Pomalidomide and dexamethasone until progression after first salvage therapy in multiple myeloma.

Lenalidomide maintenance in myeloma is well established. Nevertheless, pomalidomide could provide an alternative. Myeloma patients in first relapse, initially treated in the Intergroupe Francophone du Myélome (IFM) 2009 trial, and subsequently in the IFM 2013-01 phase 2 trial, received four cycles of salvage therapy with pomalidomide plus cyclophosphamide plus dexamethasone (PCD) with transplantation plus 2 PCD consolidation or without transplantation but with 5 PCD and for all patients pomalidomide plus dexamethasone maintenance therapy. This consisted of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dexamethasone 20 mg weekly until progression. The primary endpoint was an improved response to treatment. A total of 75/100 patients reached therapy. The median follow-up time was 73 months. The median duration of treatment was 23.7 months. One third of patients improved their response from the initiation of treatment: 11%, 19% and 4% to a very good partial response, complete response or stringent complete response respectively. The median progression-free survival time was 33.2 months and the median overall survival time was not reached. Among the 75 patients, the reasons for pomalidomide discontinuation were progressive disease (54%), adverse events (AEs) (30%), investigator discretion (11%) and consent withdrawal (5%). Grade (G) 3/4 haematological AEs included neutropenia (51%) and lymphopenia (35%); G3/4 drug-related non-haematological AEs (>5%) comprised 13% infections. Long-term administration of pomalidomide and dexamethasone is feasible and one third of the patients improved their response.

Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma.

It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with multiple myeloma.

BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.

Inhibition of mTORC1 activity by REDD1 induction in myeloma cells resistant to bortezomib cytotoxicity.

The combination of bortezomib and dexamethasone is becoming the reference induction treatment for multiple myeloma patients younger than 65 years. Despite its advantage over vincristin adryamicin dexamethasone induction treatment, bortezomib does not benefit all patients. We hypothesize that heterogeneity of the response experienced by myeloma patients is, at least in part, due to genomic variations in the malignant plasma cells. To test this hypothesis we used gene expression profiling to identify early responsive genes induced by bortezomib in resistant myeloma cells. Our study revealed: (i) a dramatic induction of REDD1, a negative regulator of mammalian target of rapamycin kinase complex 1 (mTORC1) activity, in these cells; (ii) a transient cell size decrease associated with REDD1 overexpression; and (iii) partial restoration of bortezomib sensitivity in REDD1 knockdown bortezomib-resistant myeloma cells. Together, these results identify a possible novel mechanism of bortezomib resistance in myeloma patients mediated by REDD1 overexpression involving inhibition of mTORC1 activity and suggest that the use of mammalian target of rapamycin inhibitors in myeloma patients could be deleterious.

Responses in multiple myeloma should be assigned according to serum, not urine, free light chain measurements.

The most recent update to the International Myeloma Working Group consensus criteria places a strong emphasis on the need for more sensitive haematological markers of response driven by the success of novel therapies. One such marker is serum free light chain (sFLC) analysis, which was first incorporated into the definition of stringent complete response in 2006. However, over the past decade there has been some reluctance to extend the role of the sFLC assays to replace 24 h urine electrophoresis for monitoring multiple myeloma (MM). In this review, we lay out the evidence in favour of serum over urine for monoclonal FLC measurements and propose modified criteria for response assignment in myeloma.

DKK1 and sclerostin are early markers of relapse in multiple myeloma.

Recent studies have shown that Dickkopf-related protein (DKK1) and sclerostin decrease when a complete response (CR) is obtained after chemotherapy in myeloma multiple (MM). To study variations in DKK1, sclerostin and P1NP in patients treated for MM, between complete response (CR) and relapse, we carried out a prospective study ancillary to the IFM 2009 protocol (IFM). The aim of IFM was to compare progression-free survival between patients treated with chemotherapy with or without transplantation. We selected 69 patients who reached CR and relapsed. We assayed by ELISA: DKK1, sclerostin and P1NP at 3 end points T1: CR, T2: 4 months before relapse and T3: relapse. There was a significant increase in DKK1 and sclerostin between T1, T2 and T3. (DKK1 medians (IQR): T1 = 30 pmol/l (20.4-41.1), T2 = 37.4 pmol/l (29.8-49.4), p < 0.0001, T3 = 42 pmol/l (33.8-55.5), p < 0.0001 sclerostin medians (IQR): T1 = 0.57 (0.47-0.69), T2 = 0.62 ng/ml (0.53-0.79), p < 0.0001, T3 = n0.64 ng/ml (0.56-0.79), p = 0.005). No significant variation was detected in the levels of P1NP. No association was observed between the characteristics of the MM, or the treatment received and the variation between T1-T3 for DKK1, sclerostin or P1NP. A significant increase in DKK1 and sclerostin was observed four months before relapse.

Partial Response at Completion of Bortezomib-Thalidomide-Dexamethasone (VTd) Induction Regimen Upfront in Multiple Myeloma Does Not Preclude Response to VTd in Consolidation.

The impact of consolidation on response rates and PFS has recently been demonstrated after induction and autotransplantation upfront in Multiple Myeloma (MM). We further showed that patients in ≥VGPR following the intensification procedure benefited most from consolidation. Question remains as to the benefit of consolidation for patients in PR at completion of induction - feature of partial resistance to the induction regimen. We collected data from 54 newly diagnosed MM treated with VTd-auto-VTd regimen that reached only PR at completion of the induction procedure. Overall, 37 patients (68%) improved depth of response (≥VGPR) at completion of consolidation, including 35% that reached CR and 38% solely related to consolidation. Of patients that remained on PR or improved depth of response after ASCT, 26% and 38% further responded to consolidation, respectively. With a median follow-up of 36 months, improved depth of response translated into lower relapse rate compared with patients remaining in PR, 19% vs. 36%. This difference was more striking in patients that reached CR vs. others, 8% and 38%, respectively (p=0.039). The median TTP was prolonged in patients that improved depth of response after consolidation (p=0.012), with a 3-year TTP of 87% vs. 18% otherwise. In multivariate analysis, lack of improved depth of response to consolidation independently predicted shorten median TTP [OR=4.4, 95%CI=1-21; p=0.039], with elevated LDH and beta2m, and adverse FISH. This study shows that VTd consolidation should be recommended to patients solely on PR at completion of induction with VTd, feature of lower sensitivity to VTd.