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Highlights of Multiple Myeloma Research Presented at ASH With Urvi Shah, MD

At the recent American Society of Hematology (ASH) Annual Meeting, numerous updates were presented with the potential to impact practice in relapsed/refractory multiple myeloma. While at the meeting, Urvi Shah, MD, Assistant Attending in the Myeloma Service at Memorial Sloan Kettering Cancer Center, shares some of most significant highlights of the clinical trials and therapeutic agents being presented. After listening to the podcast, be sure to watch Dr. Shah's free CME activity or book a live meeting for your institution to hear more expert perspectives on new directions in multiple myeloma treatment!  

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're here live at the ASH Annual meeting, and I'm joined by Dr. Urvi Shah. Thank you so much for coming on today.

Urvi Shah, MD: Thank you, Keira. It's nice to be here.

Oncology Data Advisor: I'm looking forward to hearing about some of the research you're presenting at ASH, as well as the session you're moderating. To start off, would you like to tell us about the relapsed multiple myeloma session which you're moderating tomorrow and the abstracts that are being presented there?

Dr. Shah: Sure, that would be great. Maybe I'm biased, but the relapsed myeloma session seems to be where we get to hear about all the new drugs and the exciting things that are coming down the pike. In this session, we have six oral abstracts.

The first is a study from the Asian Myeloma Network, conducted in Singapore mainly. This was a phase 3 study looking at relapsed/refractory myeloma patients with prior proteasome inhibitor (PI) or lenalidomide exposure, but they were not exposed to pomalidomide. There were 122 patients who were randomized—about 60 in each arm—to get pomalidomide/cyclophosphamide/dexamethasone or pomalidomide/dexamethasone. These patients had received three prior lines of therapy. The primary objective was progression-free survival (PFS).

The median PFS on the interventional arm of pomalidomide/cyclophosphamide/dexamethasone was 10.9 months versus 5.8 months with pomalidomide/dexamethasone. The overall response rate was about 55% versus 32%, suggesting that the combination triplet is a good overall option that we could consider for patients. Overall, it was well-tolerated too.

The next abstract that was presented by Dr. Chari was looking at talquetamab dosing. The MonumenTAL-1 study looked at reduced and less frequent dosing of talquetamab to see if the responses were maintained or sustained long-term. The results are encouraging and suggest that the frequency of dosing can be reduced so that patients can tolerate these treatments better and reduce some of the treatment-related side effects as well with this less frequent dosing.

The third abstract was on sonrotoclax, which is a new next-generation BCL2 inhibitor. It is more potent and selective than the BCL2 inhibitor venetoclax. This drug was looked at in a phase 1b/2 study in relapsed/refractory myeloma patients with translocation (11;14) and who had received three or more lines of therapy. There were 19 patients treated in total, and the overall response rate was about 58%. In the higher dose cohort of 640 mg, the overall response rate was about 70%. The treatment was safe. Infections and cytopenias were the main issues, and I think they're planning their recommended phase 2 dose to be 640 mg. This looks like a promising new therapy with greater potency compared to venetoclax for t(11;14) myeloma. It's a new drug that could be used in patients with t(11;14) myeloma.

The next new drug that we heard about was HPN217, a TriTAC®. This is a trispecific antibody, so it actually targets BCMA and CD3 on T cells, as well as albumin in the blood. The reason for this trispecific nature is that if it's also binding to albumin, it's thought that this would prolong or extend the half-life of the drug. There were 97 patients total on this study with a dose escalation plan. The overall response rate was 55%, and it was well-tolerated. The dosing is every two weeks, given that it has this trispecific nature binding to albumin. That suggests that it makes it a bit less frequent and easier for patients. I think that there's still more for us to hear about that, but it's encouraging to see that we could do less frequent dosing.

The next abstract was on mezigdomide. Mezigdomide is a novel potent cereblon E3 ligase modulator (CELMoD™) with enhanced tumoricidal and immune modulatory effects compared to an immunomodulatory drug (IMiD) like lenalidomide and pomalidomide. In this study, they looked at mezigdomide/daratumumab/dexamethasone or mezigdomide/elotuzumab/dexamethasone in relapsed/refractory myeloma patients with two to four prior lines of therapy. There were about 59 patients in the mezigdomide/daratumumab/dexamethasone cohort.

The overall response rate ranged, based on the difference in frequency of dosing of mezigdomide, between 61% and 89%. The adverse events were mainly related to cytopenias, about 77%. The elotuzumab/dexamethasone arm had 20 patients, and the overall response rate was closer to 45% and similarly had about 91% of grade 3 to 4 treatment-emergent adverse events. I think the main thing with this drug is looking at the cytopenia risk and managing it, but otherwise it does have promising efficacy in these patient populations.

The the last abstract was looking at talquetamab, which, as you all know, is recently FDA-approved. This looked at it in combination with pomalidomide in the MonumenTAL-2 study. They presented the data from the cohort of talquetamab and pomalidomide in relapsed myeloma with two or more prior lines of therapy. There were two cohorts, one with 0.4-mg dosing once weekly and the other one with 0.8-mg dosing every two weeks. They saw some high-grade neutropenia, about 54%. Hypogammaglobulinemia was also seen, and 80% of patients had infections, 22% of which were grade 3 or 4. There's also quite a bit of dysgeusia, about 91%. This suggests that overall, while this is a drug that is effective and has a good likelihood of response, we still have to manage some of these side effects and see how tolerable it is. Most of the dysgeusia and skin nail side effects were all grade one or two.

That concludes all of the six oral abstracts being presented in this session. I think you will see a lot of new exciting combinations there, as well as new drugs.

Oncology Data Advisor: Amazing, that was such a helpful overview of these abstracts. It's so exciting to hear about all the new research. Thank you so much for summarizing everything for us. I'm also curious to hear about your paper on monoclonal gammopathy of undetermined significance (MGUS) and dietary factors that was recently published.

Dr. Shah: Yes, we're excited about this because there have really not been a lot of studies looking at dietary risk factors for MGUS, and there's not a lot of data available on this for patients. Patients ask this question all the time. Since more than 3% of the population over the age of 50 have this MGUS or smoldering myeloma, it is important to be able to understand what the modifiable risk factors could be for the development of this disorder.

In this study, we looked at a population of over 25,000 individuals who had been tested for MGUS through the surplus sera program. Amongst these 25,000 that had been tested, 373 cases of MGUS were present in that population. We matched these patients 1:4 with cases to controls, and we had about 1,406 controls that matched based on age, sex, race, body mass index (BMI), and National Health and Nutrition Examination Survey (NHANES) release time.

When we matched these patients, we also had a very diverse population, which is unusual for most studies. In the study, there were about 28% non-Hispanic Blacks and about 19% of races and ethnicities other than non-Hispanic Black or White. What we did in this study is we looked at the association of different food groups. Patients on the NHANES study had been asked to fill out or complete dietary recalls, where they talked about what they ate in the last 24 hours. This was done at multiple time points. We had dietary data predating the MGUS diagnosis or the sample collection.

What we saw was that soda, soft drinks, or artificially sweetened drinks and beverages were all associated with a higher risk of MGUS. This was in the range of 30% to 60% increased risk with these sugary drinks. Additionally, we also looked at other food-related factors that could lower risk. Consistently, we saw that vegetables, tomatoes, whole-wheat bread, fruits, vegetables, and cruciferous vegetables reduced the risk by about 30%.

This work was done in collaboration with Roswell Park and Memorial Sloan Kettering Cancer Institute. Janine Joseph, who works at Roswell Park, is the lead author and the last author on this paper. I think that this is very exciting data for us to look at, where we actually now have information to share and use to think about how we can reduce the risk of something that has a known risk of progression to myeloma.

Oncology Data Advisor: That's really fascinating to hear about. Thanks so much for sharing this one as well. Final question I'll ask you is about your poster, which you're presenting tomorrow, of the NUTRIVENTION trial. Would you like to tell us a little bit about this poster too?

Dr. Shah: The NUTRIVENTION trial is a study of patients with MGUS and smoldering myeloma. As we know, there's a lot of data around risk factors for cancer development, including dietary risk factors, microbiome, obesity, and diabetes. What we don't know is whether an interventional study can actually delay progression. In this study, we looked at patients with MGUS and smoldering myeloma with a BMI over 25. The reason we took patients with an elevated BMI is because we do know from other studies that have looked at associations that patients with an elevated BMI are twice as likely to progress to myeloma than somebody with a normal BMI.

We gave patients three months of a high-fiber, plant-based diet, gave them six months of coaching during that period, and then followed for a year on the study. These 20 patients actually had a mean BMI reduction of about 8.3% at three months, and this was sustained at one year as well through similar values. We saw an improvement in dietary compliance. Their unprocessed plant food intake at baseline was only 20%, similar to a Western diet. This improved to 90% on the study, but it was maintained even a year out, at about 70%.

We also saw an improvement in dietary fiber intake, which went up to the recommended daily allowance (RDA). We saw an improvement in insulin resistance and improvement in quality of life and global health status in the NUTRIVENTION study, as well as reduction of dyspnea and fatigue. All patients, when we surveyed them post-intervention, said this was somewhat or very easy to follow and that they would be interested in signing up again. The study also enrolled about 43% non-Hispanic White patients.

We saw an improvement in other biomarkers like the microbiome, improvement in gut microbiome diversity, improvement in the relative abundance of butyrate producers in the stool, and changes in immune function such as improvement in the monocytes fraction. The non-classical monocytes were reduced, and the classical or anti-inflammatory monocytes increased. Additionally, we had two patients who actually had rising M-proteins before going on the study, and with the sustained weight loss, we saw a slowing of their trajectory of the M-spike progression. We calculated the rate of change of M-spike for 20 months before and 20 months after, and we looked at the change in P value, which was significant.

With all of this, just to summarize, this weight loss, high-fiber dietary intervention did lead to improvements in insulin resistance and to microbiome changes such as improvement in gut microbiome diversity and butyrate producers, all things that we do know are associated with risk of progression and have been looked at in association studies. Additionally, we saw some immune changes as well as delayed progression for a few patients, which are encouraging findings. We are actually looking at this with a much bigger study called the NUTRIVENTION-3 study that's currently enrolling at Memorial Sloan Kettering. This includes patients with MGUS and smoldering myeloma with any BMI. We're looking at diet versus supplements—omega 3 and curcumin versus placebo supplements.

Hopefully in the next few years we'll have data on that, because the study's enrolling fast. If you ever have patients interested in participating, they would need to come to Memorial Sloan Kettering spread out over a year—six times—and we can get the intervention shipped to them anywhere across the country. They don't really need to be living in New York, but as long as they're willing to travel to see us about five to six times spread out across a year, we are able to make it work from anywhere across the country.

Oncology Data Advisor: That's amazing that you're able to ship it to them and make it so accessible. It's also great that the majority of the patients said it was easy to follow and that they would do it again. I'm sure that's a huge testament to the program itself.

Dr. Shah: I think it also made patients feel better, and their quality of life got better. I think that helps and motivates patients to continue it after the study too.

Oncology Data Advisor: Awesome. Thank you so much for talking to us today about the multiple myeloma research and your poster.

Dr. Shah: Thank you.

About Dr. Shah

Urvi Shah, MD, is an Assistant Attending in the Myeloma Service at Memorial Sloan Kettering Cancer Center and an Assistant Professor of Medicine at Weill Cornell Medical College. She specializes in the treatment of patients with multiple myeloma, smoldering myeloma, and related plasma cell disorders. Dr. Shah's clinical and translational research focuses on nutritional and metabolic factors in plasma cell disorders, as well as immune therapies. She is currently studying the link between nutrition and myeloma via immune, epigenetic, and microbiome mechanisms. In 2021, Dr. Shah opened the first nutrition trial in plasma cell disorders to date.

For More Information

Song Y, Kim JS, Chim CS, et al (2023). Randomized phase 3 study of pomalidomide cyclophosphamide dexamethasone (PCD) versus pomalidomide dexamethasone (PD) in relapse or refractory myeloma: an Asian Myeloma Network (AMN) study. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 1009. Available at: https://ash.confex.com/ash/2023/webprogram/Paper184723.html

Chari A, Oriol A, Krishnan A, et al (2023). Efficacy and safety of less frequent/lower intensity dosing of talquetamab in patients with relapsed/refractory multiple myeloma: results from the phase 1/2 MonumenTAL-1 study. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 1010. Available at: https://ash.confex.com/ash/2023/webprogram/Paper181228.html

Quach H, Sborov D, Kazandjian D, et al (2023). Sonrotoclax (BGB-11417) in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma with t(11;14): safety, efficacy, and determination of recommended phase 2 dose. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 1011. Available at: https://ash.confex.com/ash/2023/webprogram/Paper178735.html

Madan S, Costello CL, Lipe B, et al (2023). Results from the completed dose escalation portion of the phase 1 study of HPN217, a half-life extended tri-specific T cell activating construct (TriTAC®) targeting B cell maturation antigen (BCMA) for relapsed/refractory multiple myeloma (MM). Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 1012. Available at: https://ash.confex.com/ash/2023/webprogram/Paper182345.html

Richardson PG, Sandhu I, Hofmeister CC, et al (2023). Mezigdomide (MEZI) plus dexamethasone (DEX) and daratumumab (DARA) or elotuzumab (ELO) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): results from the CC-92480-MM-001 trial. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 1013. Available at: https://ash.confex.com/ash/2023/webprogram/Paper174443.html

Matous JV, Biran N, Perrot A, et al (2023). Talquetamab + pomalidomide in patients with relapsed/refractory multiple myeloma: safety and preliminary efficacy results from the phase 1b MonumenTAL-2 study. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 1012. Available at: https://ash.confex.com/ash/2023/webprogram/Paper187706.html

Joseph J, Tang L, Hillengass J, et al (2023). Risk of MGUS, a multiple myeloma precursor, in relation to food and beverage intake in the National Health and Nutrition Examination Survey (NHANES). J Clin Oncol, 41(suppl_16):e20062. DOI:10.1200/JCO.2023.41.16_suppl.e20062

Shah UA, Castro F, Derkach A, et al (2023). A whole foods plant-based weight loss intervention improves quality of life, metabolic, microbiome and immune profile in MGUS/SMM as well as progression trajectory in a subset – the NUTRIVENTION trial. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 4771. Available at: https://ash.confex.com/ash/2023/webprogram/Paper182878.html

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor 


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