I-OPen: inferior outcomes of penta-refractory compared to penta-exposed multiple myeloma patients
Open accessAbstract
Multiple myeloma (MM) is a clinically and biologically heterogeneous malignancy characterized by structural and numerical chromosomal abnormalities, mutational and copy number abnormalities that have impact on prognosis and responsiveness to various therapies [ 1 , 2 ]. The treatment paradigms and outcomes for patients with MM have improved significantly over the past 15 years with increased understanding of the disease biology and expansion of therapeutic options [ 3 , 4 ]. The five most active anti MM drugs that define the term “penta-refractory” are proteasome inhibitors (PIs) bortezomib and carfilzomib, immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide and the anti-CD38 monoclonal antibodies (CD38 MoABs) [ 4 , 5 ]. Triplet and quadruplet therapies for induction and/or relapse have led to improved survival [ 6 , 7 ]. Despite these advances in treatments, relapse of MM is inevitable. With each relapse, there may be acquisition of new mutations, epigenetic changes, and changes in the bone marrow microenvironment but there is also shift in the distribution of preexisting clones as selective pressures are applied rendering the disease more resistant and leading to ultimate development of relapsed/refractory MM (RRMM), extramedullary disease, and plasma cell leukemia, where further options are unlikely to result in deep or durable remissions [ 8 , 9 ]. To date, there have been no large-scale single-center “real-world” studies with long-term follow-up among quad-and penta exposed and/or refractory MM patients. We report the patient characteristics of this patient population to provide a benchmark for new therapies. The study included consecutive patients from John Theurer Cancer Center at Hackensack University Medical Center who were quad and penta exposed and/or refractory between the dates of 1/1/2015 and 3/1/2021. Quad-exposed was defined as having had prior exposure to two proteasome inhibitors (PIs): bortezomib or ixazomib and carfilzomib and 2 immunomodulatory drugs (IMiDs): lenalidomide and pomalidomide. Penta-exposed was defined as having prior exposure to 2 PIs and 2 IMiDs and additional exposure to an anti-CD38 monoclonal antibody (CD38 MoABs). Penta or quad refractory was defined as having stable disease (as best response) or progressive disease while on all of the above drugs, per International Myeloma Working Group (IMWG) definition of refractory [ 10 ]. The time point at which patients met the above criteria for progression was referred to as time zero (T0 r ) for the refractory group and the time point of exposure to the last drug of the above treatment was referred to as T0 e for the quad/penta exposed group. Study data were collected between March 2021 and November 2021 and managed using electronic data tools available at Hackensack University Medical Center. For analysis, patients were classified into four groups based on Quad/Penta and Exposed/Refractory: Quad exposed, Quad refractory, Penta exposed and Penta refractory. Overall response rate (ORR) used the IMWG criteria. Overall survival (OS) time was measured from T0 until death or last follow up. For the subset of patients who underwent further therapy after T0, we analyzed the response to subsequent therapy and progression-free survival (PFS), here defined as the time between the onset of the next line of therapy and disease progression or death. We compared categorical variables between two or more groups utilizing Fisher’s exact test or Pearson’s chi-squared test and continuous variables utilizing the Kruskal-Wallis non-parametric test. For ORR, the exact binomial 95% confidence interval (CI) was calculated. The median PFS and OS were estimated using the Kaplan-Meier method for the entire population and for subgroups of patients. Comparisons of OS and PFS between groups were performed using a log-rank test. Univariate and multivariable adjusted Cox proportional hazard regression models examined patient-disease and treatment features affecting OS. One hundred and sixty patients were included in this study: the median age at diagnosis was 68.5 (range 60–74), 56% patients were male and 44% were stratified as high risk. Extramedullary disease was present in 24% of patients. The majority of patients ( N = 109, 68%) were “penta-refractory”, 32 (20%) were “quad - refractory” and 19(12%) were “quad and penta exposed”. Median interval from diagnosis of MM to T0 was 59 months (IQR 37–99) for all patients. The median number of prior therapies for all patients was 6 (IQR 4–8) prior to T0; 82% of all patients underwent prior autologous hematopoietic cell transplantation (AHCT). The median overall survival (OS) from the time of penta or quad refractoriness or exposure (T0) for the entire cohort was 8.09 months (95% CI, 5.8–15.03). The median OS for the penta- refractory group was 6.6 months (95% CI, 4.8–12.4) (Fig. 1a ). The median OS for the quad/penta refractory group combined was 6.0 months (95% CI, 4.4–8.2) versus median OS for quad/p
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Patients with advanced disease stage (R-ISS stage III) have consistently shown poorer outcomes irrespective of the therapy received.
“Similarly, patients with advanced disease stage (R-ISS stage III) have consistently shown poorer outcomes irrespective of the therapy received4–6,19–22.”
From Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results (2023) · cites this paper as [22]
The To the Editor section reports poorer outcomes for quad- or penta-refractory patients than for exposed patients, but it does not establish outcomes by R-ISS stage or across therapies. Searches for “R-ISS,” “stage III,” and staging-related survival findings found no passage addressing the claim about R-ISS stage III. (LLM, conf=0.74)
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- Authors
- Gill, S. K., Unawane, R., Wang, S., Ahn, J., Aleman, A., Siegel, D. S., Vesole, D. H., Parmar, H., Phull, P., & Biran, N.
- Affiliations
- Hackensack University Medical Center (US)
- Georgetown University (US)
- Corresponding author
- Gill, Sarvarinder K.
- ORCID
- Venue
- Blood Cancer Journal
- Published
- 2022-09-23
- Volume
- 12
- Issue
- 9
- Pages
- 138-138
- ISSN
- 2044-5385 (ISSN-L)
- PMC
- PMC9508328
- OpenAlex
- W4297037038
- Cited by
- 16
- References
- 15
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 5 · 2022: 2
- FWCI
- 2.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Blood Cancer Journal (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Oncology › Bone health and treatments
- Keywords
- multiple myeloma, relapsed/refractory multiple myeloma, treatment exposure, proteasome inhibitors, immunomodulators, anti-CD38 monoclonal antibody, treatment outcomes, real-world data, long-term follow-up, prognostic factors, progression-free survival
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Dexamethasone, Humans, Multiple Myeloma, Rubiaceae
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