Differences in safety profiles of newly approved medications for multiple myeloma in real-world settings versus randomized controlled trials

Abstract

Background

Four new agents (elotuzumab, ixazomib, panobinostat, and daratumumab) were approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of multiple myeloma. Our objective was to compare the safety profiles of these new medications in real-world settings and their randomized controlled trial(s).

Material and methods

An analysis was conducted of the FDA Adverse Event Reporting System (FAERS) for each drug consisting of the quarter that the drug received its FDA approval and the eight subsequent quarters. Reporting odds ratios and corresponding 95% confidence intervals were then calculated for each drug for each of the 10 most frequent adverse drug reactions. The randomized controlled trials that led to initial FDA approval for these medications were subsequently reviewed to assess the 10 most frequently reported adverse drug reactions in these trials.

Results

There were only two adverse drug reactions in the top 10 of both FAERS and its randomized controlled trials for elotuzumab (anaemia, diarrhoea) and for daratumumab (cough, back pain), five for ixazomib (diarrhoea, constipation, fatigue, nausea, peripheral neuropathy), and four panobinostat (diarrhoea, fatigue, nausea, constipation). Ixazomib had two adverse drug reactions with a significant reporting odds ratios greater than a 10-fold increased risk (plasma cell myeloma, peripheral neuropathy); elotuzumab had three adverse drug reactions (infusion site reaction, malignant neoplasm progression, deep vein thrombosis); daratumumab had three adverse drug reactions (infusion site reaction, bronchospasm, chills), while panobinostat had four (malignant neoplasm progression, decreased platelet count, diarrhoea, increased blood creatinine).

Conclusion

This analysis helps to highlight the importance of conducting postmarketing pharmacovigilance studies to better understand the potential adverse reactions of these medications.

Keywords

Drug safety pharmacovigilance adverse drug reactions real-world evidence adverse event reporting

Introduction

Multiple myeloma (MM) is a cancer of plasma cells that accounts for approximately 17% of all hematologic cancers in the US.^1,2 Approximately 130,000 patients in the US have MM with 32,000 patients diagnosed annually.^2–4 This condition generally affects older populations with a median age at diagnosis of approximately 69 years. In addition, almost 85% of patients are at least 65 years of age at diagnosis.^3–5 Survival rates differ depending on a multitude of factors including stage of disease at diagnosis.^6–8 The advancement of new and novel therapeutic options over the past couple decades has substantially improved overall survival and transformed patient care.^9–13 Although new advancements in therapeutic options have improved patient outcomes, MM is still not curable.

In 2015, four new medications were approved in the US for the treatment of relapsed MM.^14–17 Panobinostat was approved as an oral capsule by the Food and Drug Administration (FDA) in February 2015 in combination with bortezomib and dexamethasone for the treatment of MM in patients who have failed two prior therapies.¹⁴ Ixazomib was approved as an oral capsule by the FDA in November 2015 in combination with lenalidomide and dexamethasone for the treatment of MM in patients who have failed at least one prior therapy.¹⁵ Elotuzumab was approved as an intravenous infusion by the FDA in November 2015 in combination with lenalidomide and dexamethasone for the treatment of MM in patients who have failed one to three prior therapies.¹⁶ Daratumumab was approved as an intravenous infusion by the FDA in November 2015 for MM patients who have failed three prior therapies.¹⁷ Although there have been several systematic reviews, meta-analyses, and review papers published assessing the safety and side effect profiles of these medications based on the results from their randomized controlled trial(s) (RCT),^18–20 there is minimal published data revealing the safety profiles of these medications in real-world settings.

Although RCTs provide high-quality data regarding the safety and efficacy of medications with minimal potential confounding, they do not paint the whole picture of a medication’s safety profile. Randomized controlled trials typically have very selective inclusion criteria and tend to recruit healthier patients and exclude patients with poorer health or comorbid conditions.²¹ Due to this selective inclusion, drug–drug and drug–disease interactions may not be detected during RCTs, meaning the safety profile is not fully known. In addition, biases in study design and data analysis may confound assessment of the study results.²² Most RCTs include a small number of patients. On average, this ranges from 130 to 4000 patients, with studies in oncology and rare diseases including patient populations on the lower end of this spectrum.²³ In addition, a substantial number of medications in the US in recent years, especially in oncology, have been approved through an accelerated approval process using primary endpoints of surrogate outcomes. This accelerated approval process allows trials with fewer patients followed for a shorter time period.^24,25 These approvals increase the risk that RCTs do not observe rare, yet serious ADRs, simply because not enough patients were enrolled, or not enough follow-up time was included to detect these outcomes.²⁶ Even after market approval, it can take years before important safety signals for medications are discovered.^27–30 A study assessing new chemical entities approved by the FDA between 1975 and 1999 found that approximately 10% of these medications eventually acquired a new black box warning or were withdrawn from the market entirely.³⁰ This highlights the importance of postmarketing pharmacovigilance studies to assess the true safety profiles of these medications.

It is important to assess how medications perform in real-world clinical practice. Extrapolating adverse events from RCTs with selective patient criteria does not always provide the guidance practitioners need for newly approved medications. The objective of this study was to assess the safety profiles of these new medications (elotuzumab, ixazomib, panobinostat, and daratumumab) for multiple myeloma in real-world settings, as well as to compare these results to those from their RCTs.

Material and methods

A disproportionality analysis was conducted using data from the FDA Adverse Event Reporting System (FAERS).³¹ The analysis for each drug (elotuzumab, ixazomib, panobinostat, and daratumumab) consisted of the quarter that the drug received its FDA approval and the eight subsequent quarters. Reports were excluded if they were missing age, gender, and event date, as well as follow-up reports, duplicate reports, or reports with the event listed as “No Adverse Event.” All adverse event reports were identified and tallied to assess the 10 most frequently reported events. Reporting odds ratios (ROR) and corresponding 95% confidence intervals (CIs) were then calculated for each drug for each of the 10 most frequent events compared to all other medications using OpenEpi (Version 3.01; Centers for Disease Control and Prevention).³² Adverse reactions reported as “Adverse Drug Reaction,” “Adverse Event,” “Adverse Reaction,” and “Hospitalization” were not considered as reactions when tallying the ten most frequent events due to the nonspecific nature of the reported reaction; however, they were included in the denominator when calculating the ROR. The phase III RCTs that led to initial FDA approval for these medications were subsequently reviewed to assess the 10 most frequently reported ADRs in these trials.^33–39 All reactions, regardless of grade and severity, were included and tallied in the analysis. This was done due to the fact that severity of adverse reaction is not included in FAERS.

Results

There were 196 patients in the daratumumab arm of its respective RCTs, 318 patients for elotuzumab, 361 patients for ixazomib, and 381 patients for panobinostat (Table 1).^33–39 The analysis of FAERS resulted in a total of 1,968,242 reactions of all medications during the study period of daratumumab, elotuzumab, and ixazomib (October 2015 through December 2017) and 1,950,320 total reactions of all medications during the study period of panobinostat (January 2015 through March 2017) (Table 2). The FAERS analysis indicated that there were a total of 935 total reactions for daratumumab (0.05%), 311 total reactions for elotuzumab (0.02%), 1712 total reactions for ixazomib (0.09%), and 318 total reported reactions for panobinostat (0.02%).

Table 1.

Comparison of top 10 most frequent adverse events in clinical trials vs. FAERS.

Daratumumab				Elotuzumab				Ixazomib				Panobinostat
RCTs (n = 196)		FAERS (#935)		RCT (n = 318)		FAERS (#311)		RCT (n = 361)		FAERS (#1,712)		RCT (n = 381)		FAERS (#318)
Reaction	#	Reaction	#	Reaction	#	Reaction	#	Reaction	#	Reaction	#	Reaction	#	Reaction	#
Fatigue	96	Infusion site reaction	78	Lymphocytopenia	316	Death	42	Rash	203	Death	332	Diarrhoea	260	Diarrhoea	56
Nasal pharyngitis	67	Death	54	Anaemia	306	Infusion site reaction	12	Diarrhoea	164	Diarrhoea	97	Peripheral neuropathy	231	Death	37
Anaemia	55	Dyspnea	44	Thrombocytopenia	266	Malignant neoplasm progression	10	Constipation	126	Fatigue	78	Fatigue	217	Fatigue	20
Nausea	54	Cough	29	Neutropenia	260	Pneumonia	8	Neutropenia	118	Pneumonia	46	Nausea	138	Malignant neoplasm progression	10
Cough	50	Chills	25	Fatigue	149	Chills	7	Thrombocytopenia	112	Nausea	43	Peripheral edema	109	Anaemia	9
Pyrexia	50	Back pain	24	Diarrhoea	149	Diarrhoea	7	Fatigue	106	Plasma cell myeloma	40	Decreased appetite	107	Platelet count decreased	6
Back pain	49	Disease progression	22	Pyrexia	119	Deep vein thrombosis	6	Anaemia	103	Constipation	35	Constipation	102	Constipation	6
Upper respiratory tract infection	43	Chest pain	22	Constipation	113	Anaemia	5	Nausea	104	Abdominal pain	27	Pyrexia	99	Confusional state	6
Thrombocytopenia	41	Neutrophil count decreased	19	Cough	100	Atrial fibrillation	5	Peripheral edema	101	Malaise	25	Vomiting	98	Blood creatinine increased	6
Diarrhoea	41	Bronchospasm	12	Muscle spasms	95	Rash	5	Peripheral neuropathy	97	Neuropathy peripheral	22	Cough	81	Nausea	5

FAERS: FDA Adverse Event Reporting System; RCT: randomized controlled trial.

Table 2.

Adverse event reporting odds ratios from FAERS.

Daratumumab					Elotuzumab					Ixazomib					Panobinostat
Reaction	D Reports	Total Reaction Reports	ROR	95% CI	Reaction	E Reports	Total Reaction Reports	ROR	95%CI	Reaction	I Reports	Total Reaction Reports	ROR	95%CI	Reaction	P Reports	Total Reaction Reports	ROR	95%CI
Infusion site reaction	78	2,109	88.07	69.57–111.50	Death	42	75,626	3.91	2.82–5.41	Death	332	75,626	6.04	5.36–6.81	Diarrhoea	56	26,886	15.32	11.48–20.45
Death	54	75,626	1.53	1.16–2.02	Infusion site reaction	12	2,109	37.62	21.10–67.10	Diarrhoea	97	29,094	4.01	3.27–4.93	Death	37	71,074	3.48	2.47–4.91
Dyspnea	44	14,989	6.45	4.76–8.74	Malignant neoplasm progression	10	2,857	22.93	12.20–43.10	Fatigue	78	46,121	1.99	1.59–2.50	Fatigue	20	45,655	2.8	1.78–4.41
Cough	29	13,242	4.73	3.27–6.86	Pneumonia	8	9,658	5.36	2.66–10.81	Pneumonia	46	9,658	5.62	4.19–7.54	Malignant neoplasm progression	10	2,299	27.63	14.70–51.93
Chills	25	5,328	10.16	6.83–15.14	Chills	7	5,328	8.49	4.01–17.97	Nausea	43	12,092	4.18	3.09–5.66	Anaemia	9	11,260	5.02	2.59–9.74
Back pain	24	12,889	4	2.67–6.01	Diarrhoea	7	29,094	1.54	0.73–3.25	Plasma cell myeloma	40	2,309	20.71	15.10–28.41	Platelet count decreased	6	1,660	22.65	10.09–50.88
Disease progression	22	5,224	9.09	5.95–13.88	Deep vein thrombosis	6	3,488	11.1	4.94–24.91	Constipation	35	9,569	4.28	3.06–5.99	Constipation	6	9,145	4.08	1.82–9.16
Chest pain	22	12,226	3.85	2.52–5.86	Anaemia	5	10,315	3.1	1.28–7.51	Abdominal pain	27	52,788	0.58	0.40–0.85	Confusional state	6	6,396	5.85	2.61–13.12
Neutropenia	12	3,015	8.5	4.81–15.05	Atrial fibrillation	5	4,776	6.72	2.78–16.28	Malaise	25	14,531	1.99	1.34–2.96	Blood creatinine increased	6	3,738	10.03	4.47–22.51
Bronchospasm	12	741	35.07	19.75–62.27	Rash	5	15,676	2.04	0.84–4.93	Neuropathy peripheral	22	2,297	11.24	7.37–17.15	Nausea	5	11,938	2.59	1.07–6.28
Total	935	1,968,242			Total	311	1,968,242			Total	1,712	1,968,242			Total	318	1,950,302

FAERS: FDA Adverse Event Reporting System; D: daratumumab; E: elotuzumab; I: ixazomib; P: panobinostat; ROR: reporting odds ratio; CI: confidence interval

The most frequently reported ADRs for daratumumab in its RCTs were fatigue, nasopharyngitis, anaemia, nausea, cough, pyrexia, back pain, upper respiratory tract infection, thrombocytopenia, and diarrhoea, whereas the most frequently reported reactions in FAERS were infusion site reactions, death, dyspnea, cough, chills, back pain, disease progression, chest pain, neutropenia, and bronchospasm.^36–39 The only ADRs for daratumumab that were in the top 10 of both its RCTs and FAERS were cough and back pain. The most frequently reported ADRs for elotuzumab in its RCT were lymphocytopenia, followed by anaemia, thrombocytopenia, neutropenia, fatigue, diarrhoea, pyrexia, constipation, cough, and muscle spasms.³⁵ This differed from FAERS, however, where the most frequently reported elotuzumab ADRs were death, infusion site reaction, malignant neoplasm progression, pneumonia, chills, diarrhoea, deep vein thrombosis (DVT), anaemia, atrial fibrillation, and rash. The only ADRs for elotuzumab that appeared in both lists were anaemia and diarrhoea. The most frequently reported ADRs for ixazomib in its RCT were rash, diarrhoea, constipation, neutropenia, thrombocytopenia, fatigue, anaemia, nausea, peripheral edema, and peripheral neuropathy, whereas in FAERS death, diarrhoea, fatigue, pneumonia, nausea, plasma cell myeloma, constipation, abdominal pain, malaise, and peripheral neuropathy were the most frequently reported.³⁴ The ADRs for ixazomib that appeared in both lists were diarrhoea, constipation, fatigue, nausea, and peripheral neuropathy. For panobinostat, the most frequent ADRs in the RCT were diarrhoea, peripheral neuropathy, fatigue, nausea, peripheral edema, decreased appetite, constipation, pyrexia, vomiting, and coughing.³³ The most frequently reported ADRs in FAERS for panobinostat were diarrhoea, death, fatigue, malignant neoplasm progression, anaemia, decreased platelet count, constipation, confusional state, increased blood creatinine, and nausea. Only diarrhoea, fatigue, nausea, and constipation appeared in both lists for panobinostat.

Elotuzumab’s top 10 reported ADRs in FAERS all had significantly increased risk estimates compared to all other medications except for diarrhoea (ROR: 1.54 [95% CI: 0.73–3.25]) and rash (ROR: 2.04 [95% CI: 0.84–4.93]) (Figure 1). The ADRs with the highest risk estimates for elotuzumab were infusion site reaction (ROR: 37.62 [95% CI: 21.10–67.10]), malignant neoplasm progression (ROR: 22.93 [95% CI: 12.20–43.10]), DVT (ROR: 11.10 [95% CI: 4.94–24.91]), chills (ROR: 8.49 [95% CI: 4.01–17.97]), and atrial fibrillation (ROR: 6.72 [95% CI: 2.78–16.28]). One of ixazomib’s top 10 FAERS ADRs, abdominal pain, had a statistically significant decreased risk compared to all other medications (ROR: 0.58 [95% CI: 0.40–0.85]) (Figure 2). The remaining ixazomib ADRs listed all had significant increased risks. The ADRs with the highest risk estimates for ixazomib were plasma cell myeloma (ROR: 20.71 [95% CI: 15.10–28.41]), peripheral neuropathy (ROR: 11.24 [95% CI: 7.37–17.15]), death (ROR: 6.04 [95% CI: 5.36–6.91]), pneumonia (ROR: 5.62 [95% CI: 4.19–7.54]), and constipation (ROR: 4.28 [95% CI: 3.06–5.99]). All of panobinostat’s top 10 ADRs in FAERS had statistically significant increased risk estimates compared to all other medications. The panobinostat ADRs with the largest risk estimates were malignant neoplasm progression (ROR: 27.63 [95% CI: 14.70–51.93]), decreased platelet count (ROR: 22.65 [95% CI: 10.09–50.88]), diarrhoea (ROR: 15.32 [95% CI: 11.48–20.45]), increased blood creatinine (ROR: 10.03 [95% CI: 4.47–22.51]), and confusional state (ROR: 5.85 [95% CI: 2.61–13.12]) (Figure 3). All of daratumumab’s top 10 reported ADRs in FAERS had significantly increased risk estimates compared to all other medications. The ADRs with the highest risk estimates for daratumumab were infusion site reaction (ROR: 88.07 [95% CI: 69.57–111.50]), bronchospasm (ROR: 35.07 [95% CI: 19.75–62.27]), and chills (ROR: 10.16 [95% CI: 6.83–15.14]) (Figure 4).

Discussion

To our knowledge this is one of the first studies assessing the safety profiles of panobinostat, ixazomib, elotuzumab, and daratumumab utilizing the FAERS database. There were only two ADRs in the top 10 of both FAERS and its RCT for elotuzumab (anaemia and diarrhoea), two for daratumumab (cough and back pain), five for ixazomib (diarrhoea, constipation, fatigue, nausea, and peripheral neuropathy), and four panobinostat (diarrhoea, fatigue, nausea, and constipation). Almost all of the top ten reactions reported in FAERS for these medications (37 out of 40) had a statistically significant higher risk represented by ROR compared to all other medications. This was true except for diarrhoea and rash for elotuzumab, which had a nonsignificant increase, and abdominal pain for ixazomib, which had a statistically significant decreased risk. Daratumumab had three ADRs with risk estimates greater than 10 compared to all other medications (infusion site reaction [ROR: 88.07 {95% CI: 69.57–111.50}], bronchospasm [ROR: 35.07 {95% CI: 19.75–62.27}], and chills [ROR: 10.16 {95% CI: 6.83–15.14}]). Elotuzumab had three ADRs with risk estimates greater than 10 compared to all other medications (infusion site reaction [ROR: 37.62 {95% CI: 21.10–67.10}]; malignant neoplasm progression [ROR: 22.93 {95% CI: 12.20–43.10}]; and DVT [ROR: 11.10 {95% CI: 4.94–24.91}]). Ixazomib had two ADRs with risk estimates greater than 10 compared to all other medications (plasma cell myeloma [ROR: 20.71 {95% CI: 15.10–28.41}] and peripheral neuropathy [ROR: 11.24 {95% CI: 7.37–17.15}]). Panobinostat had four ADRs with risk estimates greater than 10 compared to all other medications (malignant neoplasm progression [ROR: 27.63 {95% CI: 14.70–51.93}]; decreased platelet count [ROR: 22.65 {95% CI: 10.09–50.88}]; diarrhoea [ROR: 15.32 {95% CI: 11.48–20.45}]; and increased blood creatinine [ROR: 10.03 {95% CI: 4.47–22.51}]. All of the top 10 ADRs observed in FAERS are listed as possible reactions in each medication’s package insert except for disease progression and death for daratumumab, DVT and death for elotuzumab, plasma cell myeloma and death for ixazomib, and malignant neoplasm progression and death for panobinostat.^14–17 Since these medications are indicated in the treatment of MM which is a malignant neoplasm, it is likely that the reported ADRs of plasma cell myeloma, malignant neoplasm progression, and disease progression are the results of the pathophysiology of the disease itself and not the medications. Several studies have shown the occurrence of DVT with elotuzumab.^40,41 In a single-center study of 33 patients receiving elotuzumab-based therapy, one patient (3%) discontinued therapy with elotuzumab following DVT despite adequate prophylaxis with low molecular weight heparin.⁴⁰ In a phase II safety study of accelerated elotuzumab infusion in 321 patients, 1.2% of patients (n = 4) experienced DVT.⁴¹ This reinforces the findings from our study of elotuzumab having a significantly increased odds of DVT. However, since elotuzumab was only approved in combination with lenalidomide and dexamethasone during the study period, it may be possible that DVT is associated with lenalidomide, which has a black box warning for venous and arterial thrombosis (including DVT), and not with elotuzumab.⁴² Clinicians should use caution in prescribing elotuzumab in patients at high risk of DVT until more evidence becomes available.

Although death was either the first or second most frequently reported ADR for all four drugs and had a statistically significant signal, this may be due to the disease itself or unrelated causes. One limitation of the FAERS database is that causality of the ADR and the medication does not need to be established in order for the report to be submitted. Patients with stage III MM are estimated to have a median overall survival of 43 months.⁴³ Since the median survival is approximately three and a half years and these medications are indicated for treatment in patients who have failed between one to three prior therapies, it is possible that patients received these medications later in their disease when they might have been at a higher risk of mortality from MM. The panobinostat RCT showed no difference in overall survival compared to placebo (HR:0.87 [95% CI: 0.69–1.10]).³³ The initial studies for ixazomib and elotuzumab did not have enough follow-up at the time of publication to assess any differences in overall survival (OS).^34,35 However, in the elotuzumab trial, there were 14 deaths observed in the elotuzumab arm (4.4%) compared to 22 (6.8%) deaths in the placebo arm.³⁵ In the ixazomib trial, there were slightly fewer deaths in the ixazomib group (n = 81, 22.5%) compared to placebo (n = 90, 24.9%).³⁴ In the panobinostat trial, one reason for treatment discontinuation was death for 21 patients on panobinostat (5.5%) compared to 17 (4.5%) on placebo.³³ By the time of data cut off, there were 135 deaths (35.2%) compared to 152 deaths (40.3%) in the placebo arm.³³ The overall survival and mortality data from these trials suggest that there is not an increased risk of death for these medications.

Only panobinostat has a black box warning for both severe diarrhoea occurring in at least 25% of patients, and severe and fatal cardiac ischemic events.¹⁴ Its most frequently reported event was diarrhoea for both its RCT as well as the FAERS reports. A previous study of drugs approved for MM found that MM drugs with black box warnings had an increase in FAERS reporting for ADRs in relation to the black box warning.⁴⁴ The fact that panobinostat has a black box warning for diarrhoea, along with the notoriety effect associated with having a black box warning, might explain why diarrhoea was the highest reported ADR for panobinostat.⁴⁵

No studies to date have been identified assessing the real-world safety of elotuzumab or panobinostat. There have been several studies assessing the safety and effectiveness of daratumumab in small sample sizes (less than 100 patients) in real-world settings.^46–49 A retrospective study was conducted in ten oncology centers in Hungary where 99 patients received daratumumab.⁴⁶ Of the 52 total ADRs, infection was the most frequently reported reaction (n = 18), followed by infusion associated reactions (n = 16), neutropenia (n = 7), anaemia (n = 3), thrombocytopenia (n = 3), neurologic reaction (n = 2), gastrointestinal reaction (n = 2), and cardiovascular reaction (n = 1).⁴⁶ A retrospective, single center study of 41 patients in France also found infection to be the most frequently reported reaction (n = 14), followed by infusion related reactions (nausea, cough, and dyspnea) (n = 12), thrombocytopenia (n = 12), anaemia (n = 10), fatigue (n = 7), and neutropenia (n = 2).⁴⁷ A retrospective multicenter study of 21 patients of Asian ancestry found the most commonly reported ADR to be fatigue (n = 11), followed by infusion related reactions (nausea, cough, and dyspnea) (n = 9), thrombocytopenia (n = 8), infection (n = 6), neutropenia (n = 6), and anaemia (n = 5).⁴⁸ A retrospective chart-review of 53 patients at a single institution in Japan found the most common ADRs of daratumumab to be lymphocytopenia (n = 28), followed by neutropenia (n = 24), anaemia (n = 20), infusion related reactions (n = 17), diarrhoea (n = 17), thrombocytopenia (n = 15), pneumonia (n = 5), and nausea (n = 3).⁴⁹ The 11 different reported ADRs seen in these real-world studies encompass seven of the ten most common reactions seen in daratumumab’s RCTs, but only represent three of the top ten reactions seen in FAERS (neutropenia, cough, and dyspnea).

A retrospective analysis was conducted assessing real-world safety and efficacy of the regimen containing ixazomib, lenalidomide, and dexamethasone using data from the Hungarian Ixazomib Named Patient Program (NPP).⁵⁰ Out of the 64 adverse reactions reported, the most frequent was infection (n = 17), followed by thrombocytopenia (n = 14), neutropenia (n = 13), diarrhoea (n = 8), and anaemia (n = 6).⁵⁰ Skin rash, thromboembolism, and cardiac events all had two events reported.⁵⁰ Although 5 of these 8 ADRs were among the top 10 ADRs from the RCT, only 2 of their 8 ADRs (diarrhoea and infection) was among the top 10 FAERS reports (pneumonia was in FAERS top 10 reports, not the broad term of infection).

A previous study was conducted that assessed differences in safety profiles of two oral oncolytics in renal cell carcinoma (sunitinib and sorafenib) by comparing the adverse event data in their clinical trials to what was reported to FAERS post marketing.⁵¹ They found that although some of the adverse events were similar between the RCT and FAERS reports, there was also variance between the two, highlighting the need for real-world safety reports.⁵¹ Although this study did not assess the same drugs as our analysis, it serves to reinforce the importance of assessing the safety of medications post FDA approval.

The follow-up period of each drug was selected as the quarter it was approved and then the subsequent two years as a way to assess the same post-market approval period for all four drugs. All four drugs received their initial FDA approval near the end of the second month of the associated quarter and therefore the total amount of time the drug was available on the market within the study period is quite similar between each drug. In addition, adverse event reporting starts to decline after two years on the market (Weber effect) and the two-year timeframe was selected as the follow-up period that would capture the period before additional underreporting would be expected to take place.^52,53 Events reported as “adverse event,” “adverse reaction,” or “hospitalization” were still counted in the denominator when calculating ROR and may bias results towards the null since the reaction causing the reporting may be the specific reaction we were assessing. In addition, to assess all safety reporting following market approval, we included the quarter each medication was approved even though the medication was not on the market for the entire time period. This allowed us to be comprehensive in our description of each medication’s safety profile. This inclusion, however, may also bias the ROR for each adverse reaction towards the null.

There were several limitations to our study in addition to the ones already described. First and foremost, there are limitations with the FAERS database that have been described extensively in previous literature along with those already mentioned in this article.^54–57 Among these, incidence and prevalence of ADRs are unable to be calculated from FAERS because the total number of patients who are taking each medication is unknown.⁵⁷ In addition, underreporting is expected due to the voluntary reporting nature of FAERS. An additional limitation is that all four of these medications are part of a combination regimen and it is possible that ADRs may have been reported to FAERS for one of the other medications in the regimen, and not the drug of interest. Of note, in November 2018, the FDA approved elotuzumab in combination with pomalidomide and dexamethasone for relapsed multiple myeloma; however, this was 11 months after our study period conclusion for elotuzumab.

Conclusions

This study found key differences in safety profiles and the most commonly reported ADRs of panobinostat, ixazomib, elotuzumab, and daratumumab in real-world settings versus RCTs. This analysis helps to highlight the importance of conducting post marketing pharmacovigilance studies to better understand the potential adverse reactions of these medications. Future studies should be conducted to assess adverse reactions of these medications to see if any additional safety signals appear or if the rates of these reactions change over time.

Footnotes

Acknowledgements

Contents of this study were presented as a poster presentation at the 2019 National Community Oncology Dispensing Association (NCODA) Fall Summit, 24–26 October 2019, in Orlando, Florida.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Eric P Borrelli

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