In recent years, multiple myeloma treatment has seen several promising developments, ranging from the advent of immunomodulatory drugs and proteasome inhibitors to monoclonal antibodies and novel immunotherapies including CAR-T cells and bispecific antibodies. For a myriad of patients, this has resulted in prolonged survival and improved quality-of-life. Yet at first diagnosis, patients remain to be in the most vulnerable phase of their therapeutic journey and struggle with severe immunosuppression from the tumor and therapy. Severe infections are common in these patients and substantially limit their benefit from modern myeloma treatment.

In 2016, my mentors and I set out to learn more about these early events in the era of modern myeloma therapy, with a particular interest in younger, transplant-eligible patients with newly diagnosed multiple myeloma who are often regarded as fit and resilient to early morbidity and mortality. Ideally, we sought to identify these patients before treatment initiation using easily assessable variables in clinical routine, and learn and develop strategies to reduce early morbidity and mortality.

Our first analysis included, among other studies, a trial containing thalidomide-based induction therapy. We quickly realized, however, that this was not sufficient anymore and decided to solely focus on trials containing contemporary induction regimens such as lenalidomide, bortezomib, dexamethasone. Together with our dedicated statistician, we identified and merged three trials with 1333 patients and conducted preliminary analyses. It became obvious that more trials would be needed to determine whether our analyses and conclusions could be validated. We were happy to receive tremendous support from our academic research colleagues at the HOVON foundation and European Myeloma Network who contributed more than 1700 additional patients. At the same time that we received data from and validated our findings in the HOVON and EMN studies, we realized that the treatment landscape had rapidly changed: anti-CD38 monoclonal antibodies had become a new standard-of-care in patients with newly diagnosed multiple myeloma. Thus, the GMMG study group steering committee decided, though this data was not fully published at that time, that the phase 3 GMMG-HD7 trial, containing isatuximab, lenalidomide, bortezomib and dexamethasone in the experimental arm could serve as an additional validation cohort and enabled us to test our scoring system in patients receiving the latest available quadruplet induction therapy.

This comprehensive international dataset from three different study groups allowed us to build and validate our proposed risk scoring system for early morbidity and mortality in patients with newly diagnosed multiple myeloma who are eligible for an autologous hematopoietic blood stem cell transplantation. As desired, we identified readily accessible baseline risk factors for early severe infection or death during induction therapy. These factors comprised low platelet count (<150/nL), International Staging System stage III, high World Health Organization performance status (>1), and age (>60 years). Together, these risk factors can be added up to a simple risk score with 1 risk factor being 1 point. Patients are stratified in low (0 points), intermediate (1 point), and high (≥2 points) risk.

Summarizing the past seven years, the development and publication of our risk score can only be considered a starting point. With this score, we aim to support clinicians regarding decisions on prophylactic and supportive care measures and potential dose reductions in the early treatment phase to avoid detrimental outcomes for their patients. We strive to test and validate our risk score in the setting of novel immunotherapies, in patients with relapsed/refractory disease, elderly patients, and other vulnerable multiple myeloma patient groups. As clinical researchers, we will develop studies to investigate how to improve the outcome in patients at high risk for early morbidity and mortality with the goal to derive the greatest possible benefit from the plethora of novel anti-myeloma drugs for each individual patient. Finally, I acknowledge that none of this work would have been possible without interprofessional international teams involving many different disciplines and people dedicated to improve outcomes in patients with hematological malignancies.