At the ASH Congress in New Orleans, the focus was on the efficacy and safety of lenalidomide plus low-dose dexamethasone in the treatment of patients with newly diagnosed multiple myeloma. It also shows good efficacy in maintenance therapy, in myelodysplastic syndrome and as an adjunct to the RCHOP21 regimen in diffuse large B-cell lymphoma. For refractory and relapsed multiple myeloma, pomalidomide with low-dose dexamethasone is a potential new therapeutic option.
(ag) Thierry Facon, MD, Lille, presented the initial results of the phase III FIRST trial, which compared the efficacy and safety of the combination of lenalidomide plus low-dose dexamethasone (Rd) with that of melphalan, prednisone, and thalidomide (MPT) [1]. “MPT is a standard of care for the treatment of newly diagnosed multiple myeloma (NDMM). The combination showed a statistically significant advantage in overall and progression-free survival over melphalan and prednisone alone. Lenalidomide, in turn, prolonged overall survival in this patient population and showed fewer side effects when combined with low-dose dexamethasone than with high-dose” [2].
The FIRST study
1623 NDMM patients who were either ≥65 years of age or ineligible for stem cell transplantation (SCT) were randomized to one of three arms:
Arm A: Rd in 28-day cycle until disease progression.
Arm B: Rd in 28-day cycle for 72 weeks (18 cycles).
Arm C: MPT on a 42-day cycle for 72 weeks (12 cycles).
Dialysis patients were excluded. Starting doses of lenalidomide and dexamethasone were adjusted according to renal function and age; melphalan according to age, absolute neutrophil measurement, platelet concentration, and renal function; and thalidomide according to age.
The primary endpoint was the difference in progression-free survival in arms A and C. Secondary endpoints were overall survival, overall response rate (ORR), time to response, and duration (DOR), safety, and quality of life (QOL).
Results: To date, 121 patients in Arm A are continuously taking Rd. The study met its primary endpoint: a 28 percent reduction in the risk of progression or death (p=0.00006). The pre-planned interim analysis of overall survival showed a 22 percent reduction in the risk of death for Arm A compared with Arm C (p=0.01685), but the previously established cutoff was not reached (p<0.0096). All other secondary endpoints also showed significant improvements. Relevant grade 3 and 4 adverse events were neutropenia, thrombocytopenia, febrile neutropenia, infection, neuropathy, and thrombosis.
“Thus, continuous treatment with Rd showed significant improvements compared with MPT therapy. The safety profile was manageable,” Dr. Facon concluded.
Lenalidomide in maintenance therapy
The role of lenalidomide in maintenance therapy in patients with multiple myeloma (MM) was investigated by Preet Paul Singh, MD, Rochester, in a systematic review and meta-analysis [3]. “We reviewed data from five randomized controlled trials (RCTs), including four phase III studies. In total, the patient population included 1935 individuals who had either already undergone autologous stem cell transplantation or induction therapy alone.”
The meta-analysis concludes that progression-free survival is significantly prolonged with lenalidomide versus placebo/no maintenance (p<0.001). In addition, there was a modest but significant improvement in overall survival (p= 0.013). The risk of grade 3 and 4 adverse events was increased, including a twofold increase in the number of subsequent primary malignancies. “Furthermore, the large heterogeneity in the calculation of overall survival within the different study protocols limits the informative value of the meta-analysis,” Singh concluded.
Relapsed and refractory multiple myeloma
“The survival of MM patients refractory to current therapeutic options is short [4],” Jesús F. San Miguel, MD, Salamanca, introduced his presentation [5]. “Depth of response plays a critical role in improving outcomes. Pomalidomide is an oral immunomodulatory agent with three primary modes of action: direct anti-myeloma activity, stromal cell support inhibition, and immunomodulation [6].”
The FDA approved pomalidomide for patients with relapsed/refractory multiple myeloma (RRMM) with ≥2 prior treatments (including lenalidomide and bortezomib and disease progression after or within 60 days of completion of the last line of therapy). The European Commission followed suit in mid-2013. A phase III RCT called MM-003 now showed significant prolongations of progression-free (primary endpoint) and overall survival (secondary endpoint) for patients on pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone. The drug was tolerated relatively well. Specifically, the study design was as follows:
Arm A: 302 patients on pomalidomide and low-dose dexamethasone.
Arm B: 153 patients on high-dose dexamethasone.
Patient characteristics were balanced in the two groups. The median number of prior therapies was five. 75% of patients were refractory to bortezomib and lenalidomide.
Results: Arm A showed a significant prolongation of progression-free survival (primary endpoint). Overall survival also improved in all subgroups analyzed. This was significant especially in patients with ≤3 prior treatments and those who were refractory to lenalidomide in the last line. The ORR, another secondary endpoint, also showed a significant increase in Arm A. In addition, 17 patients (6%) achieved a very good partial response.
“In this heavily pretreated collective, pomalidomide with low-dose dexamethasone showed consistent efficacy, regardless of the number or type of prior therapies. Thus, the combination should be considered the standard of care for RRMM patients. Significant overall survival benefits were observed in patients who received this combination early and in those who were refractory to lenalidomide. Importantly, lenalidomide as the last prior therapy did not negatively affect response or survival rates,” Dr. San Miguel concluded.
Lenalidomide in MDS and DLBCL.
Results on lenalidomide in the treatment of myelodysplastic sydrome (MDS) [7] and diffuse large B-cell lymphoma [8] were also presented at ASH.
The efficacy and safety of lenalidomide in transfusion-dependent MDS patients with low or intermediate risk and del(5q) were confirmed by two large multicenter trials (MDS-003, MDS-004) [9, 10]. In an analysis with 181 patients, the individual factors were now examined in more detail. It was shown: In those patients with IPSS-defined low- or Int-1-risk MDS, del(5q)/del(5q) plus one additional abnormality, achievement of cytogenetic response on lenalidomide was related to a “red blood cell transfusion-independence” (RBC-TI) of ≥26 weeks and a reduced risk of acute myeloid leukemia (AML) or death. While further investigation is needed due to the small sample size, the data nevertheless provide further evidence for lenalidomide as a disease-modifying agent in MDS patients dependent on RBC transfusion.
“The standard of care for older, untreated diffuse large B-cell lymphoma (DLBCL) is the RCHOP21 regimen, which is rituximab, cyclophosphamide, hydroxidaunorubicin, vincristine, plus prednisolone. However, 40% of patients experience failure. Lenalidomide (L) showed activity in heavily pretreated DLBCL, and in vivo and in vitro data highlighted synergism with rituximab,” said Annalisa Chiappella, Turin. A phase I study concluded that LRCHOP21 may be a plausible treatment option for older untreated DLBCL [11]. Now, these results have been confirmed in a phase II study presented at ASH: 15 mg lenalidomide plus RCHOP21 was used. After six runs (each from day 1-14), ORR was 92%, complete remission was 86%, and partial remission was 6%. The two-year overall survival rate was 92%, and the progression-free rate was 80%. Hematologic and extra-hematologic toxicity were mild.
So, in summary, LRCHOP21 is effective, according to Chiappella. This was also evident in the comparison of the so-called “germinal center B-cell-like” (GCB) subgroups: “The data are encouraging and warrant a future phase III trial comparing LRCHOP21 to RCHOP21 in untreated non-GCB DLBCL.”
Source: 55th ASH Annual Meeting, December 7-10, 2013, New Orleans.
Literature:
- Facon T, et al: Initial Phase 3 Results Of The First (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) In Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) Ineligible For Stem Cell Transplantation (SCT). ASH Abstract #2.
- Rajkumar SV, et al: Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol 2010 Jan; 11(1): 29-37. doi: 10.1016/S1470-2045(09)70284-0. epub 2009 Oct 21.
- Singh PP, et al: Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials. ASH Abstract #407.
- Kumar SK, et al: Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia 2012 Jan; 26(1): 149-157. doi: 10.1038/leu.2011.196. Epub 2011 Jul 29.
- San Miguel JF, et al: Patient Outcomes By Prior Therapies and Depth Of Response: Analysis Of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM). ASH Abstract #686.
- Quach H, et al: Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma. Leukemia 2010 Jan; 24(1): 22-32. doi: 10.1038/leu.2009.236. Epub 2009 Nov 12.
- Sekeres MA, et al: Association Of Cytogenetic Response (CyR) With RBC Transfusion-Independence (RBC-TI) And AML-Free Survival In Lenalidomide (LEN)-Treated Patients (Pts) With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) With Del(5q). ASH Abstract #390.
- Chiappella A, et al: Final Results Of Phase II Study Of Lenalidomide Plus Rituximab-CHOP21 In Elderly Untreated Diffuse Large B-Cell Lymphoma Focusing On The Analysis Of Cell Of Origin: REAL07 Trial Of The Fondazione Italiana Linfomi. ASH Abstract #850.
- List A, et al: Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006 Oct 5; 355(14): 1456-1465.
- Fenaux P, et al: A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 2011 Oct 6; 118(14): 3765-3776. doi: 10.1182/blood-2011-01-330126. epub 2011 Jul 13.
- Chiappella A, et al: Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. Haematologica 2013 Nov; 98(11): 1732-1738. doi: 10.3324/haematol.2013.085134. epub 2013 Jun 28.
InFo Oncology & Hematology 2014; 2(1): 28-30.
