Isatuximab: ASH 2022 Irene Ghobrial Phase 3 Ithaca Study

Isatuximab: ASH 2022 Irene Ghobrial Phase 3 Ithaca Study

By Irene Ghobrial, MD

What does the Ithaca clinical trials updated safety run-in results show for patients with High-Risk Smoldering Multiple Myeloma? We presented in the American Society of Hematology (ASH). Several abstracts related to MGUS and smoldering multiple myeloma. Some of them about risk stratification, who should be treated for smoldering myeloma because we know that many people are diagnosed with MGUS and smoldering myeloma, but not everyone will to active disease. So we need to be very selective in understanding better who should be treated for the disease and who should be watched without evidence of disease progression. And then we also presented some of the early data of the phase 3 trial of ITHACA randomizing patients to Isatuximab, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone in high risk smoldering myeloma. 

 

I think I’ll start first with risk stratification. In general, if we think about MGUS and smoldering multiple myeloma, the ultimate goal is that we prevent myeloma from happening. We want to make sure that no one will develop the disease, no one will develop fractures, anemia, renal failure, or high calcium because there is nothing good about waiting for people to have symptoms and then we treat them.

So we’re talking about several pillars that we’ve been developing. One of them is early detection, and we started the PROMISE study with 30,000 individuals who are being screened here in the United States, and we had multiple posters presented this year about updates from the PROMISE study, including people from South Africa that we screened.

 

So I would encourage everyone to look at our posters, including the re-screening of some of those very low monoclonal proteins showing that indeed when we re-screen them, that we still identified it. Once you screen a patient, you want to think of EMGs and smoldering myeloma. Can I define biomarkers of disease progression?

 

We know that 2220, which is based on M- spike and Light-chain and bone marrow percentage is very good clinically, but can we improve on it? So we showed multiple oral presentations this year on single cell sequencing of either the tumor cells or the immune cells to better understand risk stratification.

And here we looked at the tumor cells at either the bone marrow microenvironment or also in the peripheral blood circulating tumor cells and trying to understand better the composition as well as the transcriptional changes that occur in the tumor cells, whether in the bone marrow or in the blood (Eg. red blood cells regardless of blood type) in those patients.

 

As we go on from progression from MGUS to smoldering to myeloma, and then we turn around and did another presentation on immune single cell. Trying to define it also, what are the alterations that happen as early as MGUS and how can we use them to understand transcriptional changes that occur in the T-cells and the T-cell repertoire, and how can we use those 4 biomarkers of disease progression?

 

We also then presented data of immune single cell sequencing from another clinical trial of Elotuzumab, Lenalidomide, and Dexamethasone showing that treatment as well as post-treatment. We can identify biomarkers that predict for us who will progress and who will not before we even start therapy, and then immune normalization post therapy to indicate who will truly have a long time remission.

 

So taking all of this data, we went on to the third pillar, which is interception. And one of the presentations was our early safety data of the patients who were treated and randomized on Isatuximab LenDex versus LenDex showing us that indeed there’s an extremely safe profile here and we’re seeing a response rate that would ultimately help us understand long-term outcome and progression-free survival in our patients treated on this large phase 3 randomized study that we’re hoping will lead to a registration in our patients with smoldering myeloma. 

 

What are the most common questions for this research?

A lot of questions from my colleagues about why should we treat smoldering myeloma and what are the risk factors that can help us predict them so that we can do, we do not over-treat or under-treat patients. We also get a lot of questions about selection, but of the clonal selection, whether treating someone will lead to clonal selection and drug resistance.

 

So I’ll take them maybe through, the first question is why should we treat smoldering myeloma? The standard of care for any of our patients when we see them is watch and weight until you have CRAB criteria and organ damage basically. Yet, if you think about it many of us treat other cancers that multiple myeloma, and I don’t think we ever tell women with breast cancer wait until you have metastasis everywhere and then I treat you.

We’re doing that for myeloma, a deadly disease, and we’re telling people, wait until you have symptoms. Fractures in your bones, anemia, renal failure, and then I treat you. And it’s basically just like telling someone wait until metastasis. So the argument for not waiting until end organ damage is that smoldering myeloma biologically, you could argue that, the cells are already cancerous cells. They look basically like a stage 1 or a stage 2 breast cancer. This is not a polyp, this is not a DCIS. This is overt cancer that just has not caused damage to the organs. So the ultimate goal for us is early treatment before people develop damage and symptoms.

 

And before there is further clonal evolution  and further neurogenesis and before there is immune dysregulation for the patients. And the question is really, or the hypothesis is if I use my best drugs, which we have a lot of them now in myeloma, and bring them earlier before we have a huge tumor burden and immune dysregulation. Will we potentially be curing patients with myeloma? Are we already at the curative stage? But we’re not doing it because we’re waiting way too long for our patients to be treated and therefore missing an amazing opportunity for us to indeed give them cure and potentially prevent an organ damage, prevent the renal failure and the symptoms and the fractures in those patients and that potentially can have a huge difference in their quality of life and in the morbidities that are part of that disease. The other thing is, yes, in the older days when we only had Melphalan or high-dose Dexamethasone, it was okay for us to wait for people to have symptoms. These days, I don’t know that was 15 or 17 drugs FDA approved for myeloma there is a true indication for us to wait for people to have symptoms and then we treat them. Now, of course, we need clinical trials to prove the benefit of early interception. The original studies by the Spanish Group and by Sagar Lonial, and Vince Kumar showed us that indeed, Lenalidomide and Dexamethasone compared to observation makes a huge difference in progression-free survival, and in one of the trials overall survival.

 

Now we’re trying to prove further benefits by adding 3 drugs together and not just 2 drugs compared to LenDex. And that’s the ITHACA study, the randomized study that we’re doing, but we’re also testing 4 drug regimens, the best drugs that we have early on, and there were multiple presentations in ASH (American Society of Hematology) about KRD and there KRD in smoldering myeloma.

 

Read and Share the Article Here: https://oncologytube.com/v/41735

Listen and Share the Audio Podcast Here: https://oncologytube.com/v/41736

 

And then we are also testing their RVD in our center as well as of course, immunotherapy, whether it’s the bispecific antibodies or even CAR T therapy in smoldering myeloma. So we’re bringing the best of the best as early as possible to do early interception and potentially prevent the disease from ever starting to have symptoms.

4 Key Takeaways from the Ithaca Clinical Trial

1. Patients (pts) with high-risk smoldering multiple myeloma (SMM) treated with lenalidomide + dexamethasone (Rd) may experience a delay in the progression to active illness compared to those who were observed. The ongoing, randomized, multi-center, Phase 3 ITHACA project is evaluating the addition of the anti-CD38 antibody isatuximab (Isa) to lenalidomide and dexamethasone (Isa-Rd) for the treatment of patients with high-risk SMM in an effort to further improve outcomes.

2. Patients were included in the trial if they had been diagnosed with SMM within 5 years (according to International Myeloma Working Group [IMWG] criteria) and had high-risk SMM according to the Mayo ’20-2-20′ and/or revised PETHEMA model criteria. Patients who had previously undergone anti-myeloma therapy were ineligible. Patients were administered Isa 10 mg/kg IV on day (D) 1, 8, 15, and 22 of cycle (C) 1, D1 and D15 C2-12, D1 C13-36; with R D1-21 (25 mg C1-9; 10 mg C10-24) and d weekly (40 mg, 20 mg for 75 yr-old patients C1-9; 20 mg C10-24). The cycle lasted for 28 days.

3. 23 patients (median age, 63 [range, 28-85] years) have received Isa 10 mg/kg once weekly then biweekly (QW-Q2W) in combination with Rd as of the cutoff date (9 May 2022). Two (9%) patients fulfilled the Mayo clinical model criteria for high-risk SMM, thirteen (57%) patients met the revised PETHEMA model requirements, and eight (35%) patients met both models’ criteria. On MRI, no patient had a focal lesion. The median period of therapy exposure was 19.7 (range: 3.7-22.1) months, and the median number of cycles was 20 (range: 4-24). Covid-19 pneumonia (n=3), sleeplessness (n=3), and pneumonia, hyperglycemia, agitation, lethargy, gastroesophageal reflux illness, retinal detachment, papular rash, and muscular spasms (n=1 each) were recorded in 11 (47.8%) patients.

4. The updated safety run-in portion of the ITHACA trial continues to demonstrate a tolerable safety profile for Isa-Rd in patients with high-risk SMM, with no decisive treatment discontinuations due to a TEAE. At a median follow-up of 19.4 months, treatment with Isa-Rd has demonstrated promising efficacy (sCR/CR in 43.5% and VGPR in 73.9% of patients), further validating the recommended dose of Isa (10 mg/kg QW-Q2W) for the randomized portion of the study, which is currently comparing the efficacy and safety of Isa-Rd versus Rd in patients with high-risk SMM.

 

Will this data affect clinicians? 

I think there are lots of patients who are being seen by every oncologist and sometimes even by their primary care physicians (healthcare professionals), and they either have MGUS or smoldering myeloma. And the first question you want to ask is, where am I in that disease spectrum? And as an oncologist, I want to know, are they truly high risk?

 

Smoldering myeloma and should I think of early intervention for them, or are they really in the lower edge of smoldering myeloma? Remember, the smoldering myeloma is a very heterogeneous disease, so you could have 10 patients and they all have 10% plasma cells, yet one of them will progress in the next 6 months, and one of them will stay perfectly fine for the next 10 years.

And you want to have biological differences between them and assess it for your own precision so that you can understand better who will progress and who will not. So yes, we use the percentage of plasma cells, we use the M- spike and the Light-chain. You also want to look at the dynamics of progression. We don’t look at one time point, we look at the constant changes that happen and those dynamic changes is basically the movie that you’re looking at and not a snapshot of that patient. We will be releasing soon a PANGEA model. This is a risk stratification model based on dynamics of the M- spike and the Light-chain and other numbers, so that there is a calculator in your hand that you can use and you can just put in the numbers and see what is the risk of that patient in 2 years, 5 years, 10 years.

 

And that builds already on the 2220, and it’s an easy model that you can enter your data. And then the data that we presented in ASH (American Society of Hematology) adds to it by doing sequencing. , and again, single cell sequencing is research level now, but hopefully we will bring it to the clinic soon where you can add to it. Do I have circulating tumor cells? Are they gnomically the bad ones? Do I have a p53 mutation or not? Can I look at the bone marrow cells, even at the single cell level and look at them both at the DNA and the RNA level and see that the patient was 17p deletion or 4;14 translocation and other mutations is higher risk for developing myeloma than someone else.

 

Can I also look at the immune system? Someone with specific signatures of T-cells or NK cells may progress much faster or may benefit from immunotherapy compared to others. And by putting all of this together, then you can have that precision of telling your patient whether they will progress to avert myeloma and whether they would benefits from therapy in the near future.

 

What is Isatuximab?

Isatuximab is a medication used in conjunction with other treatments to treat multiple myeloma in adults. It is administered to cancer patients who have already had at least two therapy, including lenalidomide and a proteasome inhibitor. It is also administered to individuals whose cancer relapsed (returned) or did not respond to one to three earlier treatments. Additionally, it is being investigated for the treatment of various forms of cancer. Isatuximab binds to CD38, a protein found on some immune cells and cancer cells, including myeloma cells. Isatuximab may inhibit CD38 and assist the immune system in destroying cancer cells. It is a monoclonal antibody type (monoclonal antibodies). Also named Sarclisa.

 

What is the next step for this research on the Ithaca clinical trail for patients with multiple myeloma?

A lot of things and we’re trying truly to prevent myeloma from happening, and we’re really working on screening and finding it early because there is nothing good about finding out that you have myeloma by having the symptoms and early detection really matters. So tell all of your patients who have myeloma to screen the rest of the family and to sign up to the PROMISE study here in the United States, or if they’re African American to consider the PROMISE study.

We want to understand more about risk stratification. And really that’s an effort not only from physicians but also from the patients to really help us understand large data and large cohorts to better define who will progress and who will not. And then of course we want to develop better therapies.

It’s an amazing opportunity for us not to repeat what we’ve done in multiple myeloma, but try to start from scratch. Think about it, you have the best available data now with so many clinical drugs that are FDA approved, and let’s bring them to the upfront. Let’s stratify our patients better. Let’s not treat an 1114 smoldering myeloma, just like a 17 piece modeling myeloma.

 

We have an opportunity for precision interception in those patients. We have a opportunity for immunotherapy for our patients also, and hopefully that will lead to the cure and prevention of myeloma from happening.

 

What are the key takeaways from the Ithaca trial research and data for patients with multiple myeloma?  

An opportunity for us to understand better the disease of multiple myeloma. Myeloma is very complex. Indeed, it is multiple myelomas, multiple types of disease, and we need to understand it better, not only in the active disease setting, but even at the earlier precursor settings because that’s an opportunity for us for early detection and early interception and potentially cure for our patient.

 

Final thoughts on the Phase 3 Ithaca Trial In multiple myeloma

I think many of us as oncologists, MGUS and smoldering myeloma patients, and I think the usual way of thinking is they’re asymptomatic, they’re fine. They’re not the problem. I’m seeing so many other patients, breast cancer, lung cancer, huge problems yet, for those patients, there is an opportunity to make a difference in their life.

 

There is an opportunity to prevent and organ damage and prevent myeloma and potentially have a cure for them. And I would encourage really, call us, email us anytime. We’re happy to help with the management of those patients and we’re happy to help understand better their disease progression, their own risk, and then of course, help with their clinical care so that we can prevent myeloma.

 

And this is truly an effort that can be done by everyone, and it really requires us as physicians thinking, can I do this in a different way? We were all trained to watch and wait as I, as my patients say, watch and worry. So let’s rethink about the way we think of it and try to change the cancer care for our patients.

 

Irene Ghobrial, MD – About The Author, Credentials, and Affiliations

Irene Ghobrial, MD, was awarded her doctorate from the Cairo University School of Medicine in Egypt in 1995. She went to Wayne State University in Michigan to get her Bachelor of Science in Internal Medicine. She then went to the Mayo Clinic College of Medicine in Minnesota to get her Master of Science in Hematology and Oncology. She began researching Waldenstrom’s macroglobulinemia and multiple myeloma at the Dana-Farber Cancer Institute in 2005. She is doing research on how B cells find their way home and move around. She is also making new medicines to treat Waldenstrom’s macroglobulinemia and multiple myeloma.

 

Reference

1. ASH Publications – Isatuximab in Combination with Lenalidomide and Dexamethasone in Patients with High-Risk Smoldering Multiple Myeloma: Updated Safety Run-in Results from the Randomized Phase 3 Ithaca Study. ASH Publications, November 15, 2022

2. NIH – isatuximab. NIH, 2023