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Are We Ready for Quads?

December 10, 2021
Ah-Reum (Autumn) Jeong, MD, and Aaron M. Goodman, MD

Dr. Aaron Goodman (@AaronGoodman33) is an associate professor in the Division of Blood and Marrow Transplantation at the University of California San Diego (UCSD) Moores Cancer Center, San Diego. His specialties include bone marrow transplantation and cellular therapies, and his clinical/research interests are rare diseases, Castleman disease, and T-cell lymphomas. Dr. Goodman hails from Chicago and attended University of Illinois for undergrad, Emory for medical school, Washington University for residency, and UCSD for hematology-oncology fellowship. Dr. Goodman also offered insight into his life outside hematology. “I play in a rock band and have played guitar since age six,” he said. 

Joining Dr. Goodman this year is Junior Author Dr. Ah-Reum (Autumn) Jeong (@AutumnJeong). Dr. Jeong is a hematology/oncology fellow at Moores Cancer Center, University of California San Diego, in La Jolla, with a clinical/research interest is in lymphoma. She studied at Cornell University for undergraduate, and received her MD at University of Southern California, where she also did her internal medicine residency. She hails from Los Angeles and played lacrosse in high school. 

Everyone with plasma cells was affected by COVID-19, including researchers in 2021. The global pandemic impacted all aspects of research with budget cuts and increased difficulties accruing patients to studies. Despite these obstacles imposed by the pandemic, the research presented at this year’s ASH annual meeting is once again filled with novel discoveries and advancements for patients with plasma cell related disorders. 

There are several oral abstracts that discuss the impact of COVID-19 and vaccines in patients with plasma cell dyscrasias. Several analyses of the iStopMM study (abstract 154 and 156), a large, population-based study in Iceland enrolling over 80,000 patients, were reported. Dr. Sæmundur Rögnvaldsson and colleagues discuss whether monoclonal gammopathy of undetermined significance (MGUS) is associated with increased risk of SARS-CoV-2 infection and/or development of severe COVID-19. Reassuringly for our patients, the authors did not find any such association. However, on the contrary, patients with multiple myeloma (MM) seem to be detrimentally affected by COVID-19 with increased susceptibility to COVID-19 infection despite the vaccine, compared to group-matched controls. Dr. Nathanael Fillmore and colleagues (abstract 400) discuss the ineffectiveness of SARS-CoV-2 vaccine in veterans with MM. The vaccine was only effective in 22.2 percent of 1,606 patients with MM versus 82.3 percent in the matched control of cancer survivors. Patients with MM are significantly immunocompromised from their underlying disease and immunosuppressive treatment; further strategies to prevent COVID-19 infection in patients with MM are urgently needed. 

Dr. Sigurdur Kristinsson and colleagues asked whether healthy, asymptomatic individuals should be screened for MGUS (abstract 156). This is a provocative question with huge financial and health care implications. More than 75,000 patients in Iceland underwent screening and 4.9 percent were found to have MGUS. Patients identified as having MGUS were then assigned to three surveillance strategies (arm 1: no surveillance, arm 2: standard of care, Arm 3: intensive surveillance). At three-year follow-up, 133 (11%) patients in arm 3 were diagnosed with lymphoproliferative disorder compared to nine (0.8%) patients in arm 1 and 92 (8%) patients in arm 2. These results are not surprising as we know some patients with MGUS will progress to MM or another lymphoproliferative disorder. However, what is clinically important is whether earlier detection of malignant clones leads to improved outcomes and prolonged survival. Risks of early detection include overtreatment and financial toxicity. This data is eagerly awaited from long-term follow-up of this study. The PROMISE study, led by Dr. Habib El-Khoury and colleagues (abstract 152) enrolled patients who were at high risk for developing MM and screened them for a monoclonal gammopathy. High risk was defined as individuals who are Black/African American and those with first degree relative with hematologic malignancy or precursor condition to MM. Screening was by mass spectrometry. Among the 2,960 participants, the prevalence of MGUS was 10 percent, with increasing prevalence in older individuals. This is higher than expected compared to those with none of the above risk factors. Again, whether identifying these patients early will result in improved outcomes is yet to be determined. 

Moving on to novel therapeutic approaches, chimeric antigen receptor T cells continue to make tremendous impact in multiple hematologic malignancies and MM is no exception. Dr. Thomas Martin and colleagues (abstract 549) present dramatic results of CARTITUDE-1, a study of ciltacabtagene autoleucel in a heavily pretreated population. Ciltacabtagene autoleucel, unlike idecabtagene vicleucel (which was approved by the U.S. Food and Drug Administration for the treatment of relapsed/refractory MM in 2021), has two BCMA-targeting domains. At 18-month follow-up, the overall response rate was 97.9 percent with 66 percent of patients progression-free, and 80.9 percent alive. It is remarkable that most of the heavily pretreated population remains in remission after only one treatment. 

Several updated analyses of trials will be reported at the 2021 ASH Annual Meeting. We know, in general, three drugs are better than two for the treatment of newly diagnosed patients with MM, but are four better than three? Dr. Jacob Laubach and colleagues (abstract 79) discuss the 24-month update of the GRIFFIN trial, a randomized phase II trial which compared addition of daratumumab to lenalidomide/bortezomib/dexamethasone (RVd) against RVd in newly diagnosed, transplant-eligible patients. The addition of daratumumab resulted in higher rates of minimal residual disease (MRD) negativity. Dr. Hartmut Goldschmidt and colleagues (abstract 463) report the results of the GMMG-HD7 trial, a phase III randomized study of RVd versus isatuximab + RVd in newly diagnosed, transplant-eligible patients with MM. The primary endpoint was MRD negativity. Similar to the GRIFFIN trial, the addition of isatuximab resulted in higher rates of MRD negativity. This is not surprising as adding another active drug is expected to improve response rates. However, it is still unknown whether moving daratumumab or isatuximab to the front-line setting improves survival. Notably, higher rates of neutropenia and upper respiratory tract infection were observed in the daratumumab + RVd arm. Dr. Aurore Perrot and colleagues (abstract 464) report the results of the IFM 2018-01 trial, which was a phase II study of daratumumab + ixazomib/lenalidomide/dexamethasone (D-IRd) in newly diagnosed, transplant-eligible and standard-risk patients with MM. A total of 45 patients were enrolled and the MRD negativity at 10-6 (the primary endpoint) was 39.5 percent. Note that recent studies question the utility of ixazomib in patients with MM. Whether the four-drug combinations become the new standard of care for newly diagnosed MM is still in question. 

Many patients with MM now live over a decade. We are hopeful that the introduction of quads up front and additional refinement of cellular therapies and immunotherapies will further improve the life expectancy. We are also optimistic that identifying patients with precursor conditions might lead to strategies to prevent patients from developing plasma cell neoplasms. However, at the same time, we must proceed with caution to ensure such interventions are not increasing patient treatment burden and toxicity without improving survival. 

Dr. Jeong and Dr. Goodman indicated no relevant conflicts of interest.  

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