Worldwide, multiple myeloma is the third most frequent hematologic malignancy after non-Hodgkin lymphoma and leukemias (1). In 2022, its incidence in Europe was estimated to 50,092 new cases; there were 31,969 deaths and the estimated 5-year prevalence was 149,397, corresponding to 20 affected individuals per 100,000 (1). In Italy there are no dedicated registries for multiple myeloma and epidemiologic data are often scattered or derived from general databases or registries. A systematic analysis of the Global Burden of Disease study 2017 focused on Italy reported 5,983 incident cases of multiple myeloma and 3,638 deaths in 2017 (2). According to this analysis, the age-standardized incidence rate per 100,000 person-years was 5.4 in males and 3.5 in females; the age-standardized death rates per 100,000 person-years were 2.8 and 1.9, respectively. According to the estimates by the Italian Association of Medical Oncology (AIOM) and the Italian Association for Tumor Registries (AIRTUM), in 2024 approximately 34,000 individuals were affected by multiple myeloma in Italy, while approximately 6,600 new patients were diagnosed with the disease (3).

Treatment options for multiple myeloma have expanded over the past two decades, leading to remarkable improvements in overall survival (4–6). Nevertheless, the natural history of the disease continues to be marked by sequential phases of relapse due to increasing drug resistance over time (7). The three main classes of novel agents that have transformed the therapeutic landscape of multiple myeloma include immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, ixazomib), and monoclonal antibodies targeting CD38 (daratumumab and isatuximab) and SLAMF7 (elotuzumab) antigens. These drugs have been combined to form doublet, triplet, and even quadruplet regimens which are currently included into the latest European Hematology Association-European Myeloma Network (EHA-EMN) and National Comprehensive Cancer Network (NCCN) guidelines as standard-of-care therapies for newly diagnosed patients, both candidates (aged less than 70 years and non-frail) and non-candidates for autologous stem cell transplant (ASCT) (8–10). Among recommended upfront treatments, those currently reimbursed in Italy and preferred in most patients include the four-drug regimen daratumumab-bortezomib-thalidomide-dexamethasone followed by lenalidomide maintenance for ASCT candidates, and the three-drug combination daratumumab-lenalidomide-dexamethasone for non-candidates to ASCT (8–10). Finding the most appropriate therapy for patients with relapsed/refractory disease in second and subsequent lines of therapy is far more complex and depends primarily on previously used agents and duration of response (8, 9).

Given the wide number of available treatment options for multiple myeloma, the optimal selection and sequencing of drugs is becoming progressively challenging (10–12). At the time of relapse, the choice of any subsequent line of therapy is driven by many patient- and disease-related factors, one of the most relevant being prior exposure, and eventually refractoriness, to one or more classes of novel agents (13). In particular, the widespread use of continuous lenalidomide as part of first-line therapies for both ASCT-eligible and -non eligible patients has progressively increased the population of patients who are lenalidomide-refractory in their second line of therapy (11, 14). Similarly, refractoriness to daratumumab and double refractoriness to both lenalidomide and daratumumab are on the increase, but reliable quantitative data are lacking (11, 14–16). Only recently have multiple studies and international guidelines begun to recommend the most appropriate and evidence-based treatment strategies for double- and triple-class exposed or refractory patients, who continue to face poor clinical outcomes with currently available options (10, 11, 17, 18). Breakthrough therapies with new mechanisms of action, including chimeric antigen receptor (CAR) T-cells and bispecific antibodies which directly harness immune effector cells to target the B-cell maturation antigen (BCMA) and other antigens, and even before the first-in-class BCMA-targeting drug conjugate belantamab-mafodotin, have demonstrated impressive efficacy in heavily pretreated patients in later treatment lines (12). Following the approval by the European Medicines Agency (EMA) of these breakthrough therapies for the treatment of triple-class exposed relapsed/refractory multiple myeloma, more recently ciltacabtagene autoleucel and belantamab-mafodotin in combination with standard-of-care agents have also been approved for the treatment of relapsed/refractory multiple myeloma after at least one prior therapy and are expected to be then reimbursed in Italy. Specifically, belantamab-mafodotin has a multimodal mechanism of action and is indicated for the treatment of relapsed or refractory multiple myeloma in combination with bortezomib and dexamethasone in patients who have received at least one prior therapy, and combined with pomalidomide and dexamethasone in patients who have received at least one prior therapy including lenalidomide (19). Ciltacabtagene autoleucel is indicated for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least one prior therapy, including an immunomodulatory agent and a proteasome inhibitor, and are refractory to lenalidomide (20).

The impact of newly approved therapies on clinical practice and the treatment algorithm for multiple myeloma in Italy remain uncertain. To explore these issues and address key areas of ambiguity in the current treatment landscape, we conducted a Delphi study designed to gather expert consensus on a series of statements concerning the epidemiology of multiple myeloma in Italy, current treatment patterns and unmet needs in later lines of therapy. Given the limited availability of robust empirical evidence in some of these areas, the Delphi method – an iterative, structured process for systematically collecting and refining expert opinion – was employed to support consensus-building in a rigorous and transparent manner (21).

Consensus on the topics of interest was reached using a modified Delphi procedure (21, 22). In this procedure, statements are submitted to a panel of experts who are asked to express their agreement or disagreement on each statement. Statements on which no consensus is reached are modified, if necessary, and resubmitted to the review by the expert panel until a predefined level of consensus is reached. The experts express their agreement or disagreement independently and anonymously. In each voting round, they have the opportunity to revise their responses after reviewing the aggregated results from the previous round. In the modified Delphi, the experts interact only at the final consensus meeting, where responses and statements with no consensus are discussed face-to-face.

Most statements (28/31, 90%) achieved consensus in two rounds of Delphi voting, while 3 statements (statements 10, 22, 23) had to be further discussed and voted at the final meeting, where consensus was reached on all statements.

This study presents a series of consensus statements outlining the current epidemiology of multiple myeloma in Italy, treatment patterns in clinical practice, unmet clinical needs, and the anticipated changes in the management of patients with multiple myeloma over the next three years, following the expected introduction in Italy of two new immunotherapies in 2026. Notably, it provides structured, expert-derived insights into critical elements of current clinical practice, as well as on future trends within the evolving therapeutic landscape where published evidence remains limited. The consensus achieved on nearly all statements, and within two Delphi rounds, reinforces the robustness and consistency of the expert panel’s perspectives on key aspects of multiple myeloma management.

The estimates concerning the prevalence and incidence of multiple myeloma validated by the expert panel and in line with evidence reported by other authors (24, 25) confirm the significant burden of this condition in Italy. Moreover, the Delphi process allowed to validate the current estimates of treatment prevalence in Italian centers, highlighting that most patients diagnosed with multiple myeloma are actively undergoing pharmacologic treatment across all lines of therapy.

Regarding current management, the study allowed to confirm that the current clinical practice is aligned on considering lenalidomide maintenance and the triplet daratumumab-lenalidomide-dexamethasone as the preferred first-line choices in post-transplant and non-transplant eligible patients, respectively. As lenalidomide is part of the backbone of current first-line therapies, most patients relapsing after ASCT are lenalidomide-refractory and are not deemed eligible for receiving lenalidomide-based regimens in the second-line setting. Among lenalidomide-free therapies available for these patients, the triplet isatuximab-carfilzomib-dexamethasone was considered one of the most active, though it is associated with a relevant burden on patients in terms of management. Therefore, after balancing efficacy and safety the expert panel expressed a sub-optimal level of satisfaction with currently available therapeutic options in Italy in this setting. Similarly, the results of our study reflect the perception that a growing number of patients (≥ 90%) who are non-transplant eligible and receive first-line therapy with daratumumab-lenalidomide-dexamethasone, at the time of relapse are double refractory to both lenalidomide and daratumumab. This observation is consistent with other published data (25). Provided that published guidelines recommend the early use of daratumumab-lenalidomide-dexamethasone in the first-line settings, it is likely that the population of double-refractory patients will face a growing unmet need as the effectiveness and safety of currently available treatment options will be insufficient in a large proportion of them (8–11). Indeed, none of the treatment options for these patients currently available in Italy (i.e., pomalidomide-bortezomib-dexamethasone, selinexor-bortezomib-dexamethasone, and carfilzomib-dexamethasone) were formally investigated in the double-refractory setting of relapsed/refractory multiple myeloma, and data supporting the possible efficacy of some of them in limited series of patients are simply anecdotal.

As for the expected evolution in the management of multiple myeloma in the near future in Italy, the number of patients who will receive second-line therapy in 2026–2028 is predicted to decrease slightly but continuously, mostly due to the efficacy of current first-line therapies, while the number of patients receiving third-line therapy will be stable. Considering the significant efficacy of available first-line options and the better prognosis of ASCT eligible patients, as well as the increased adoption of daratumumab-lenalidomide-dexamethasone for the treatment of patients ineligible for ASCT, according to the consensus reached among clinicians it can be expected that most patients progressing to second-line therapy in the near future will be frail and possibly characterized by a worse prognosis in second- and subsequent lines of therapy.

The need for treatments with new mechanisms of action that have been evaluated in difficult-to-treat populations (e.g., double-refractory patients) are widely acknowledged among clinicians. Therefore, the expert panel members in our study expressed great expectations about the ability of immunotherapies (e.g., belantamab mafodotin-pomalidomide-dexamethasone, belantamab mafodotin-bortezomib-dexamethasone, ciltacabtagene-autoleucel) to meet the needs of current second-line treatment of multiple myeloma. In addition, the expert panel members also agreed about the insufficient effectiveness and safety of current third-line therapies.

This study has some limitations. Notably, the limited size and homogeneity of the expert panel may have influenced the findings, resulting in opinions and predictions that do not fully reflect the heterogeneity of clinical practice across Italy. However, the inclusion of participants with a proven experience in managing multiple myeloma patients working in reference centers across Italy was considered appropriate to capture relevant opinions in current clinical practice. In addition, the initial survey involving the expert panel members may have influenced the responses in following rounds. This survey was nevertheless useful for collecting insights for which limited or no evidence was available at the time of statement drafting. The timeframe considered (three years from the introduction of the new treatment options) is relatively short and may not represent long-term trends relevant for the therapeutic area considered in the present study. However, given the rapid and ongoing evolution in the availability of new therapies and management recommendations for multiple myeloma, extending the timeframe might have compromised the reliability of the estimates. Finally, the findings of this study should be interpreted in light of the Italian healthcare context in which it was conducted, including country-specific epidemiological data and treatment patterns. Differences in national clinical guidelines, physician preferences, and availability of therapies may limit the extent to which these results can be generalized to other healthcare settings or countries.

In conclusion, there is clearly a continuous need for novel treatment options for patients with relapsed/refractory multiple myeloma, as the increasing use of effective combined regimens, including triplets and quadruplets, as frontline treatment of newly diagnosed patients is leading to growing numbers of patients exposed to multiple drug classes who eventually become refractory. The present Delphi study has enabled to capture the perceptions of expert clinicians about the current treatment algorithm of multiple myeloma and the anticipated implications of adopting novel therapies in the near future in Italy. More in detail, the study has highlighted clinicians’ views on the current and future unmet needs in multiple myeloma management and the potential of upcoming therapies to address these gaps. Treatment options, along with the dynamics of refractoriness, are evolving rapidly. To optimally implement novel treatments in clinical practice, reliable tools for predicting this evolution are needed.