Daratumumab in the Treatment of Multiple Myeloma: Real World Evidence (2018-2024) at the a. Gemelli Polyclinic (Rome) and Comparison With Registration Studies

Abstract

Objectives:

Multiple myeloma is a malignant neoplasm characterised by uncontrolled growth of monoclonal plasma cells in the bone marrow, leading to the overproduction of nonfunctional intact immunoglobulins or immunoglobulin chains with several complications, including anaemia, bone lesions, infections, hypercalcaemia, renal failure, fatigue, and pain. In recent years, treatment with daratumumab, a monoclonal antibody that binds to the CD38 protein, has proved to be the most effective in slowing the progression of the disease. This mAb acts by inducing the destruction of target cells that express CD38, which are highly prevalent in patients with multiple myeloma. The following study aims to evaluate the response to treatment with daratumumab in patients treated at the Haematology Day Hospital of the Agostino Gemelli Polyclinic in Rome and to compare the overall survival results obtained using Kaplan-Meier curves for patients treated at our hospital with those in registration studies, to evaluate any variability in response.

Methods:

First, data was extracted from the Policlinico’s anti-cancer therapy management portal, extrapolating all infusions carried out between June 2018 and April 2024. The data for each individual patient was completed also taking additional information from the AIFA (Italian Medicines Agency) portal. Once this database was obtained, we proceeded with the processing of the data, evaluating parameters such as treatment persistence, dose intensity or treatment adherence, follow-up, budget impact, and pharmacovigilance.

Results:

Real-world OS was generally lower than in clinical trials, highlighting complexities in an unselected patient population with advanced age and comorbidities. Treatment adherence varied markedly with some patients showing persistence up to 2100 days. In relapsed/refractory MM patients treated with DRd protocol, 63-month OS was around 30%, compared to about 50% in corresponding clinical trials (MMY3004), while newly diagnosed patients not eligible for transplant had 30-month OS nearing 75% compared to about 80% in corresponding clinical trials (MMY3007).

Conclusion:

Real-world data therefore offer a more realistic view of the efficacy and safety of treatments because they reflect the use of drugs in everyday clinical practice, on patients who are more heterogeneous than those in trials and allow evidence to be collected more quickly and at lower cost.

Introduction

Multiple myeloma (MM) is a malignant neoplasm characterised by abnormal proliferation of plasma cells in the bone marrow, leading to overproduction of non-functional intact immunoglobulins or immunoglobulin chains. The accumulation of these immunoglobulins and the interaction of aberrant monoclonal plasma cells with other cells in the bone marrow lead to a number of complications, including anaemia, bone lesions, infections, hypercalcaemia, renal failure, fatigue, and pain. ¹

Over the past 2 decades, the introduction of innovative therapies, such as proteasome inhibitors (PIs) and immunomodulatory drugs (IMIDs), has significantly improved both the quality and duration of life for patients with MM. However, the disease tends to become progressively refractory to available therapies, inevitably leading to the death of the patient.

Multiple myeloma accounts for approximately 1% of all cancers and 10% of haematological malignancies. ² Every year, more than 180 000 new cases of multiple myeloma are diagnosed worldwide and approximately 120 000 people lose their lives to the disease (Figure 1).

Figure 1.

Incidence and mortality of multiple myeloma worldwide.

The introduction of various drugs in the treatment of MM, including thalidomide, lenalidomide, bortezomib, pomalidomide, carfilzomib, elotuzumab, and daratumumab, often in combination with dexamethasone, has significantly improved survival both at diagnosis and in cases of relapse.

Daratumumab is a human IgG1κ anti-CD38 monoclonal antibody (mAb), produced in a mammalian cell line (Chinese Hamster Ovary, CHO) using recombinant DNA technology. It binds to the CD38 protein, which is highly expressed on the surface of multiple myeloma cells and, to varying degrees, also in other types of cells and tissues.

The CD38 protein has multiple functions, such as receptor-mediated adhesion, signal transduction activity, and enzymatic activity. CD38 is highly and uniformly expressed on myeloma cells and is present at relatively low levels in normal lymphoid and myeloid cells and in some non-haematopoietic tissues, making it a potential target for the treatment of myeloma.

Preclinical studies ³ have shown that daratumumab induces the destruction of target cells expressing CD38 through several mechanisms, including complement-mediated and antibody-dependent cell cytotoxicity, antibody-dependent cellular phagocytosis, apoptosis and, to a lesser extent, inhibition of CD38 enzymatic activity.

Daratumumab is used for the following indications ⁴ :

• in combination with lenalidomide and dexamethasone or with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplantation.

• in combination with bortezomib, thalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplantation.

• in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 1 prior therapy.

• as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose previous therapies have included a proteasome inhibitor and an immunomodulator, and who have shown disease progression during their last therapy.

The dosage of daratumumab is related to the patient’s weight in the case of intravenous (IV) infusion; in the case of subcutaneous (SC) administration, the dosage is 1800 mg.

There are various treatment protocols that involve the administration of daratumumab:

• DRd → daratumumab (16 mg/kg or 1800 mg) + lenalidomide + dexamethasone

• DVMP → daratumumab (16 mg/kg or 1800 mg) + bortezomib + melphalan + prednisone:

• DVTd → daratumumab (16 mg/kg or 1800 mg) + bortezomib + thalidomide + dexamethasone:

This regimen is used to treat newly diagnosed patients who are eligible for autologous stem cell transplantation (ASCT). The transplant will be performed after the 16th week of high-dose chemotherapy in the induction phase.

• DVd → daratumumab (16 mg/kg or 1800 mg) + bortezomib + dexamethasone

Subcutaneous administration is preferred over intravenous administration both for greater convenience (less invasive, fewer devices used, less pain associated with needle insertion into the vein) and for a significant reduction in infusion time. Subcutaneous administration of daratumumab takes approximately 3 to 5 minutes, compared to intravenous administration, which proceeds at a maximum rate of 200 ml/h.

The following study aims to evaluate the response to treatment with daratumumab in patients treated at the Agostino Gemelli University Hospital Foundation (FPG) in Rome. Through an analysis of real-world data covering a 6-year period (2018-2024), Kaplan-Meier curves were developed to evaluate the overall survival of patients with multiple myeloma treated at the Gemelli Haematology Day Hospital.

Materials and Methods

First, data was extracted from the Gemelli Polyclinic’s anti-cancer therapy management portal, extrapolating all infusions carried out between June 2018 and April 2024.

Using Microsoft Excel to process the data, the data for each individual patient was completed by also taking additional information from the AIFA (AIFA: Italian Medicines Agency) portal.

The AIFA monitoring registries are computerised platforms managed by the Italian Medicines Agency (AIFA) to oversee the appropriate prescribing of innovative drugs, off-label uses, or those subject to conditional reimbursement.

Co-managed with Italy’s Regional Health Authorities, these registries enable uniform nationwide access to therapies by tracking data on efficacy, safety, adherence, and expenditure through clinical information entered by authorised physicians and pharmacists.

For non-Italian audiences, these registries exemplify a pharmacovigilance and real-world evidence (RWE) system unique to Italy’s centralised yet regionally collaborative healthcare model, ensuring cost containment while generating longitudinal data to inform drug policy and clinical guidelines.

The final spreadsheet presented the following information for each patient:

• - Drug administered

• - Route of administration

• - Indication

• - Stage of the disease

• - Previous lines of therapy

• - Combination with other drugs

• - Patient cytogenetics

• - Sequential code of administrations in chronological order per patient

• - Progressive patient code: each patient has their own fictitious code so that the data remains anonymous

• - Date of birth

• - Patient gender

• - AIC drug used

• - Date of administration of treatment

• - Requested drug dose in milligrammes

• - Date of last prescription

• - Prescribed daily dose (PDD), obtained as the ratio between the dose administered and the time interval in days between 1 administration and the next

• - Department where the drug was administered

Once this database was obtained, the data was processed by evaluating parameters such as treatment persistence, dose intensity or treatment adherence, follow-up, budget impact, and pharmacovigilance.

Results

This study evaluated the response to treatment with daratumumab in patients treated at the Agostino Gemelli University Hospital in Rome over a period of 6 years (2018-2024). Kaplan-Meier curves were then calculated to assess the overall survival of patients with multiple myeloma treated at the haematology day hospital and compared with those reported in the registration studies included in the SPC.

The data for each approved indication for use of the drug was then analysed:

• Relapsed or refractory multiple myeloma

• Newly diagnosed multiple myeloma in patients not eligible for autologous stem cell transplantation

• Newly diagnosed multiple myeloma in patients eligible for autologous stem cell transplantation

A summary Table 1 is first presented, providing data on drug utilisation across the cohorts of treated patients.

Table 1.

Summary Table of Treatments.

Indication	Number of patients treated	First dispensing in the cohort	Last dispensation in the cohort	M	F	Average age	Median follow up (months)	Median TTD (months) Kaplan Meier	On treatment (%)*	Adherence (MPD)
Relapsed or refractory MM	183	20/06/18	18/04/24	41	62	68.0	42.96	21.0	78.4 (6 mo)	0.9
									66.1 (12 mo)
									54.8 (24 mo)
Newly diagnosed MM NO transplant	78	09/03/21	18/04/24	42	24	75.2	17.52	Not estimable	92.3 (6 mo)	0.94
									73.5 (12 mo)
									56 (24 mo)
Newly diagnosed MM transplant	62	07/01/22	17/04/24	40	22	68.8	14.6	Not estimable	/	/

^*% Of patients undergoing treatment not out of the initial total but considering the number of patients remaining after 6-12-24 months.

The table provides a concise description of the characteristics of the 3 cohorts of patients with multiple myeloma included in the analysis, distinguishing them according to therapeutic indication (relapsed or refractory multiple myeloma, newly diagnosed not eligible for transplantation, newly diagnosed eligible for transplantation).

In the summary table, for each indication, are provided the total number of patients treated, the dates of the first and last dispensing within the cohort, the sex distribution (M/F), and the mean age of patients at cohort entry are reported.

The table also presents the median follow-up duration (in months), the median time to discontinuation (TTD) when estimable, the proportions of patients remaining on treatment at 6, 12, and 24 months according to Kaplan-Meier analysis, and treatment adherence measured by the medication possession ratio (MPR).

In the cohort with relapsed or refractory multiple myeloma, the median follow-up duration is longer and the median TTD is estimable, allowing quantification of long-term treatment persistence, although the proportion of patients remaining on therapy progressively decreases at 12 and 24 months.

In the newly diagnosed cohorts (with and without transplantation), the median TTD is not estimable over the observation period, and the proportions of patients on treatment at 6, 12, and 24 months suggest good persistence, particularly among patients not undergoing transplantation, who also show MPR values close to unity.

Patients with relapsed or refractory multiple myeloma were analysed (Table 2).

Table 2.

Table of Patients Treated with Daratumumab with Recurrent or Refractory MM.

Previous lines	No. of treatments	Lena-desa	Bort-desa	Poma-desa	Mono therapy	Bort-melf-pred	Bort-talid-desa	Stage I	Stage II	Stage III	Average age
1	85	67	16	1	0	0	1	40	35	10	71.7
2	38	17	18	1	1	1	0	5	25	8	73.1
3	12	7	4	0	1	0	0	2	7	3	73.5
4	5	1	1	1	2	0	0	1	3	1	70.8
5	2	1	1	0	0	0	0	0	2	0	83.5
6	1	1	0	0	0	0	0	0	0	1	71

The minimum adherence for patients with relapsed or refractory multiple myeloma was observed in 1 patient who had an adherence of 0.3 (30%), with a lower actual dose of the drug administered than the theoretical dose (theoretical dose defined as the total amount of drug that the patient should have received over the entire treatment cycle, assuming an adherence level of 100; his persistence with treatment was also low, with a treatment duration of 200 days. The maximum persistence for this therapeutic indication was approximately 2100 days.

In patients with newly diagnosed MM who are not eligible for autologous stem cell transplantation, the same parameters as previously described were considered (Table 3):

Table 3.

Table of Patients Treated with Daratumumab with Newly Diagnosed MM in Patients Not Eligible for Autologous Stem Cell Transplantation.

Prevous lines	No. of treatments	Bort-desa	Lena-desa	Bort-talido-desa	Bort-melf-pred	Stage I	Stage II	Stage III	Average age
N	76	1	46	1	28	34	34	8	77

The minimum adherence in this case was 0.48 for a patient with a persistence of less than 200 days; the maximum persistence achieved by a patient was around 1100 days.

Finally, data are reported for patients with newly diagnosed multiple myeloma eligible for autologous stem cell transplantation (Table 4):

Table 4.

Table of Patients Treated with Daratumumab with Newly Diagnosed MM in Patients Eligible for Autologous Stem Cell Transplantation.

Previous lines	No. of treatments	Bort-thalidomide-desa	Stage I	Stage II	Stage III	Average age
N	62	62	26	26	8	62

Since interruption for transplantation is possible, TTD and treatment adherence data are not relevant for this indication because, after a period of time, all patients interrupt therapy to undergo autologous stem cell transplantation. However, the graphs prepared for this information are reported.

The minimum adherence in this case was 0.3 for a patient with a persistence of 500 days; the maximum persistence achieved by a patient was 600 days. Patients then discontinue treatment to undergo autologous stem cell transplantation.

For the ASCT indication, Kaplan-Meier curves were not calculated for patients treated with daratumumab, as daratumumab therapy is discontinued in order for the patient to undergo ASCT.

Analysing the MMY3003 study, which evaluated treatments for patients undergoing DRd protocol therapy and with relapsed or refractory MM, it can be seen that, with the same therapeutic protocol, the OS at approximately 63 months is approximately 0.5 in the MMY3003 study and approximately 0.3 in FPG patients (Figure 2).

Figure 2.

Comparison between OS in the MMY3003 study and FPG patients treated with the DRd protocol in relapsed or refractory MM. A vertical red line has been added to highlight the month of the end of the monitoring period for the corresponding FPG patients.

In the MMY3004 study, the OS reported at 66 months of monitoring is approximately 0.5, unlike the data obtained from FPG patients, in whom the combination of daratumumab with bortezomib and dexamethasone led to an OS value of 0.3 after 66 months (Figure 3).

Figure 3.

Comparison between OS in the MMY3004 study and FPG patients treated with the DVd protocol in relapsed or refractory MM. A vertical red line has been added to highlight the month of the end of the monitoring period for the corresponding FPG patients.

Comparing FPG patients with those in the MMY3007 study, at 30 months of monitoring the results are almost identical, with a survival rate of approximately 0.75 for FPG patients and approximately 0.8 for MMY3007 patients (Figure 4).

Figure 4.

Comparison between OS in the MMY3007 study and FPG patients treated with the DVMP protocol in MM in patients not eligible for autologous stem cell transplantation. A vertical red line has been added to highlight the month of the end of the monitoring period for the corresponding FPG patients.

As in studies MMY3003 and MMY3004, study MMY3008 also shows the same difference in OS value of approximately 0.2 between study patients (OS of 0.8 at 35 months) and FPG patients (OS of 0.6 at 35 months; Figure 5).

Figure 5.

Comparison between OS in the MMY3008 study and FPG patients treated with the DRd protocol in MM in patients not eligible for autologous stem cell transplantation. A vertical red line has been added to highlight the month of the end of the monitoring period for the corresponding FPG patients.

In addition, data on suspected ADRs related to the use of daratumumab since 2016, updated on 25/03/2025, taken from the EudraVigilance portal, are reported below.

EudraVigilance is the European Medicines Agency’s (EMA) centralised web-based system for managing and analysing reports of suspected adverse reactions to medicines authorised or under clinical investigation in the European Economic Area (EEA).

It comprises 2 main modules: the Clinical Trial module (EVCT) for collecting Suspected Unexpected Serious Adverse Reactions (SUSARs) from interventional clinical trials, and the EudraVigilance Post-Marketing Module (EVPM) for all post-marketing adverse event reports from healthcare professionals, patients, and marketing authorisation holders.

Operational since 2001 and enhanced in 2017, EudraVigilance supports pharmacovigilance by detecting safety signals, enabling rapid risk mitigation, and facilitating data sharing across EU member states to ensure ongoing monitoring of medicine safety.

A serious ADR is an adverse drug reaction that results in death, is life-threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability/incapacity, or causes a congenital anomaly/birth defect.

A non-serious ADR is an adverse drug reaction that does not meet any of the seriousness criteria above, typically involving clinically relevant but less severe outcomes that do not lead to death, are not life-threatening, and do not require or prolong hospitalisation or result in significant disability (Table 5).

Table 5.

Number of Adverse Reactions in Patients Treated with Daratumumab, Reported on the EudraVigilance Portal.

	Number of individual cases
Reaction groups/severity	Non-severe	Serious	Total
Injuries, poisonings, and procedural complications	222	1977	2199
General disorders and administration site conditions	222	1732	1954
Respiratory, thoracic, and mediastinal disorders	127	1119	1246
Blood and lymphatic system disorders	30	1134	1164
Benign, malignant, and unspecified neoplasms (including cysts and polyps)	3	1148	1151
Infections and infestations	63	1017	1080
Under investigation	81	994	1075
Nervous system disorders	73	755	828
Gastrointestinal disorders	98	508	606
Heart disorders	20	483	503
Skin and subcutaneous tissue disorders	129	305	434
Vascular disorders	35	336	371
Immune system disorders	25	338	363
Musculoskeletal and connective tissue disorders	48	277	325
Metabolism and nutrition disorders	20	198	218
Renal and urinary disorders	8	203	211
Eye disorders	24	144	168
Psychiatric disorders	14	150	164
Surgical and medical procedures	8	121	129
Hepatobiliary disorders	9	104	113
Ear disorders and labyrinthitis	8	27	35
Product-related issues	8	18	26
Social circumstances	1	14	15
Reproductive system and breast disorders	3	8	11
Congenital, familial, and genetic disorders	1	9	10
Endocrine disorders	1	8	9
Conditions related to pregnancy, childbirth, and the perinatal period	0	0	0
Total	1281	13 127	14 408

Discussion

The introduction of daratumumab into the treatment protocols for patients with multiple myeloma has significantly increased survival rates, as reported in the SPC, when compared with the same drug treatments without this monoclonal antibody.

An analysis of the overall survival (OS) data of patients treated with daratumumab at the Policlinico Gemelli hospital shows that the Kaplan-Meier curves for FPG patients tend to differ from those in the registration studies reported in the SPC.

This discrepancy in values suggests that the survival rates of FPG patients treated outside a controlled setting such as a clinical trial are lower than those reported in registration studies.

This discrepancy between real-world data (RWD) and clinical trial values (RCT) is related to factors such as:

• - Population selection bias

  • ○ RCT: patients are selected according to very strict criteria (inclusion/exclusion), often excluding elderly patients, those with multiple morbidities or those undergoing multiple therapies.
  • ○ RWD: includes ‘real’ patients, who are often more complex and have very heterogeneous clinical characteristics.

Effect: Trial results tend to overestimate efficacy compared to that observed in the real world (effectiveness).

• - Treatment control and standardisation

  • ○ RCT: high control over dosages, adherence, administration methods, and regular monitoring.
  • ○ RWD: variability in prescribing, adherence, follow-up, and daily clinical practice.

Effect: Greater variability in real-world outcomes, especially in terms of adherence and persistence with treatment.

• - Study duration and setting

  • ○ RCT: often of limited duration, conducted in highly specialised centres.
  • ○ RWD: data collected over longer periods of time, in more heterogeneous clinical settings (local hospitals, general practice).

Effect: RWD can better highlight rare events or long-term effects.

• - Data collection method

  • ○ RCT: highly controlled data collection, with little variability.
  • ○ Effect: Possible biases or inaccuracies in estimating the effect of treatment.

Effect: Possible bias or inaccuracies in estimating the effect of treatment.

• - Bias and confounders

  • ○ RCT: randomisation minimises bias and confounding factors.
  • ○ RWD: absence of randomisation → risk of indication bias, unmeasured confounders.

Effect: Estimates of efficacy/equivalence may be distorted.

• - Patient adherence and behaviour

  • ○ RCT: patients often more motivated, monitored and informed.
  • ○ RWE: includes real-world variability in treatment adherence.

Effect: Reduction in treatment efficacy in the real world.

Conclusions

In summary, RWDs offer a more realistic view of the efficacy and safety of treatments because they reflect the use of drugs in everyday clinical practice, on patients who are more heterogeneous than those in trials and allow evidence to be collected more quickly and at lower cost.