Pomalidomide plus low-dose dexamethasone in relapsed refractory multiple myeloma after lenalidomide treatment failure

Patients with relapsed/refractory multiple myeloma (RRMM) for whom the benefits of lenalidomide have been exhausted in early treatment lines need effective therapies. In cohort A of the phase 2 MM-014 trial, we examined the safety and efficacy of pomalidomide plus low-dose dexamethasone immediately after lenalidomide-based treatment failure in patients with RRMM and two prior lines of therapy. Pomalidomide 4 mg was given on days 1 to 21 of 28-day cycles. Dexamethasone 40 mg (20 mg for patients aged >75 years) was given on days 1, 8, 15 and 22 of 28-day cycles. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. The intention-to-treat population comprised 56 patients; all received prior lenalidomide (87·5% lenalidomide refractory) and 39 (69·6%) received prior bortezomib. ORR was 32·1% (28·2% in the prior-bortezomib subgroup). Median PFS was 12·2 months (7·9 months in the prior-bortezomib subgroup). Median OS was 41·7 months (38·6 months in the prior-bortezomib subgroup). The most common grade 3/4 treatment-emergent adverse events were anaemia (25·0%), pneumonia (14·3%) and fatigue (14·3%). These findings support earlier sequencing of pomalidomide-based therapy in lenalidomide-pretreated patients with RRMM, including those who have become refractory to lenalidomide. Trial registration: www.ClinicalTrials.gov identifier NCT01946477.     

Expanded safety experience with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma

Lenalidomide gained Food and Drug Administration (FDA) approval for treatment of patients with relapsed or refractory multiple myeloma (MM) in combination with dexamethasone in June 2006. In April 2005, the FDA and patient advocacy groups requested an expanded access programme to both provide lenalidomide to patients likely to benefit and obtain additional safety information. Relapsed/refractory MM patients received lenalidomide 25 mg/d (days 1–21) and dexamethasone 40 mg/d (days 1–4, 9–12, and 17–20 of cycles 1–4; days 1–4 only from cycle 5 onwards), in 4-week cycles until disease progression, study drug discontinuation, or lenalidomide approval. Of the 1438 patients enrolled, ∼60% were male, median age was 64 years, and 61·7% had Durie-Salmon stage III disease. Median time on study was 15·4 weeks (range: 0·1–49·1) and median dose was 25 mg. The most common adverse events (AEs) were haematological (49%), gastrointestinal (59%), and fatigue (55%). The most common grade ≥3 AEs were haematological (45%), fatigue (10%), and pneumonia (7%). The most common serious AEs were pneumonia (8%), pyrexia (4%), and deep-vein thrombosis (3%). Primary cause of death was disease progression (10%). Safety data confirmed known AEs of lenalidomide plus dexamethasone therapy in patients with relapsed/refractory MM.     

Perifosine plus lenalidomide and dexamethasone in relapsed and relapsed/refractory multiple myeloma: a Phase I Multiple Myeloma Research Consortium study

The combination of lenalidomide-dexamethasone is active in multiple myeloma (MM). Preclinical data showed that the Akt inhibitor, perifosine, sensitized MM cells to lenalidomide and dexamethasone, providing the rationale for this Phase I, multicentre, single-arm study to assess the safety and determine the maximum-tolerated dose (MTD) of perifosine-lenalidomide-dexamethasone in relapsed and relapsed/refractory MM. Patients received escalating doses of perifosine 50-100 mg daily and lenalidomide 15-25 mg once daily on days 1-21 of each 28-d cycle, plus dexamethasone 20-40 mg weekly thereafter, as indicated. Thirty-two patients were enrolled across four dose cohorts. MTD was not reached, with 31 patients evaluable for safety/tolerability. The most common all-causality grade 1-2 adverse events were fatigue (48%) and diarrhoea (45%), and grade 3-4 neutropenia (26%), hypophosphataemia (23%), thrombocytopenia (16%), and leucopenia (13%). Among 30 evaluable patients, 73% (95% confidence interval, 57·5-89·2%) achieved a minimal response or better, including 50% with a partial response or better. Median progression-free survival was 10·8 months and median overall survival 30·6 months. Response was associated with phospho-Akt in pharmacodynamic studies. Perifosine-lenalidomide-dexamethasone was well tolerated and demonstrated encouraging clinical activity in relapsed and relapsed/refractory MM.     

Better quality of response to lenalidomide plus dexamethasone is associated with improved clinical outcomes in patients with relapsed or refractory multiple myeloma

Background

This retrospective pooled analysis of two phase III trials (MM-009/MM-010) compared clinical outcomes of patients who achieved a complete response or very good partial response to treatment with lenalidomide plus dexamethasone with the outcomes of those who only achieved a partial response.

Design and Methods

Patients (n=353) received lenalidomide (25 mg/day for 21 days of each 28-day cycle) plus dexamethasone (40 mg on days 1–4, 9–12, and 17–20 for four cycles, and only on days 1–4 after the first four cycles). Time to response, duration of response, time-to-progression, overall survival, and adverse events were investigated for patients who had a complete or very good partial response and compared with those of patients who had a partial response.

Results

At the time of unblinding, 32% of patients had achieved a complete or very good partial response and 28% had a partial response. Half (50.5%) of the patients who had a partial response as their initial response achieved a complete or very good partial response with further treatment. The probability of achieving a complete or very good partial response with continued lenalidomide treatment decreased with delayed achievement of a partial response (by cycle 4 versus later); however, it remained clinically significant. With an extended follow-up of 48 months, the median response duration, time-to-progression, and overall survival were longer in patients with a complete or very good partial response than in those with a partial response (24.0 versus 8.3 months, P<0.001; 27.7 versus 12.0 months, P<0.001; not reached versus 44.2 months, P=0.021, respectively). The benefit of a complete or very good partial response was independent of when it was achieved.

Conclusions

Continuing treatment with lenalidomide plus dexamethasone to achieve best response, in the absence of disease progression and toxicity, provided deeper remissions and greater clinical benefit over time for patients in this study.     

Carfilzomib,lenalidomide, and dexamethasone in patients with relapsed multiple myeloma categorised by age: secondary analysis from the phase 3 ASPIRE study

A primary analysis of the ASPIRE study found that the addition of carfilzomib to lenalidomide and dexamethasone (carfilzomib group) significantly improved progression‐free survival (PFS ) compared with lenalidomide and dexamethasone alone (control group) in patients with relapsed multiple myeloma (RMM ). This post hoc analysis examined outcomes from ASPIRE in patients categorised by age. In the carfilzomib group, 103/396 patients were ≥70 years old, and in the control group, 115/396 patients were ≥70 years old. Median PFS for patients <70 years old was 28·6 months for the carfilzomib group versus 17·6 months for the control group [hazard ratio (HR ), 0·701]. Median PFS for patients ≥70 years old was 23·8 months for the carfilzomib group versus 16·0 months for the control group (HR , 0·753). For patients <70 years the overall response rate (ORR ) was 86·0% (carfilzomib group) and 66·9% (control group); for patients ≥70 years old the ORR was 90·3% (carfilzomib group) and 66·1% (control group). Within the carfilzomib group, grade ≥3 cardiovascular adverse events occurred more frequently among patients ≥70 years old compared with patients <70 years old. Carfilzomib‐lenalidomide‐dexamethasone has a favourable benefit‐risk profile for patients with RMM , including elderly patients ≥70 years old. Trial Registration: clinicaltrials.gov identifier: NCT01080391.     

Low-dose lenalidomide and dexamethasone combination treatment in elderly patients with relapsed and refractory multiple myeloma

Objective: This study investigated the efficacy and safety of low-dose lenalidomide combined with dexamethasone in elderly patients with relapsed and refractory multiple myeloma (MM).

Methods: Thirty-two elderly patients with refractory and recurrent MM (median age: 64 years) were treated with low-dose lenalidomide (LD-R) combined with dexamethasone (D). LD-R (10?mg/d) was administered orally for 21 days and D (40?mg/d) was administered twice a day on days 1–4, 9–12, and 17–20. The treatment lasted 2–8 28-day cycles.

Results: After two cycles, the complete, very good partial, and partial remission rates were 12.5% (4/32), 25.0% (8/32), and 34.4% (11/32), respectively. The overall response rate was 71.9% (23/32). After a 24-month follow-up, 23 patients responded to therapy, three were in complete remission, four were stable, and 16 exhibited disease progression. In addition, median time-to-progression was 13 months. Observed side effects were hypodynamia, gastrointestinal reaction, peripheral neuritis, and mild hypocytosis.

Conclusion: Low-dose lenalidomide in combination with dexamethasone is an effective and safe treatment for relapsed and refractory MM in elderly patients.     

A comparison of lenalidomide/dexamethasone versus cyclophosphamide/lenalidomide/dexamethasone versus cyclophosphamide/bortezomib/dexamethasone in newly diagnosed multiple myeloma

Novel agents are considered standard components of induction therapy for newly diagnosed patients with multiple myeloma. We retrospectively compared the results of three consecutive phase 2 clinical trials; RD (lenalidomide/dexamethasone, n = 34), CRD (cyclophosphamide/lenalidomide/dexamethasone, n = 53) and CyBorD (cyclophosphamide/bortezomib/dexamethasone, n = 63) (N = 150). Response rates after four cycles of treatment were: ≥near complete response (nCR), 12% vs. 2% vs. 41%, P < 0·0001 and very good partial response or better, 35% vs. 30% vs. 65%, P = 0·0003, respectively. With all cycles of therapy considered, ≥nCR was 35%, 15% and 41%, P = 0·006. However, there is no evidence that one regimen produced superior progression‐free survival (PFS) (median: 3·2 vs. 2·3 vs. 2·7 years, P = 0·11) or overall survival (3‐year: 88% vs. 79% vs. 88%, P = 0·23). Transplantation did not impact PFS (median: 2·7 vs. 2·3 years, P = 0·41) but was associated with improved OS (3‐year: 93% vs. 75%, P ≤ 0·001). High genetic risk patients (n = 40) had earlier relapse despite lenalidomide or bortezomib (median: 2·1 vs. 2·7 years, P = 0·45). Grade 3/4 toxicities were least with CyBorD while CRD had most toxicity. In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4 years.     

High expression of cereblon (CRBN) is associated with improved clinical response in patients with multiple myeloma treated with lenalidomide and dexamethasone

Cereblon (CRBN) has recently been identified as a target for immunomodulatory drugs (IMiDs) and its downregulation has been linked to resistance to lenalidomide. Here, we studied CRBN expression by real time polymerase chain reaction in 49 bone marrow samples of newly diagnosed patients with multiple myeloma treated with lenalidomide and dexamethasone. Median CRBN expression was 3·45 in patients who achieved complete response, and 3·75, 2·01, 0·78, and 0·70 in those with very good partial response, partial response, stable disease and progressive disease respectively. CRBN expression levels correlated significantly with response to lenalidomide treatment (r = 0·48; P < 0·001). Among established prognostic parameters, only beta‐2‐microglobulin correlated with cereblon (r = 0·66; P < 0·001). A close association of CRBN with interferon regulatory factor 4 (IRF4) (P < 0·001) and with CTNNB1 (P < 0·001) was found. Overall, a statistically significant association between baseline CRBN expression and response in MM patients treated with lenalidomide is shown. CRBN expression is closely associated with IRF4, which is an important target of IMiD therapy.     

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma

Background: The goal of this retrospective study was to compare the efficacy and toxicity of lenalidomide–dexamethasone (len/dex) vs. melphalan–prednisone–lenalidomide (MPR) as upfront therapy for newly diagnosed elderly patients with myeloma. Methods: Data from 51 patients enrolled in an Italian phase I/II trial and treated with MPR were analyzed and compared with data from 38 patients, seen at the Mayo Clinic, treated with len/dex and enrolled in phase II/III trials. Results: On intention‐to‐treat analysis, time to progression (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.903), progression‐free survival (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.926), and overall survival (2‐yr overall survival: 86.2% in MPR vs. 89.1% in len/dex, P = 0.730) were not significantly different between the two groups. Results were confirmed when the analysis was restricted to MPR and len/dex matched pair mates. Hematologic grade 3–4 toxicities were more common with MPR (neutropenia: 66.7% vs. 21.1%, P < 0.001; thrombocytopenia: 31.4% vs. 2.6%, P < 0.001). Grade 3–4 gastrointestinal events (13.2% vs. 3.9%, P = 0.132), thrombotic events (13.2% vs. 5.9%, P = 0.279), and fatigue (10.5% vs. 3.9%, P = 0.395) were more common with len/dex. Conclusions: Results show that both MPR and len/dex are efficacious regimens for elderly patients with myeloma. Randomized trials are needed to confirm these results.     

Bortezomib,cyclophosphamide, dexamethasone versus lenalidomide,cyclophosphamide, dexamethasone in multiple myeloma patients at first relapse

Bortezomib- and lenalidomide-containing regimens are well-established therapies in multiple myeloma (MM). However, despite their extensive use, head-to-head comparisons have never been performed. Therefore, we compared bortezomib and lenalidomide in fixed-duration therapies. In this open-label, phase III study, we randomized MM patients at first relapse to receive either nine cycles of bortezomib plus cyclophosphamide plus dexamethasone (VCD) or lenalidomide plus cyclophosphamide plus dexamethasone (RCD). The primary endpoint was achievement of a very good partial response (VGPR) or better at six weeks after nine treatment cycles. From March 2011 to February 2015, 155 patients were randomized. VGPR or better was achieved by 12 patients (15%) in the VCD arm and 14 patients (18%) in the RCD arm (P = 0·70). Median progression-free survival (PFS) was 16·3 (95% CI: 12·1–22·4) with VCD and 18·6 months (95% CI: 14·7–25·5) with RCD, and the two-year overall survival (OS) was 75% (95% CI: 66–86%) and 74% (95% CI: 64–85%) respectively. In subgroup analyses, no differences in PFS were observed in bortezomib- and lenalidomide-naïve patients, nor in patients who received a bortezomib-based regimen in first line. Adverse events were consistent with the well-established safety profiles of both drugs. Bortezomib and lenalidomide treatments were equally effective in terms of depth of response, PFS, and OS in MM patients at first relapse.     

Thalidomide–dexamethasone as up‐front therapy for patients with newly diagnosed multiple myeloma: thrombophilic alterations,thrombotic complications,and thromboprophylaxis with low‐dose warfarin

Background: Venous thromboembolism (VTE) is a major complication of myeloma therapy recently observed with the increasing use of up‐front thalidomide and dexamethasone (thal–dex). The pathogenesis of thal‐induced VTE is not well recognized, and the role of prothrombotic factors, especially of thrombophilic abnormalities, is not yet determined. Material and methods: Two hundred and sixty‐six patients with newly diagnosed multiple myeloma (MM) were primarily treated with thal–dex in preparation for subsequent high‐dose therapy and autologous stem‐cell transplantation. Out of these 266 patients, 190 were evaluated for thrombophilic alterations at baseline, and 125 of them were also re‐assessed after thal–dex therapy. Results: The presence of genetic thrombophilic polymorphisms among patients with MM was superimposable to that of normal controls and was associated with a twofold increase in the relative risk of VTE. aAPCR and elevated factor VIII levels were frequent, albeit transient, alterations and were not associated with a significant increase in the risk of VTE. Two hundred and forty‐six patients received a thromboprophylaxis with fixed low‐dose warfarin (1.25 mg/day) during thal–dex therapy. Of these patients (or 10.6%), 26 had symptomatic VTE events. Their patients‐years rate of VTE (35.5%) was significantly lower in comparison with the 86.2% rate recorded among the first 19 patients who initially entered the study and did not receive any kind of thromboprophylaxis (P = 0.043). Conclusions: On the basis of these data, a baseline thrombophilic work up is not recommended in patients with receiving up‐front thal–dex. For these patients, fixed low‐dose warfarin may be a valuable prophylaxis against VTE.     

A phase IIb trial of vorinostat in combination with lenalidomide and dexamethasone in patients with multiple myeloma refractory to previous lenalidomide‐containing regimens

Clinical trials of vorinostat, a Class I/II histone deacetylase inhibitor, in combination with proteasome inhibitors and immunomodulatory agents have shown activity in relapsed/refractory multiple myeloma. This phase IIb, open‐label, single‐institution study evaluated the efficacy of vorinostat in combination with lenalidomide and dexamethasone in lenalidomide‐refractory patients. Patients were considered lenalidomide‐refractory if they had no clinical response (<minimal response) on a previous lenalidomide‐containing regimen (lenalidomide non‐responsive) or if they had progressive disease on or within 60 days of discontinuing a previous lenalidomide‐containing regimen (lenalidomide relapsed/refractory). Patients received oral vorinostat 400 mg days 1–7 and 15–21, lenalidomide 25 mg days 1–21, and dexamethasone 40 mg days 1, 8, 15 and 22 in 28‐day cycles. Twenty‐five patients were enrolled, median age was 65 years and patients had received a median of 5 prior regimens. The overall response rate was 24% (6 partial responses) and clinical benefit rate (≥stable disease) was 80%. Median time to a partial response was 1·9 months and median duration of response was 3·3 months. Median progression‐free survival was 5·3 months. Most common grade 3/4 adverse events were neutropenia (48%), thrombocytopenia (32%), anaemia (20%) and gastrointestinal toxicities (16%). In this heavily pre‐treated population, vorinostat in combination with lenalidomide and dexamethasone was active in lenalidomide‐refractory patients.     

Thalidomide and lenalidomide in multiple myeloma

Multiple myeloma is a treatable but not necessarily a curable plasma-cell cancer. After decades of minimal progress, two new classes of drugs with novel mechanisms of action - immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) - have been introduced for the treatment of this disease. Thalidomide and lenalidomide have shown great activity as single agents and in combination with glucocorticoids for the treatment of chemotherapy-refractory myeloma. Thalidomide - and more recently lenalidomide - in combination with dexamethasone have shown promising results as induction therapy. These drugs can easily be combined with other chemotherapeutic agents to potentiate the anti-myeloma effect. The immunomodulatory function of these drugs can be successfully exploited to control residual disease during remission. Thus, both thalidomide and lenalidomide have ushered in a new era of optimism in the management of this incurable cancer.     

Post‐transplant consolidation plus lenalidomide maintenance vs lenalidomide maintenance alone in multiple myeloma: A systematic review

Background

In newly diagnosed multiple myeloma (NDMM), autologous stem cell transplantation (ASCT) remains the standard approach for transplant‐eligible patients. To control the inevitable relapse, post‐transplant consolidation/maintenance strategies are commonly used. However, the benefit of post‐transplant consolidation is still uncertain

Method

We conducted a systematic review of phase II/III studies to compare the efficacy of post‐ASCT consolidation plus lenalidomide maintenance (CON+LEN) vs lenalidomide maintenance alone (LEN alone) in NDMM. A meta‐analysis using fixed and random effects models was performed.

Results

Fourteen studies were included with 2275 participants with NDMM treated with ASCT and lenalidomide maintenance. Two groups were identified: CON+LEN group (n = 1102) and LEN alone group (n = 1173). There was no statistically significant difference in the complete response rate between the two groups [RR = 1.1; 95% CI: 0.83‐1.44; P = .490]. Interestingly, we found that very good partial response or better rate is around 1.5‐fold significantly higher in the CON+LEN group compared to LEN alone group [RR: 1.46; 95% CI: 1.25‐1.70; P < .0001]. However, there was no significant difference between the two groups regarding PFS [RR: 1.0; 95% CI: 0.92‐1.08, P = .929] and OS [RR: 0.9; 95% CI: 0.92‐1.01; P = .148] at 3‐4 years follow‐up. The risk of secondary primary malignancy (SPM) was also similar between the two groups (RR: 1.2; 95% CI: 0.84‐1.92; P = .2). Data on adverse events were limited.

Conclusion

Our data suggest that, in NDMM patients treated with upfront ASCT, post‐transplant consolidation may improve depth of response, but does not add to OS or PFS, compared to lenalidomide maintenance alone. However, data in this context are still immature.     

Low-dose thalidomide plus low-dose dexamethasone therapy in patients with refractory multiple myeloma

We report the results of a non-randomized phase II study of low-dose thalidomide plus low-dose dexamethasone therapy in 66 patients with refractory multiple myeloma. The overall response rate (near complete, partial and minimal response) was 63.6%, and progression-free and overall survival periods were 6.2 and 25.4 months. In adverse events, the incidence of peripheral neuropathy and deep vein thrombosis was lower than the data reported in USA and Europe. On the other hand, leukopenia was observed in 41% of patients, including 11% of those with Grade 3. Leukopenia was closely related to pretreatment pancytopenia, especially thrombocytopenia. The incidence of adverse events related to dexamethasone was low. In conclusion, low-dose thalidomide plus low-dose dexamethasone therapy was as effective as high-dose thalidomide plus high-dose dexamethasone therapy in patients with refractory multiple myeloma. Leukopenia is one of the most serious adverse events in Japanese patients, especially in patients with pretreatment pancytopenia.