Does Dexamethasone Work in Combination With Lenalidomide, Ixazomib in Newly Diagnosed Multiple Myeloma? The MM-6 Trial

15 Key Statistics from the MM-6 Trial for Multiple Myeloma

• Median age was 73 years (range, 48-90 years), with 81% aged >65 years; 97% had ≥1 comorbidity at the start of IRd therapy.

• Efficacy data after an additional 11 months of follow-up (data cut-off: May 4, 2021) showed that iCT to IRd improved responses.

• Overall response rate (ORR) had improved from 65% (CR 9%, VGPR 25%, PR 32%), at the end of 3 cycles of V-based induction, to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%) following iCT to IRd.

• At a median follow-up of 18.5 months, the 18-month PFS rate was 84%. The safety profile of IRd was consistent with previous clinical studies.

• Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 64% of patients and treatment-related serious TEAEs in 12% (including 4 on-study deaths), while 16% of TEAEs led to study drug discontinuation.

• Here we have analyzed updated data for this patient subset with an additional 11 months of follow-up to further evaluate efficacy and safety, and to determine reasons for premature (within 4 cycles of IRd) discontinuation.

• Sixty-eight patients (67%) had completed or discontinued the study since first patient enrolment on November 15, 2017.

• Among these patients, 14 (21%) discontinued within 2 cycles of IRd and 27 (40%) discontinued within 4 cycles.

• With longer follow-up, use of iCT from V-based induction to IRd to achieve long-term PI-based therapy in NDMM patients demonstrates efficacy via improved response rates and acceptable PFS in this real-world setting.

• Over 80% of US MM-6 patients were aged >65 years and most had ≥1 comorbidity prior to study entry.

• The rate of patients discontinuing within 4 cycles of iCT (7 cycles of PI-based therapy in total) is concerning because these patients may not receive the full benefit of long-term PI-based treatment.

• To date, the majority of premature discontinuations were reported as being due to patient request (44%) followed by TEAEs (30%).

• Dosing - 4 mg ixazomib + 25 mg lenalidomide + 40 mg dexamethasone.

• For up to 3 years, all participants are requested to take ixazomib 4 mg on Days 1, 8, and 15, lenalidomide 25 mg on Days 1 through 21, and dexamethasone 40 mg on Days 1, 8, 15, and 22 in 28-day cycles until progression or intolerable toxicity.

• The treatment phase of this trial is expected to last up to 78 months, including a 42-month enrolment period and a 36-month IRD treatment term (39 cycles) with ixazomib and/or lenalidomide and/or dexamethasone for the final subject recruited.

This is a review of a combination clinical trial including Dexamethasone, Ixazomib, and Lenalidomide from the European Hematology Association (EHA). The abstract of interest is a little bit unusual in its design. A previous trial has been conducted called "MM-6." And that was a little bit unique in that we studied newly diagnosed multiple myeloma patients, and they could have received any Velcade based induction, whether it was a double or a triplet.

After three cycles, if they had stable responding disease, they were then switched to an all-oral triplet combination, which consisted of Ixazomib, Lenalidomide, and Dexamethasone, otherwise known as IRD. And we've previously published on this group showing the feasibility and potential benefits of an in-class transition.

Inclusion Criteria for the MM-6 Trial

We studied around 100 patients in that single-arm study. However, this abstract is a little bit different in that what we did was we took the 6 databases and then we also started to do matched para-analysis with a large myeloma registry known as INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma.

We matched patients with those who were in treatment phase in the United States, and they were treated with a slightly different regimen where there was parental Velcade given as a subcutaneous injection. So, this was not an all-oral dosing schedule. One of our aims was to see if with all oral regimens we could improve compliance, adherence, and keep people on clinical trial therapy longer.

Myeloma has become a maintenance treatment disease, so what we did was match pair analysis with some of the increased risk I've alluded to. Using the six data points with the in-class transition, we showed, when compared to the INSIGHT MM registry, a higher overall response rate and a longer duration of therapy.

This was somewhat nice and added some validity to the in-class transition approach and, more importantly, the ability to stay on a prolonged all-oral maintenance treatment with Ixazomib, lenalidomide, and dexamethasone. And while this is preliminary data, I think it's encouraging and may pave the way for future class transitions in multiple myeloma treatment.

There's a tremendous number of multiple myeloma drugs being developed into a lot of new treatments, some of which are CAR-T cell specific antibodies, antibody drug conjugate molecules with novel mechanisms of action, some of which are oral, some of which are not. I think this approach provides some good evidence that in class transition, and even using all oral regimens like Ixazomib, lenalidomide, and dexamethasone will really help people stay on maintenance treatment longer and hopefully improve our overall outcome in multiple myeloma and decrease missed dose.

An all-oral MULTIPLE MYELOMA TREATMENT regimen you can take at home

So, although the study design is a bit unusual, it really demonstrates the value of an all-oral regimen, especially in the COVID era. Interestingly, when we designed 6, INSIGHT MM was already up and running. COVID changed a lot of things. A lot of them are now very difficult to analyze. but in the MM-6 trial, COVID was something that played very well with the study because it was an all-oral regimen and patients didn't really have to go to the physician's office frequently. They could stay at home, practice isolation, and monitor themselves for adverse reactions while staying away from COVID. The data analysis is still in progress. So, I think overall, this showed that using the in-class transition and avoiding parental medication increased our response rates and duration of maintenance treatment.

The next step for the MM-6 Trial research would be to design a successor study with some in-class transitions. I know we're looking at the feasibility of doing that, but certainly the concept of in-class transition will be here to stay. And it's how we exploit that in myeloma. And then, obviously, with the insight database and that registry, now closed for a little bit. All that data and insight will start to mature and will be the foundation for a lot of future analyses. I don't know that we'll be able to quite do this same comparison between a registry and a retrospective study, while it has some shortcomings as an eye opener in terms of response rates and duration of therapy.

I think that the clinical trials data overall speaks for itself. As providers become more comfortable with all oral regimens and doing final dose reduction and dose adjustments, toxicities, and then importantly, really measuring patients’ quality of life while watching for new or worsening symptoms. Multiple myeloma patients are on therapy for a very long time, hopefully using Ixazomib, lenalidomide, and dexamethasone, and all the medicines get to minimal residual disease negativity, which is really our goal.

If you remain minimal residual disease negative for a long period of time, at some point you may be able to stop therapy for multiple myeloma, following symptoms, of course. So, this database can, in part, serve as a small part of the foundation for achieving minimal residual disease negativity in newly diagnosed patients. Although that wasn't really our primary endpoint, I think that's everybody's goal at the end of the day.

MM6-Trial Trial Design of Ixazomib Lenalidomide Dexamethasone (IRD)

Long-term PI based treatment duration can enhance results in multiple myeloma across treatment settings. However, there are a variety of physical, geographical, and/or socioeconomic challenges to long-term parenteral PI therapy in community practice. The US MM-6 research (NCT03173092) is looking at in-class transition (iCT) from parenteral bortezomib (V)-based induction to all-oral ixazomib-based therapy with ixazomib, lenalidomide, and dexamethasone (IRd) in a heterogeneous community population in the United States. The study's goal is to extend the length of PI-based treatment while maintaining quality of life and enhancing outcomes. We previously presented promising efficacy and safety data for the first 101 MM-6 patients in the United States (Girnius Blood 2020). We reviewed updated data for this patient subset with an additional 11 months of follow-up to assess effectiveness and safety, as well as causes for premature (within 4 cycles of IRd) discontinuation.

Ixazomib Lenalidomide Dexamethasone (IRD) Methodology

Transplant-ineligible/transplant-delayed (24 months) Patients with Newly Diagnosed Multiple Myeloma at community sites in the United States who had achieved stable disease or better after three cycles of Velcade based induction were given xazomib, Lenalidomide, and Dexamethasone (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 28-day cycles, or until progressive disease or unacceptable toxicity. The primary goal is to achieve 2-year diesease progression-free survival (PFS). The rates of partial response (PR), very good partial response (VGPR), and complete response (CR), as well as the length of therapy, are important secondary endpoints. For the current study, sites with patients who had stopped using US MM-6 trial were contacted for extra information.

MM-6 Clinical Trial Outcomes

As of June 1, 2020, 101 individuals had been registered and treated at 21 sites. The median age was 73 years (range, 48-90 years), with 81% older than 65 years and 97% having at least one comorbidity at the commencement of ixazomib, lenalidomide, and dexamethasone therapy. After a further 11 months of follow-up (data cut-off: May 4, 2021), efficacy data showed that iCT to Ixazomib Lenalidomide Dexamethasone improved response and disease progression. Following iCT to IRd, the overall response rate (ORR) increased from 65% (CR 9%, very good partial response 25%, PR 32%) at the end of three cycles of V-based induction to 78% (molecular CR [mCR] 1%, stringent CR [sCR] 3%, CR 32%, VGPR 25%, PR 17%). At the most recent data cut-off, 33 patients (33%) were still on therapy; the median duration of ixazomib, lenalidomide, and dexamethasone was 11.7 months, and the overall median duration of therapy (for all PI-based therapy, including Velcade based induction) was 14.6 months. The 18-month PFS rate was 84% at a median follow-up of 18.5 months. Ixazomib Lenalidomide Dexamethasone safety profile was similar to earlier clinical trials. Treatment-emergent adverse events (TEAEs) of grade 3 were documented in 64% of patients, and treatment-related significant TEAEs in 12% of patients (including 4 on-study deaths), with 16% of TEAEs leading to study drug cessation. Since the first patient's enrolment on November 15, 2017, 68 patients (67%) either completed or discontinued the trial. 14 (21%) of these patients ceased ixazomib, lenalidomide, and dexamethasone within two cycles, and 27 (40%) discontinued within four cycles.

MM-6 Trial Conclusion

In this real-world situation, the use of iCT from Velcade based induction to Ixazomib Lenalidomide Dexamethasone to achieve long-term PI-based therapy in Newly Diagnosed Multiple Myeloma patients reveals efficacy via enhanced response rates and acceptable progression-free survival with longer follow-up. Over 80% of MM-6 patients in the United States were over the age of 65, and the majority had at least one comorbidity prior to study entry. The rate of patients discontinuing iCT after four cycles (seven cycles of PI-based therapy total) is problematic since these patients may not benefit fully from long-term PI-based treatment. To date, the bulk of early discontinuations (44%) have been attributed to patient requests, followed by TEAEs (30%). The planned US MM7 iCT oncology research in relapsed or refractory MM will address expanded site education and improved patient follow-up to reduce premature discontinuations.

Oral treatment for multiple myeloma?

An all-oral regimen triplicate of Ixazomib, Lenalidomide, and Dexamethasone can be taken at home.

What class of drug is Ixazomib?

Ixazomib is used in conjunction with lenalidomide (Revlimid) and dexamethasone to treat multiple myeloma (bone marrow plasma cell cancer) that has progressed despite treatment with other chemotherapy drugs. Ixazomib belongs to a class of drugs known as proteasome inhibitors. It works by assisting in the death of cancer cells.

Is Lenalidomide an immunotherapy?

Lenalidomide is an oral medication used to treat multiple myeloma. It belongs to a class of medications known as immunomodulatory drugs (IMiDs), which fight against cancer cells in part by enhancing immune system function.

Multiple Myeloma Cancer Explained

Multiple myeloma is a type of plasma cell malignancy. Plasma cells are present in bone marrow and play a vital role in the immune system. The immune system is made up of various cell types that collaborate to fight infections and other disorders. Lymphocytes (lymph cells) are a type of white blood cell that includes T cells and B cells in the immune system. Lymphocytes can be found in various parts of the body, including lymph nodes, bone marrow, the intestines, and the circulation.

When B cells respond to an infection, they develop into plasma cells. Plasma cells produce antibodies (also known as immunoglobulins), which aid the body in attacking and killing infections. Plasma cells are mostly present in bone marrow. The soft tissue inside bones is known as bone marrow. Other blood cells, such as red cells, white cells, and platelets, live in normal bone marrow in addition to plasma cells.

Multiple myeloma is a malignant condition in which plasma cells grow uncontrollably. Plasma cells produce an aberrant protein (antibody) recognized by several names such as monoclonal immunoglobulin, monoclonal protein (M-protein), M-spike, or paraprotein.

Author Credentials and Affiliations

Robert M. Rifkin, MD, FACP - Rocky Mountain cancer Centers

Dr. Rifkin is a board-certified medical oncologist and hematologist specializing in malignant and benign hematology, treating cancer and blood disorders. He has an advanced sub-specialty expertise in coagulation disorders, multiple myeloma and biosimilars. Dr. Rifkin practices evidence-based medicine and follows National Comprehensive Cancer Network (NCCN) guidelines for cancer treatment.

References

American Cancer Society - What Is Multiple Myeloma? American Cancer Society, February 28, 2018.

ASH Publications - Extended Characterization of Newly Diagnosed Multiple Myeloma (NDMM) Patients with In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy in the Community-Based United States (US) MM-6 Study: Updated Efficacy and Safety, and Reasons for Premature Discontinuation. ASH Publications, November 6, 2021.