular TP53 and KRAS mutations as well as bi-allelic inactivation of TP53 were frequently seen. These alterations explain – at least in part – the aggressive disease behavior of pPCL. We did not find a mutation specific or pertinent to pPCL that would distinguish it from non-pPCL MM. It rather appears that pPCL is a disease highly enriched in high risk genomic MM alterations. Of all highly prevalent genomic alterations in pPCL, only KRAS mutations offer a potential for already available therapeutically targeting with MEK inhibitors, which should be further explored.

ORAL: Double-Hit, High-Risk Bi-Allelic Inactivation

By Cody Ashby, Ph.D.

Copy number changes and translocations have been studied extensively in many datasets with long term follow-up. The impact of mutations remains debated given the short time follow-up of most cohorts.

To answers this question, we performed targeted panel sequencing covering 140 myeloma specific genes and the translocations loci on 225 newly diagnosed myeloma samples recruited into one of the Total Therapy Trial. The median follow-up of patients was 8.14 years.

We thus confirmed the prognostic impact of the previously published “Double-Hit” whereby a high risk group is defined by either Biallelic TP53 inactivation or Amplification of CKS1B (≥ 4 copies) on the background of ISS III. Double-Hit comprises 8.5% of newly diagnosed MM patients and was associated with a poor outcome in terms of EFS and OS on univariate analysis.

Double Hit, BRAF and DIS3 mutations were independent markers of outcome alongside classical risk factors. Regarding BRAF, we were able to identify both V600E and non-V600E mutations, 58% of which were predicted to be hypo or inactivating. Interestingly, 47% of the inactive or hypoactive BRAF patients showed co-occurring alterations in KRAS, NRAS, and activating BRAF.

Overall, these data highlight the importance of mutational screening to better understand NDMM and may lead to patient specific mutation-driven treatment approaches

 

POSTER: Predicting the progression of smoldering to symptomatic myeloma in the era of novel IMWG criteria

By Eileen Boyle, M.D.

Despite novel International Myeloma Working Group (IMWG) criteria, Smoldering Myeloma (SMM) remains a heterogeneous disease for which correctly identifying patients that will eventually progress to myeloma (MM) is essential. The genetic and molecular factors that underlie disease progression are not well elucidated, therefore, we examined samples from SMM patients in order to identify molecular determinants of progression.

Targeted sequencing consisted of 140 genes and additional regions of interest for copy number, as well as tiling of the immunoglobulin and MYC loci for detection of translocations.

SMM appears less complex than MM with fewer mutations and copy number changes than MM. The nature of mutations and copy number changes are similar but differed in frequency with evidence for MAPK, NF-κB and DNA-repair pathway alterations.

The 5-year progression rate is 37% with no plateau suggesting an ongoing risk for progression.

KRAS mutations, del(1p), del(14q), and TP53 alterations can be used alongside GEP4 or classical tumor burden feature to predict outcome The presence of either event will translate in a 3.74 hazard ratio resulting in a median PFS of 4-year.

Overall we showed that we could identify molecular determinants of outcome in SMM that could help towards precision medicine.