Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA

Author(s): Michele Cavo ¹, Jesus San-Miguel ², Saad Z Usmani ³, Katja Weisel ⁴, Meletios A Dimopoulos ⁵, Hervé Avet-Loiseau ⁶, Bruno Paiva ², Nizar J Bahlis ⁷, Torben Plesner ⁸, Vania Hungria ⁹, Philippe Moreau ¹⁰, Maria-Victoria Mateos ¹¹, Aurore Perrot ¹², Shinsuke Iida ¹³, Thierry Facon ¹⁴, Shaji Kumar ¹⁵, Niels W C J van de Donk ¹⁶, Pieter Sonneveld ¹⁷, Andrew Spencer ¹⁸, Maria Krevvata ¹⁹, Christoph Heuck ¹⁹, Jianping Wang ²⁰, Jon Ukropec ²¹, Rachel Kobos ¹⁹, Steven Sun ²⁰, Mia Qi ²⁰, Nikhil Munshi ^{22 23}

Source: 2022 Feb 10;139(6):835-844. doi: 10.1182/blood.2021011101.

Dr. Lucio Gordan's Thoughts

MRD status in MM has unquestionable prognostic informational value, however many questions remain as how to address positive / negative MRD results. Should we de-escalate or stop Rx? When? Can we escalate Rx if + MRD? Which regimen, how long? It will be another few years till objective data are available. I do see value in at least having identification of clonality established upfront for tracking.

KEY POINTS

Patients who are MRD negative with ≥CR have improved PFS, regardless of therapy, vs those who do not reach CR or are MRD positive.
Daratumumab-based therapies lead to higher rates of ≥CR with MRD negativity compared with the standard of care.

VISUAL ABSTRACT

Combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA

ABSTRACT

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10⁻⁵ sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

Author Affiliations

¹IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “Seràgnoli”, Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy. ²Clínica Universidad de Navarra, Centro de Investigación Medica Aplicada (CIMA), IDISNA, CIBER-ONC, Pamplona, Spain. ³Levine Cancer Institute/Atrium Health, Charlotte, NC. ⁴Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. ⁵National and Kapodistrian University of Athens, Athens, Greece. ⁶Unite de Genomique du Myelome, IUC-Oncopole, Toulouse, France. ⁷Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, AB, Canada. ⁸Vejle Hospital and University of Southern Denmark, Vejle, Denmark. ⁹Clinica Medica São Germano, São Paulo, Brazil. ¹⁰Hematology, University Hospital Hôtel-Dieu, CHU Nantes, Nantes, France. ¹¹University Hospital of Salamanca/IBSAL/Cancer Research Center-IBMCC (USAL-CSIC), Salamanca, Spain. ¹²Hematology Department, University Cancer Institute IUCT, Toulouse, France. ¹³Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku Nagoya, Japan. ¹⁴University of Lille, CHU Lille, Service des Maladies du Sang, Lille, France. ¹⁵Department of Hematology, Mayo Clinic Rochester, Rochester, MN. ¹⁶Department of Hematology, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. ¹⁷Erasmus MC, Rotterdam, The Netherlands. ¹⁸Malignant Haematology and Stem Cell Transplantation Service, Alfred Health-Monash University, Melbourne, Australia. ¹⁹Janssen Research & Development, LLC, Spring House, PA. ²⁰Janssen Research & Development, LLC, Raritan, NJ. ²¹Janssen Global Medical Affairs, Horsham, PA. ²²Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and. ²³Veterans Administration Boston Healthcare System, West Roxbury, MA.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma

Dual Targeting of Extramedullary Myeloma with Talquetamab and Teclistamab

This is a very impressive signal in a notoriously difficult population—seeing a 79% response rate and median progression-free survival (PFS) of 15.4 months in true extramedullary, triple-class–exposed myeloma is better than expected. Toxicity is real and management-intensive, but the depth and durability of response make this dual-bispecific approach feel like a meaningful advance.

Lisocabtagene Maraleucel Versus Standard of Care for Second-Line Relapsed/Refractory Large B-Cell Lymphoma: 3-Year Follow-Up From the Randomized, Phase III TRANSFORM Study

CAR-T therapy outperformed standard of care (SOC) as a second-line treatment, with progression-free survival (PFS) not reached in the CAR-T group compared to 6.2 months in the SOC group. Despite two-thirds of patients crossing over, CAR-T still demonstrated a three-year overall survival rate of 63%, versus 52% with SOC. These are impressive and durable results. The SOC regimen consisted of three cycles of chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant. This positions CAR-T as a viable second-line option for eligible patients.

Isatuximab Subcutaneous by On-Body Injector Versus Isatuximab Intravenous Plus Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase III IRAKLIA Study

Guess who’s coming as an option beyond AI (OBI)? Yes—this study showed no safety concerns and demonstrated comparable efficacy.

Measurable Residual Disease–Guided Therapy in Newly Diagnosed Myeloma

Quadruplet induction with isatuximab, carfilzomib, lenalidomide, and dexamethasone (Isa‑KRd) has reset expectations for transplant‑eligible NDMM and enables measurable residual disease (MRD)‑adapted strategies; MRD‑negativity at 10^-5 is strongly prognostic, and the necessity of autologous stem-cell transplantation (ASCT)—particularly tandem ASCT—amid deep responses is being re‑examined. Practically, MRD‑adapted consolidation after Isa‑KRd suggests no added depth from ASCT in MRD patients and no advantage for tandem ASCT over single ASCT + Isa‑KRd in MRD+ patients. So in day‑to‑day practice, this looks like a chance to de‑escalate transplant intensity while awaiting mature progression-free survival (PFS)/overall survival (OS) data.