Most recent clinical trials of drugs for hematologic malignancies are either nonrandomized or use surrogate endpoints, according to a systematic review.1

The review included 2609 trials that began between 2015 and 2020 and were registered on The trials enrolled patients with multiple myeloma, leukemias, and lymphomas.

Overall, 21% of the trials were randomized, and the proportion of randomized trials decreased from 26% in 2015 to 19% in 2020 (P <.00001). 

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“Unfortunately, what we are seeing, especially over the last 5 to 10 years in some of the blood cancers, is an explosion of single-arm studies,” said review author Aaron Goodman, MD, of the University of California, San Diego. 

Dr Goodman and his colleagues also examined the relationship between trial design and the funding source. Industry sponsors funded 54% of the trials in the review, and trials with industry sponsors were less likely to be randomized compared with non-industry-sponsored trials — 18% and 23%, respectively (P =.0022).

Dr Goodman said that nonrandomized clinical trials can be important for drug development, but these studies are insufficient, as they do not indicate how effective treatment will be in the real-world setting.

Many blood cancer treatments have recently been approved by the US Food and Drug Administration (FDA) on the basis of single-arm, phase 2 studies alone, Dr Goodman noted. 

One example is melphalan flufenamide (melflufen). The FDA granted accelerated approval for melflufen to treat relapsed or refractory multiple myeloma in 2021.2 However, the drug was withdrawn from the US market that same year, after a phase 3 randomized trial showed inferior overall survival with melflufen plus dexamethasone, compared with pomalidomide plus dexamethasone.

Use of Surrogate Endpoints 

Dr Goodman and colleagues also looked at the use of surrogate and clinical endpoints in their review.1

Of the randomized trials, 15% used a clinical primary endpoint, which was defined as either overall survival or quality of life. The remainder of the trials used a surrogate primary endpoint, which was most commonly response rate (44%), followed by progression-free survival (38%) and safety (13%).

Most trials used surrogate primary endpoints regardless of their funding source, the researchers noted. 

“Only 2 things truly matter to patients when they are signing up to receive therapy for their cancer: whether this will make them live longer, and whether they will feel better,” not whether their tumor will shrink or other surrogate endpoints, Dr Goodman said. 

The patterns observed in this review are not limited to trials in hematologic cancers. A cohort study published last year showed that the most common endpoint in randomized trials of solid tumors published between 2010 and 2020 was progression-free survival, and the vast majority of trials were industry funded.3 

Implications for Practice, Drug Approval

Although the findings of the review were not surprising, it was disappointing to see the “trend is going in the wrong direction” in terms of fewer randomized trials in recent years, Dr Goodman said. 

The result is that more treatment options are available for patients, he acknowledged. However, it is hard for clinicians to know which treatments provide real survival benefits, and how to use these drugs, whether alone or in combination. 

Dr Goodman said this issue could be addressed if the FDA were to say it will no longer approve drugs based on nonrandomized trials or surrogate endpoints. “That would be the easiest fix,” he said. 

He suggested that the FDA could also continue to allow accelerated approvals based on surrogate endpoints, so as not to slow drug development, but require randomized trials with clinical endpoints to be completed within a reasonable period of time. 

Disclosures: Dr Goodman disclosed consulting for EUSA Pharma and Seagen. His coauthors also declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.


1. Wesson W, Galate VL, Sborov DW, et al. Characteristics of clinical trials for haematological malignancies from 2015 to 2020: A systematic review. Eur J Cancer. 2022;S0959-8049(22)00047-8. doi:10.1016/j.ejca.2021.12.037

2. Olivier T, Prasad V. The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA. Transl Oncol. 2022;18:101374. doi:10.1016/j.tranon.2022.101374

3. Del Paggio JC, Berry JS, Hopman WM, et al. Evolution of the randomized clinical trial in the era of precision oncology. JAMA Oncol. 2021;7(5):728-734. doi:10.1001/jamaoncol.2021.0379