Lenalidomide versus lenalidomide + dexamethasone prolonged treatment after second-line lenalidomide + dexamethasone induction in multiple myeloma.
Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single-agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first-line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25 mg/day) or Len+Dex (25 mg/day and 40 mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6-9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2 years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36 months median follow-up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9 months (95% confidence interval 12.5-not calculable, P < 0.001) with Len. Three-year OS among the total observational study population was 61% (95% CI, 52-69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60-83%) and was significantly lower among those patients who achieved ≥PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short-term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile.
Lund J
，Gruber A
，Lauri B
，Duru AD
，Blimark C
，Swedin A
，Hansson M
，Forsberg K
，Ahlberg L
，Carlsson C
，Waage A
，Gimsing P
，Vangsted AJ
，Frølund U
，Holmberg E
，Gahrton G
，Alici E
，Hardling M
，Mellqvist UH
，Nahi H
... -
《Cancer Medicine》
DNA methylation inhibition in myeloma: Experience from a phase 1b study of low-dose continuous azacitidine in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.
The DNA methyltransferase inhibitor azacytidine (aza) may reactivate pathways associated with plasma cell differentiation, cell cycle control, apoptosis, and immune recognition and thereby restore sensitivity to lenalidomide (len) and dexamethasone (dex) in relapsed and/or refractory multiple myeloma (RRMM). We aimed to develop an aza regimen that reaches epigenetically active levels 8 times in 28 days with less bone marrow toxicity than the myeloid malignancy standard of 7 consecutive doses to enable safe combination with len. Aza was escalated from 30 mg/m2 once a week up to a predefined maximum of 50 mg/m2 twice a week in combination with GFR-adjusted len (≥ 60 mL/min: 25 mg, 3059 mL/min: 10 mg) day 1 to 21 every 28 days and dex 40 mg once a week followed by a limited expansion study to a total N of 23 at the highest tolerated dose. Fifty-one patients (pts) with RRMM were screened, 42 were treated and 41 were evaluable for response based on at least 1 response assessment or progression after treatment start. The median number of prior lines of therapy was 5 (1-11) and 81% (34) were refractory to len and/or pomalidomide (pom). Two DLTs occurred in different cohorts, 1 neutropenic fever in 1/6 pts on the aza 40 mg/m2 twice a week GFR ≥ 60 mL/min cohort and 1 GGT elevation in 1/6 pts on the aza 50 mg/m2 GFR 30-59 mL/min cohort. An MTD was not reached and aza 50 mg/m2 SC twice a week was chosen for the expansion study. At least possibly related Grade 3/4 AEs occurred in 28 pts (67%) with the following in > 1 pt: neutropenia (N = 16, 38%), anemia (N = 6, 14%), lymphopenia (N = 5, 12%), thrombocytopenia (N = 4, 10%), leukopenia (N = 4, 10%), febrile neutropenia (N = 4, 10%), fatigue (N = 3, 7%), fever (N = 2, 5%), and infection (N = 2, 5%). At a median follow up time for alive pts of 60.2 months (range: 36.1-82.5 months), the overall response rate (≥ partial response) and clinical benefit response rate (≥ minor response) was 22 and 32%, respectively, with 4 very good partial responses (10%), 5 partial responses (12%), and 4 minor responses (10%). The median PFS was 3.1 months (95% confidence interval [CI]: 2.1-5.1 months), median TTP 2.7 months (95% CI: 2.1-7.5 months), and median OS 18.6 months (95% CI: 12.9-33.0 months). Achieving at least minor response and reaching TTP > 6 months was associated with approximately 35% lower median plasma levels of the enzyme that inactivates aza, plasma cytidine deaminase (CDA, P< .0001). Two of the len refractory pts achieved longer disease control than with any prior regimen and 1 responded immediately after progression on len, bortezomib, and prednisone. Analyses of the methylation state of over 480,000 CpG sites in purified myeloma cells at screening were possible in 11 pts and on day 28 in 8 of them. As in other studies, the majority of differentially methylated CpGs compared to normal plasma cells were hypomethylated in myeloma. Treatment decreased the number of CpGs that were differentially methylated in normal plasma cells by > 0.5% in 6 and by > 5% in 3 of the 8 pts, most pronounced in 2 pts with clinically convincing aza contribution who achieved a reduction in overall differentially methylated CpGs by 23 and 68%, respectively, associated with increased expression of immunoglobulin genes. The study demonstrated tolerability of twice a week SC aza at 50 mg/m2 with len and dex in RRMM and suggested aza may help overcome the len/pom refractory state, possibly by activating differentiation pathways. Relatively low response rates and association of clinical benefit with low plasma levels of the aza inactivating enzyme CDA suggest the aza regimen will need to be optimized further and pt selection may be required to maximize benefit.
Khouri J
，Faiman BM
，Grabowski D
，Mahfouz RZ
，Khan SN
，Wei W
，Valent J
，Dean R
，Samaras C
，Jha BK
，Lazarus H
，Campagnaro EL
，Malek E
，Reed J
，Karam MA
，Hamilton K
，Fada S
，Kalaycio M
，Liu H
，Sobecks R
，Saunthararajah Y
，Chew Y
，Orloff M
，Reu FJ
... -
《-》
Lenalidomide plus dexamethasone for patients with relapsed or refractory multiple myeloma: Final results of a non-interventional study and comparison with the pivotal phase 3 clinical trials.
Lenalidomide (LEN) is an immunomodulatory drug with significant clinical activity against relapsed and refractory multiple myeloma (r/r MM). Based on the pivotal phase 3 trials MM-009 and MM-010, LEN in combination with dexamethasone (DEX) is approved for treatment of patients with MM who have received at least one prior therapy. LEN monotherapy is also approved in first line treatment. Here, we evaluated LEN/DEX combination therapy in a non-interventional study in patients with r/r MM in routine clinical practice. Patients received LEN/DEX as per Summary of Product Characteristics. Ninety-eight patients were treated with at least 1 cycle of LEN/DEX (median age 71 years; range, 42-88), forty-eight patients with at least 6 cycles. The Kaplan-Meier estimate for overall median time to progression was 12.0 months, 13.9 months for patients receiving second-line therapy and 10.3 months for third-line or higher-line therapy. The overall response rate was 60.2%. The median overall survival was 24.3 months. The most common adverse events were anemia (32.7%), thrombocytopenia (27.6%) and leukopenia (24.5%). Seven (7.1%) patients developed thromboembolic events despite prophylaxis. In conclusion, the combination of LEN/DEX administered to patients with r/r MM in routine clinical practice showed similar effectiveness and safety as demonstrated in the registration trials.
Knauf W
，Aldaoud A
，Losem C
，Mittermueller J
，Neise M
，Niemeier B
，Harde J
，Trarbach T
，Potthoff K
... -
《-》
Secondary primary malignancies during the lenalidomide-dexamethasone regimen in relapsed/refractory multiple myeloma patients.
Lenalidomide in combination with dexamethasone (Len-dex) represents a highly effective treatment in relapsed/refractory multiple myeloma (RRMM) patients. However, an increased risk of secondary primary malignancies (SPMs), including myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) has been described in patients receiving lenalidomide. In order to assess the incidence and features of this complication, we reviewed 195 patients with RRMM treated with Len-dex at our institution. The median follow-up time from diagnosis of MM was 73 months (10-234 months) and from initiation of Len-dex was 19 months (1-104 months). The median duration of Len-dex for all patients was 7.8 months (range 1-90 months). The incidence rate (IR) for all SPMs from start of Len-dex was 2.37 per 100 patient-years, which reflected an IR of 1.29 for MDS/AML and 1.08 for nonhematologic malignancies (NHM). MDS was the most common SPM noted. The cumulative IR of SPM at 5 years was 1.54% from the time of MM diagnosis and 5.24% from starting Len-dex. Multivariable cumulative incidence of SPM analysis identified older age (P = 0.005) and prior number of regimens (P = 0.026) as adverse risk factors. We found more concomitant G-CSF use (P = 0.029) in patients with MDS/AML, however, causal association is not clear. The progression-free survival after Len-dex was the longest for patients in MDS/AML group, and the 5-year overall survival did not differ among groups. Although the rate of SPM was relatively low with Len-dex, concomitant G-CSF should be used judiciously and patients receiving this regimen should be observed for the development of this complication.
Kotchetkov R
，Masih-Khan E
，Chu CM
，Atenafu EG
，Chen C
，Kukreti V
，Trudel S
，Tiedemann R
，Reece DE
... -
《Cancer Medicine》
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