1 Department of Medical Oncology, Inselspital, University Hospital Bern; University of Bern; Bern, Switzerland.
2 Department of Hematology and Central Hematology Laboratory, Inselspital, University Hospital Bern; University of Bern; Bern, Switzerland.
Received: September 23, 2020
Accepted: December 14, 2020:
Mediterr J Hematol Infect Dis 2021, 13(1): e2021012 DOI 10.4084/MJHID.2021.012
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under the terms of the Creative Commons Attribution License
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CAR-T cell therapy is likely to be introduced starting from 2021 in
patients with relapsed/refractory myeloma (r/r MM) in Europe. In order
to qualify for commercial CAR-T treatment, it is assumed that r/r MM
patients will have to be exposed to at least three lines of previous
treatments including lenalidomide, bortezomib and anti-CD38 treatment.
However, the outcome of this particular subgroup of r/r MM patients is
largely unknown whereas this knowledge is crucial to estimate the
possible benefit of eventual CAR-T treatment.
Since 2019, therapy with genetically modified T-cells expressing a chimeric antibody receptor (CAR-T) was commercially introduced for the treatment of relapsed/refractory (r/r) aggressive B-cell lymphomas and acute lymphoblastic B-cell leukemia in Switzerland. Currently, CAR-T cell therapy is further evaluated for patients with r/r MM in clinical studies and will soon be in commercial use.[3,6,9,18-33] The majority of the clinical CAR-T cell trials in multiple myeloma target the B-cell maturation antigen (BCMA), which shows predominant expression on myeloma and normal plasma cells, in contrast to low or absent expression on other cell compartments.[6,34-36]
As CAR-T therapy will soon be introduced for commercial treatment of r/r MM patients, it is of utmost interest to learn the possible benefit of this novel therapeutic option for this subset of myeloma patients. As a basis, knowledge of the outcome of such r/r MM patients in the pre-CAR-T era is crucial. In the present study, we, therefore, aimed at characterizing this group of r/r MM patients as a basis for later comparisons with CAR-T treated MM patients. CAR-T in MM will most likely be restricted to patients with at least three previous lines of treatment with at least one PI, one IMID and one anti-CD38 antibody. Consequently, this study intends to describe the outcome of MM patients effectively receiving further treatment for progressive disease after three lines of treatment including at least one PI, one IMID and one anti-CD38 antibody.
Treatment. We summarized lenalidomide, thalidomide and pomalidomide as immunomodulatory drugs (IMiD’s). The group of proteasome inhibitors (PI) comprised carfilzomib, bortezomib and ixazomib. Alkylating agents (Alky) were melphalan, bendamustine, cyclophosphamide, vincristine, doxurubicin and etoposide. Antibody treatment comprised anti-CD38-antibodies (daratumumab; isatuximab) and anti-SlamF7 antibody (elotuzumab).
Definitions. Progression-free survival (PFS) was calculated from the start of the first treatment after inclusion in the study until first progression of MM or death of any cause, whichever occurred first. Progression was defined as an increase of at least 25% in measurable monoclonal immunoglobulin in serum or urine or an increase of ≥25% in urinary light chains.[37,38] Overall response rate (ORR) was defined as the percentage of patients with at least partial response or better according to IMWG Uniform Response Criteria. Time to next treatment (TTNT) was the time between start of the first treatment after inclusion in the study until the first day of the next treatment regimen. Overall survival (OS) was assessed from the start of the first treatment after inclusion in the study until death or last follow-up with a data cut-off at April 04, 2020, whichever occurred first.
Statistical analysis. PFS, TTNT, and OS were calculated according to the Kaplan-Meier method and were depicted using Graphpad (Graphpad, Prism 8, Version 8.2.1 (441), August 20, 2019). Statistical analyses were double-sided, and p-values below .05 were considered significant.
1. Patient characteristics at first diagnosis of the multiple myeloma.
Prior therapies including daratumumab. Among the 34 patients fulfilling the criteria of three treatment lines, including PI, IMID, and anti-CD38 treatment, and effectively receiving subsequent therapy line(s), the median number of previous lines was 4.5 (range 2-12 lines). 24 (55%) patients had four or more prior therapy lines, mainly because anti-CD38 treatment was first given late in these patients. HDCT and ASCT were performed in 31 (91%) patients. The prior treatment lines are summarized in Table 2. 14 (40%) patients were quad-refractory, thus refractory to bortezomib, lenalidomide, carfilzomib, and pomalidomide, and 13 (37%) patients were penta-refractory, thus refractory also to daratumumab.
|Table 2. Treatments prior and including first daratumumab treatment.
First treatment line after inclusion. The median interval from the initial diagnosis to the first treatment after fulfilling the study criteria was 67 months (range 19 to 189 months). 11 (32%) patients received one subsequent treatment line, 13 (38%) patients received two subsequent treatment lines, and 8 (24%) patients received three or more lines of treatment (Table 3). The most frequent treatment line was IMID/dexamethasone in 11 (32%) patients, followed by PI/dexamethasone in 10 (29%) patients, alkylating agents in 9 (26%) patients, daratumumab combined with a PI in 6 (18%) patients, and PI combined with IMID in 6 (18%) patients. Six (18%) patients received HDCT/ASCT during relapse treatment.
|Table 3. Treatments after first daratumumab treatment.
The ORR to the first treatment after study inclusion was 41%, with a median duration of response of 5 months (range 1 to 37 months). 12% of the patients had an excellent partial response or better, with a median duration of this response of 8 months (range 3 to 37 months). So far, 33 (59%) patients have died, all due to disease progression.
Outcome. The median PFS after the first treatment line after inclusion in the study was 6.6 months (range, 0 to 36.6 months; Figure 1A). For the patients with two or more further treatment lines, the median PFS was 6.6 months (range, 0 to 24.5 months) compared to median PFS of 5 months (range, 0.1 to 36.6 months) for those with only one further line. The median TTNT between the first and the second treatment line was 7.5 months (range 1.4-24.6 months) for the patients with effectively at least two further lines of treatment (Figure 1B). The median OS of the cohort was 13.5 months (range, 0.1 to 38.0 months) after starting the first line of treatment within the study (Figure 1C). For patients with two or more further treatment lines, the OS was 15.6 months (range, 3.5 to 38) compared to 7.5 months (range, 0.1 to 36.6 months) for the patients with only one further treatment line.
The patients in our CAR-T candidate cohort had a median of five prior therapy lines, similar to pretreated myeloma patient cohorts described in the literature that had received a median of two to seven previous therapies.[3,9,12,40,42-45] In particular, 40% of our patients were quad-refractory, and 37% were penta-refractory. These proportions were comparable to previous studies on similar patient cohorts.[12,13]
Patients received a median of two further therapy lines. Following the start of the first treatment line in our study, we found a short median PFS of 6.6 months, highlighting the short duration of response in the advanced disease stages of r/r MM patients. Related studies on retreatment with IMiD’s and PI’s after anti-CD38 treatment reported even shorter survival rates, with a median PFS of 4 months for patients receiving PI’s, and three months for IMID’s. In similar patient cohorts, the median PFS was 3.7 months for selinexor and 3.4 months for nelfinavir.[12,16]
In contrast, CAR-T studies describe a median PFS between 7.7, 7.9 and 11.8 months in patients with r/r MM. Therefore, there is a difference of 3 to 5 months of the median PFS compared to our findings in this heavily pretreated myeloma patient group. This difference emphasizes the anti-myeloma efficacy of CAR-T cell treatment compared to conventional therapies in r/r MM patients.
Overall survival (OS) rates were reported between 1.7 and 5.5 months in anti-CD38 refractory patients.[45,48] Selinexor and nelfinavir studies found OS rates of 9.3 and 21.6 months, respectively. This suggests that the OS rate of 13.5 months in our cohort compares rather favorably to other series. The heavier pretreated patient group might explain the difference in the selinexor studies and the less heavily pretreated patient group in the nelfinavir studies, respectively, as well as in the higher proportion of quad- and penta–refractory patients in the post daratumumab studies by Pick et al. and Lakshmann et al.[45,48].
We identified a median TTNT of 7.5 months in our cohort. Lakshman et al reported a median TTNT of 5.7 months in patients refractory to daratumumab and combination therapies similar to our results. In contrast, Driessen et al. described better TTNT (10 and 12 months) in two patients treated with nelvinavir.
The overall response rate was 41% in this study; in others, the ORR was 21% and 25% in the selinexor studies, 33% and 55% in the nelfinavir studies 28.6%, 52%, and 67% in three studies investigating retreatment after daratumumab.[45,46] In contrast, the ORR was higher with 60%, 81%, and 85% in three CAR-T cell studies.
Similarly, the response duration was 4 months for nelfinavir, 4.4 months and 5 months for selinexor. In contrast, CAR-T studies reported response duration between 7.9 and 13 months, with a dose-dependent duration of the responses, with a median duration of response of 10.9 months.
In our study, the median follow-up from the start of the first treatment was 12 months, comparable to previous myeloma studies, which reported median follow-ups between 5.5 and 36 months.[9,16,45,47,48] The median interval from initial diagnosis until the first treatment in the study was 67 months (range 19 to 189 months). This seems comparable to other reports with intervals between 45.6 and 79.2 months for similar patient groups.[9,12,13,45,48]
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