14th Annual Summit of the IMF’s IMWG Top experts in myeloma focus on MGUS, SMM, MRD, frontline therapy, relapse, and immunotherapies

By Brian G.M. Durie, MD IMF Chairman of the Board & Chief Scientific Officer IMWG Summit Chair

On June 6, more than 130 of the world’s leading myeloma researchers gathered for an intensive three-day program of meetings at the 2023 Summit of the International Myeloma Working Group (IMWG). The IMWG is a collaborative initiative focused on improving outcomes for patients with myeloma. It is the most prestigious organization for myeloma researchers from around the world, and the IMWG Summit is an important annual activity for top myeloma experts who work together to fulfill the patient-centric mission of the organization.

Members of the IMWG collaborate to identify, support, and implement the most promising research to prevent the onset of myeloma, to improve treatment, and to find a cure. Hosting the important work of the IMWG and its members is a critical element of the IMF’s commitment to expand myeloma research and to educate myeloma patients on a global level.

Each year for 14 years, the IMWG Summit has been both a unique and an extraordinary experience. It is different from other medical meetings in general, and from other myeloma meetings in particular. Our collective primary goal is to move the field of myeloma forward for the utmost benefit of patients. During the 2023 IMWG Summit, we focused on the following topics that formed the majority of the meeting, and included a combination of presentations and brainstorming discussions:

MGUS and SMM

Dr. S. Vincent Rajkumar (Mayo Clinic, Rochester, MN) co-chaired the 2023 IMWG Summit with me, and also chaired the session on monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). These asymptomatic disorders are characterized by monoclonal plasma cell proliferation in the bone marrow and absence of end-organ damage.

Prevalence of MGUS and SMM

Dr. Sigrun Thorsteinsdóttir (University of Iceland) summarized her findings from the iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma) population-screening study, which is part of the IMF’s Black Swan Research Initiative® (BSRI®). The iStopMM project screened more than 80,000 adults over the age of 40 in Iceland in order to better understand the rates of MGUS, SMM, and active myeloma and to better understand the early stages of myeloma.

Notably, 5% of people over age 50 have MGUS, a condition with a small risk (1% per year) of progressing to SMM or active myeloma. A surprising finding was that the risk of IgA myeloma does not increase with age, unlike the other types of myeloma (IgG, IgD, IgE, or IgM). Understanding this may lead to insights that can prevent patients from progressing to active myeloma.

Because this research is at an early stage, screening all people for MGUS is not recommended. New testing methods like mass spectrometry are very sensitive and can detect even extremely low levels of myeloma protein (M-protein), and it is not clear whether it is appropriate to identify patients with extremely low levels of M-protein as having MGUS.

Risk stratification and management of SMM

Dr. María-Victoria Mateos (University of Salamanca, Spain) discussed two ways of identifying patients with high-risk SMM (HR SMM): the Mayo Clinic risk model and the Spanish risk model. Although these risk models use different approaches, (continues on next page)

2023 IMWG SUMMIT – CONTINUED FROM PAGE 5 they both are effective at identifying patients at high risk of progression. Dr. Mateos said that the management of SMM should be risk-adapted. In patients with a 50% risk of progression to myeloma at 2 years, current clinical trial results support the use of Revlimid® (lenalidomide) + the steroid dexamethasone (Rd) induction therapy followed by maintenance with Revlimid to delay or prevent progression.

Dr. Mateos also reviewed data from the ongoing CESAR and ASCENT clinical trials, which took different approaches to SMM, with both studies demonstrating excellent results. In the ensuing discussion, Summit participants examined how the assessment of SMM is continuing to evolve, suggesting that HR SMM is more appropriately grouped with active myeloma because that is how it is treated. However, the doctors deemed it important that the designation of SMM remain since it defines a group of patients who benefit from lower-intensity treatment.

Minimal residual disease

Dr. Rajkumar and I co-chaired the session on minimal residual disease (MRD), which included the following presentations:

Peripheral blood-based MRD approaches

Dr. Noemi Puig (University of Salamanca, Spain) presented a talk about how myeloma cells are detected in the blood. These are called circulating tumor cells (CTCs). Based on current methods, she found that not all patients who have myeloma cells detectable in their bone marrow have CTCs detectable in the blood. Research is underway to find more sensitive ways of detecting CTCs, perhaps using mass spectrometry.

Blood samples are more accessible than bone marrow samples and can be monitored over time in a way that is impossible to do with bone marrow samples. Most doctors do not think that blood tests for CTCs will replace bone marrow for diagnosing and staging myeloma, but blood tests for CTCs could become useful, sensitive monitoring tools over time.

Bone marrow-based MRD

approaches

Dr. Nikhil C. Munshi (Dana-Farber Cancer Institute, Boston, MA) reviewed current approaches to measuring MRD in patients with myeloma. He said that sustained MRD-negative status is relevant, predictive, and meaningful. Patients who achieve and maintain an MRD-negative status via sensitive testing methods do not tend to experience relapse.

Does it matter when MRD-negativity is achieved during treatment? Doctors do not have evidence that it does. Over time, maintenance therapy can induce MRD-negativity in patients who were previously MRD-positive, so continuing on treatment is worthwhile.

Can decisions to start or stop treatment be made based on MRD test results? In most cases, doctors think MRD status should not direct clinical decision-making. However, most doctors agreed that patients with high-risk myeloma and continued MRD-positive status would feel comfortable escalating treatment to try to achieve MRD-negativity. High-risk disease is defined as myeloma with one or more high-risk chromosomal mutations.

Frontline therapy

Dr. Jesús San Miguel (University of Navarra, Spain) chaired the session on frontline therapy, the first therapy a patient receives after they are diagnosed with myeloma.

Newly diagnosed myeloma and treatment strategies

Dr. Nisha Joseph (Winship Cancer Institute, Emory University, Atlanta, GA) reviewed the clinical data for using anti-CD38 monoclonal antibodies in induction therapy, including the GRIFFIN clinical trial, which examined the addition of Darzalex® (daratumumab) to the 3-drug (“triplet”) induction regimen of Velcade® (bortezomib) + Revlimid + dexamethasone (VRd) and the GMMG-HD7 clinical trial that explored the “quadruplet” of Sarclisa® (isatuximab) + VRd (Isa-VRd). In addition, Dr. Joseph shared institutional data from Emory.

All the studies demonstrated an increasing depth of response with higher rates of MRD-negativity with the addition of anti-CD38 antibodies to the induction regimen. Doctors agreed that based on the increased depth of response, using an anti-CD38 antibody as part of the induction regimen should be the standard of care (SOC) for most newly diagnosed myeloma. Note that approximately 85% of myeloma patients have standard-risk disease and 15% of patients have high-risk disease. The doctors agreed that a combination of an anti-CD38 antibody + VRd was superior for standard-risk patients. For high-risk patients, results were inconclusive when compared to therapy with VRd.

Dr. Joseph also reviewed the evidence for the use of proteasome inhibitors in frontline regimens, including Velcade and Kyprolis® (carfilzomib). She concluded that there is a role for proteasome inhibitors in the frontline setting for patients with high-risk myeloma.

Transplant strategy

Dr. Peter Voorhees (Atrium Health Levine Cancer Institute, Charlotte, NC) reviewed the past and discussed the present and future of stem cell transplantation in myeloma. He stated that the path to a myeloma cure runs through MRD. Patients who achieve and maintain MRD-negative status tend to remain in remission longer. Data from many clinical trials show that the best path to sustained MRD-negativity is an upfront triplet or quadruplet induction/consolidation followed by an autologous stem cell transplant (ASCT).

Dr. Voorhees spoke of ongoing clinical trials that will inform future myeloma treatment. The MIDAS study is exploring the concept of risk-adapted consolidation and maintenance using MRD testing. CARTITUDE-6 is studying ASCT vs. CAR T-cell therapy with Carvykti® (cilta-cel). Several phase II studies are examining bispecific antibodies (also called T-cell engagers) in newly diagnosed patients. Doctors expressed optimism that improved treatments will bring us closer to a cure.

Management of early relapse

Dr. Philippe Moreau (University Hospital of Nantes, France) chaired the session on early relapse management.

Approach to early relapse

Dr. Meletios A. Dimopoulos (University of Athens School of Medicine, Greece) discussed early relapse, defined as relapses occurring during the first 3 lines of therapy. Dr. Dimopoulos made the point that disease, treatment, and patient-related factors all play a role when selecting therapy at first relapse. Treatment goals include maximizing response, maintaining disease control, and balancing efficacy with tolerability and quality of life. Considerations about drugs that a patient may be resistant or refractory to, and the length of their prior remission are essential in selecting the subsequent therapy.

Many patients are resistant or refractory to Revlimid at relapse because many have received Revlimid maintenance for an extended period of time. Although anti-CD38 antibodies have been a staple of second-line treatment, as these become more common in frontline use, other therapies like CAR T-cell therapy and bispecific antibodies may be moved up earlier in treatment.

The 10%–15% of myeloma patients who relapse quickly after their first treatment are challenging to treat because this tends to indicate aggressive disease. Doctors agreed that clinical trials may be a good option for many of these patients.

Immunotherapy

Dr. Munshi served as session chair. CAR T-cell therapy and bispecific therapy: patient selection, side effect management

Dr. Ajai Chari (Icahn School of Medicine at Mount Sinai, New York, NY) reviewed CAR T-cell therapy and bispecific antibodies, which have demonstrated unprecedented response rates in myeloma of approximately 70%–100%. However, these new approaches to treatment also have some notable side effects that are new to the myeloma space. Cytokine release syndrome (CRS), an acute systemic inflammatory syndrome characterized by fever and flu-like symptoms, occurs in most patients but is mild in most cases. It can be treated with steroids and/ or tocilizumab. Infection is also common in patients treated with CAR T cells or bispecific antibodies.

The IMWG recently published recommendations to help address prevention of infection, which can be dangerous in patients with myeloma. Neurotoxicity, a rare but serious side effect, can also occur. Doctors must monitor patients closely to watch for signs of neurotoxicity so they can intervene early. Given the multiple new immunotherapies available to patients, and the changing standards of care in the frontline setting, attention must be paid to the sequencing of treatment.

New and emerging immunotherapies

Dr. Thomas Martin (UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA) discussed the unprecedented response to CAR T-cell therapies and bispecific antibodies that target B-cell maturation antigen (BCMA),

2023 IMWG SUMMIT – CONTINUED FROM PAGE 7 a protein found on the surface of myeloma cells, and noted that many more new targets are forthcoming. There are opportunities to use therapies in new ways, new combinations, and at new times (e.g., in earlier lines of therapy or as maintenance). Preliminary data suggest that CAR T-cell therapies and bispecific antibodies may have even better outcomes in earlier lines of treatment because immunotherapies harness the patient’s own immune system to kill myeloma cells, and patients tend to have more robust immune systems in earlier lines of therapy.

The RedirecTT-1 clinical trial combined the bispecific antibody Tecvayli™ (teclistamab) with talquetamab, another bispecific antibody that has a different target. This study demonstrated an impressive 96.3% response rate in one of the dosing cohorts. It also was effective in patients with extramedullary disease.

IMWG committees

Despite all the advances, questions remain, and real-world datasets are needed to best match the individual patient and the optimal therapy, and to sequence the therapies. As the Summit drew to a close, members of the following IMWG committees presented their reports: the SMM Committee, the Bone Disease Committee, the Immune Therapy Committee, and the Mass Spectrometry & MRD Committee.

By any measure of success, the 14th Annual IMWG Summit was lively and productive. No doubt, such exemplary collaboration in research will bring forth new and exciting developments that improve the lives of patients with myeloma. MT

Visit videos.myeloma.org to view IMWG Conference Series: Making Sense of Treatment as well as the helpful Ask Dr. Durie videos. Visit blogs.myeloma.org to read the Week in Review series by Dr. Brian G.M. Durie.