Insights from ASH: Treating Myeloma Is a Marathon, Not a Sprint

The American Society of Hematology (ASH) Annual Meeting and Exposition is considered the premier event in malignant and non-malignant hematology, empowering global networking and collaborations across the world community of hematologists. The 2021 gathering held last December lived up to its billing. Promising new data in hematology was released, and in-depth presentations were given that will be tremendously helpful in guiding how multiple myeloma (MM) is treated moving forward. The time immediately following the conference is important as the data is synthesized, and changes in clinical practice are implemented. After reflecting on the conference, my take on the key findings from ASH 2021 is presented below.

Treating multiple myeloma is a long-term journey
Thanks to nearly a decade of advances in research and therapy, MM has actually become a chronic illness that is manageable as patients experience various remissions and relapses over the course of the disease. This is perhaps the key takeaway from the conference, and a critical concept for providers to understand.

We now have a strong knowledge base to guide treatment decisions. For instance, we are no longer in the dark about when active treatment should begin, as we have gained an understanding of the significance of smoldering myeloma and the optimal time to treat active disease. We are better at predicting who will get myeloma, due to improved risk stratification systems, and we have learned that first symptoms may be catastrophic, so waiting until symptoms present may not be the best option.

Additionally, treatments have greatly improved. While many past therapies were toxic with limited efficacy, today there are highly effective treatments supported by strong evidence from phase 3 trials demonstrating improved survival. The advances have been dramatic, giving once terminal patients new hope with innovative targeted treatment options that can be utilized over the long-term course of the disease.

A conference highlight: A critical update on how to treat multiple myeloma
One very important presentation at the conference was the 2022 Multiple Myeloma Care Algorithm, presented utilizing the Clinical Care Options Platform. This is a valuable compendium updating how to care for MM patients in the coming year. The Care Algorithm was created by a group of experts led by Philippe Moreau, MD, from University Hospital Hôtel-Dieu, Nantes, France, and S. Vincent Rajkumar, MD, from the Mayo Clinic, Rochester, Minnesota. Collaborating on this massive project, this dedicated group utilized information from ASH to meticulously develop a 6-part series designed to help clinical practices adapt to the rapidly changing MM therapeutic landscape. This comprehensive international guide reviews current standards and updates recommendations based on recent developments, putting this valuable diagnostic and treatment information conveniently at the fingertips of clinicians for quick and easy reference.

The Care Algorithm covers many critical areas and starts with a very important concept, namely when treatment should begin for myeloma, the subject of much discussion at the conference. The evolution from plasma cell disorders to smoldering myeloma was explored, and this information was incorporated into the Care Algorithm by adding what are referred to as Myeloma Defining Events which help identify a potentially new active myeloma. While the definitions did not change much, physicians should start to treat very high-risk smoldering myeloma the same as early symptomatic MM.

Diagnostic Criteria were also reviewed in the Care Algorithm, but recommendations were mostly unchanged except to more precisely incorporate new bone marrow and lab findings, as well as imaging studies. Recommendations for front-line myeloma remained the same, with the disease still treated with the not-so-new paradigm of who is a candidate for stem cell transplant and who is not.

For those wanting to take a look at the entire 2022 Multiple Myeloma Care Algorithm, it can conveniently be accessed on the Clinical Care Options website.

Additional insights
The conference also featured some interesting discussions of new treatment approaches for monoclonal gammopathy of undetermined significance (MGUS) and Smoldering Multiple Myeloma. These approaches varied and included multiple cycles of chemotherapy, as well as offering stem cell transplants before the disease has progressed to active myeloma. The hope is this could cure patients by treating them earlier in the course of the disease when it is still classified as smoldering MM. This concept remains in evolution.

One other important major point from the conference is that there are now multiple novel agents to treat not only newly diagnosed myeloma but also relapsed and refractory multiple myeloma (RRMM). At last count, there are at least 15 novel agents now available and many more coming soon, some of which explore new treatment targets.

New targets are being explored, putting us on the edge of being able to offer even more promising personalized treatments. XPO1 is a new target inhibitor currently being investigated, as well as the B-cell maturation antigen (BCMA). While this is also a rich target, and great progress is occurring with CAR T-cell therapy and bispecific antibodies, and antibody-drug conjugates, the list continues to expand at a rapid rate.

Takeaways from some important studies
While there were numerous studies presented at ASH, there are a few that may provide an updated clinical foundation for going forward, as they may offer insight into the optimal use of new novel agents for MM:

• Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the Connect® Multiple Myeloma (MM) Disease Registry [1]
  

This study used the ongoing Connect® MM Disease Registry to examine treatment patterns and outcomes in patients with triple-class refractory MM. The Connect Registry was started in 2009, so it is now roughly 13 years old. We are trying to decide what else to investigate with the Registry, as more than 700 of the original 3,000 participants are still alive. The study highlighted some things already known, namely that treatment resistance is an ongoing challenge that most patients with triple-class refractory MM encounter over the course of their disease, and with each subsequent line of therapy, outcomes, and quality of life worsen. Survival starts to go down, while morbidity and mortality increase. Researchers concluded “Patients with triple-class refractory MM experienced poor survival, substantial hospitalizations, and a clinically meaningful decline in health-related quality of life. This study suggests novel tolerable and efficacious therapeutic agents are needed to address the burden of illness in patients with MM.” [2]

Although many therapies are currently working well for some patients, such as immunomodulatory drugs, proteasome inhibitors, and anti-CD38 antibodies, when patients become refractory to all of these agents, a new approach is needed. These are the patients we are starting to treat with novel agents, including CAR T-cells, new monoclonal antibodies, and antibody-drug conjugates (ADCs). Educating providers so they are comfortable with these new therapies is critical for success, and timely use of these agents becomes very important. The hope is that some of these will soon be available for outpatient administration in the clinic.

• Late vs Early Response and Depth of Response Are Associated with Improved Outcomes in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with Ixazomib-Lenalidomide-Dexamethasone (IRd) or Placebo-Lenalidomide-Dexamethasone (pbo-Rd) in the Phase 3 TOURMALINE-MM2 Trial [3]
  

This study compared a triplet to a doublet oral combination in newly diagnosed MM patients, and it was one of the very first early trials of the triplet combination. It examined an all-oral regimen using ixazomib (Ninlaro®; Takeda Pharmaceuticals) , an oral proteasome inhibitor, Lenalidomide, an immunomodulatory drug, and Dexamethasone, a steroid, (IRd) compared to a Placebo-Lenalidomide-Dexamethasone combination.

Since two all-oral regimens were compared, a very credible controlled double-blind placebo trial could effectively be implemented. The study found a clinically meaningful progression-free survival benefit with higher rates of deep responses utilizing the IRd triplet versus the placebo combination. [4]

• 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. [5]

The US Oncology Network was the leading accruer for this unique trial in which patients transitioned within a class of proteasome inhibitors. The study was one of the very early readouts of MM6 where patients shifted from an injectable proteasome inhibitor to an oral one. Patients were switched from a bortezomib (Velcade®; Takeda Pharmaceuticals)-based induction injectable proteasome inhibitor, to an all-oral regimen of Ixazomib-Lenalidomide-Dexamethasone (IRd), the same regimen studied in the Phase 3 TOURMALINE-MM2 Trial. Patients who received three 3 cycles of Velcade® and were stable or responding were eligible for the switch to the all-oral IRd regimen.

The study occurred during the COVID-19 pandemic, and fortunately, it turned out to be very pandemic–friendly. Patients were concerned about coming to the office due to possible COVID exposure, so participants were engaged through telehealth visits at home once they transitioned to the all-oral regimen. The results were very promising, as responses were deep and sustained, [6] which was exciting for all of us involved in the trial. Some premature discontinuation did occur, and that issue is currently being explored. Discontinuation may be due to a lack of provider familiarity with the IRd regimen.

• A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) [7]
  

The magrolimab study, which is still in the recruitment phase, is investigating the efficacy of this new monoclonal antibody when combined with commonly used myeloma therapies in RRMM patients. Eligible participants must have received at least three previous lines of therapy for MM, including an immunomodulatory agent and a proteasome inhibitor.

Magrolimab blocks the immune checkpoint CD47, a do not kill signal overexpressed on tumor cells, driving the pathogenesis of MM. When magrolimab binds to CD47, it leads to phagocytosis of cancer cells, so blocking CD47 with magrolimab may provide therapeutic benefits for MM patients.[8]

Since past studies have shown combination therapies are more effective than single-agent therapy for newly diagnosed RRMM patients.[9] this study is focusing on combining agents. In vitro studies demonstrated synergy between magrolimab and daratumumab on MM, and enhanced efficacy has been suggested in other combinations as well.¹⁰ The magrolimab combinations being evaluated in this trial include: magrolimab+daratumumab; magrolimab+pomalidomide+dexamethasone; and magrolimab+bortezomib.

Great progress is being made
This is a very exciting time for researchers, physicians, and patients, as much headway has been made in the battle against myeloma. When I started my fellowship over 30 years ago, the median survival for MM was only a year and a half. Today patients routinely live 10 years or more due to the many advances that have occurred.

Progress has been dramatic, changing the way the disease is treated, as well as how we research and develop new therapies. Patients are being treated earlier due to new definitions for MM, and there is new interest in determining the optimal time to start treatment for relapse. While transplantation still remains a viable option, today there are many other individualized therapies that can be tailored to the patient.

The goal is to develop and select effective therapy options that are safe with minimal toxicity, but also convenient for the patient so adherence is supported. As MM has become more of a chronic illness, dealing with it has become more of a marathon, rather than a sprint, requiring patience and dedication to keep moving forward on the journey to better outcomes.

Clinical trials
IXAZOMIB Plus Lenalidomide and Dexamethasone Versus Placebo Plus Lenalidomide and Dexamethasone in Adult Patients With Newly Diagnosed Multiple Myeloma – NCT01850524

Highlights of prescribing information
Ixazomib (Ninlaro®; Takeda Pharmaceuticals)(Prescribing Information)
Bortezomib (Velcade®; Takeda Pharmaceuticals) (Prescribing Information)

References
[1] Tang D, et al. 117 Real-World Treatment Patterns and Clinical, Economic, and Humanistic Burden in Triple-Class Refractory Multiple Myeloma: Analysis of the Connect® Multiple Myeloma (MM) Disease Registry. Presented during 2021 American Society Of Hematology Annual Meeting and Exposition, December 8-17, 2021. Accessed online March 24, 2022. https://ash.confex.com/ash/2021/webprogram/Paper146830.htm
[2] Ibid.
[3] Richardson P, et al. 2733 Late vs Early Response and Depth of Response Are Associated with Improved Outcomes in Newly Diagnosed Multiple Myeloma (NDMM) Patients (pts) Treated with Ixazomib-Lenalidomide-Dexamethasone (IRd) or Placebo-Lenalidomide-Dexamethasone (pbo-Rd) in the Phase 3 TOURMALINE-MM2 Trial. Presented during 2021 American Society Of Hematology Annual Meeting and Exposition, December 8-17, 2021. Accessed online March 24, 2022. https://ash.confex.com/ash/2021/webprogram/Paper148481.html
[4] Ibid.
[5] Rifkin R, et al. 2726 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. Presented during 2021 American Society Of Hematology Annual Meeting and Exposition, December 8-17, 2021. Accessed online March 24, 2022. https://ash.confex.com/ash/2021/webprogram/Paper150094.html
[6] Paul B, et al. 2757 A Phase 2 Multi-Arm Study of Magrolimab Combinations in Patients with Relapsed/Refractory Multiple Myeloma. Presented during 2021 American Society Of Hematology Annual Meeting and Exposition, December 8-17, 2021. Accessed online March 28, 2022. https://ash.confex.com/ash/2021/webprogram/Paper145903.html
[7] Ibid.
[8] Ibid.
[9] Ibid.

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