Real-world outcomes of pomalidomide therapy after lenalidomide induction in relapsed/refractory multiple myeloma

Aim: To demonstrate the efficacy of pomalidomide for relapsed/refractory multiple myeloma (RRMM) following treatment in real-world, community practice using retrospective database analysis. Materials & methods: US-based community oncologists identified patients with RRMM treated with or without pomalidomide following first-line lenalidomide. Disease response (≥ very good partial response) and progression-free survival were compared. Results: Disease response was 78.6 and 51.7% for pomalidomide (n = 126) and nonpomalidomide cohorts (n = 174), respectively (p < 0.0001). Multivariate adjusted odds of response were 4.5-times greater for pomalidomide cohort (p < 0.0001). Median progression-free survival was not reached for pomalidomide cohort and 16.7 months for nonpomalidomide cohort (log-rank p < 0.01). Conclusion: Following lenalidomide induction in RRMM, pomalidomide is an effective treatment.

A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma

Background TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. Methods This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. Results In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9–68.1) and the overall response rate was 84.4% (95% confidence interval 67.2–94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3–not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. Conclusions The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. Clinicaltrials.gov identifier NCT02917941; date of registration September 28, 2016.

Quantification of measurable residual disease in patients with multiple myeloma based on the IMWG response criteria

Stringent complete response (sCR) is defined as a deeper response than complete response (CR) in multiple myeloma. Whether achieving sCR correlates with better survival remains controversial. We evaluated the outcomes in patients with intact immunoglobulin multiple myeloma (IIMM) and light chain multiple myeloma (LCMM) who achieved a very good partial response (VGPR) or better. Multicolour flow cytometry was used to assess the depth of response. LCMM patients with sCR had significantly lower measurable residual disease (MRD) levels than those with CR (median MRD: 7.9 × 10–4 vs. 5.6 × 10–5, P < 0.01). Nonetheless, no significant difference was observed in MRD levels across the responses in groups of patients with IIMM (VGPR vs. CR: 3.5 × 10–4 vs. 7.0 × 10–5, P = 0.07; CR vs. sCR: 7.0 × 10–5 vs. 5.4 × 10–5, P = 0.81. In accordance with MRD levels, the median overall survival of patients with sCR was significantly longer (sCR, CR, VGPR; not reached, 41 months, and 58 months, respectively; VGPR vs. CR, P = 0.83; CR vs. sCR, P = 0.04) in LCMM, but not in IIMM (sCR, CR, VGPR; not reached, 41 months, and not reached, respectively; VGPR vs. CR, P = 0.59; CR vs. sCR; P = 0.10). Our results show that sCR represents a deeper response that correlates with longer survival in patients with LCMM, but not IIMM.

Pegylated Liposomal Doxorubicin in Vindesine-Based and Bortezomib-Based Regimens for Patients With Newly Diagnosed Multiple Myeloma: A Retrospective Study of Efficacy and Safety

PurposeAlthough pegylated liposomal doxorubicin (PLD) has been approved in combination with bortezomib for relapsed/refractory multiple myeloma (MM), the antitumor efficacy and tolerability of PLD in different regimens for patients with newly diagnosed MM (NDMM) have not been fully defined.MethodsA total of 249 NDMM patients diagnosed between January 2008 and October 2019 were included in this retrospective study. Among them, 112 patients received vindesine-based chemotherapy (35 vDD and 77 vAD) and 137 received bortezomib-based chemotherapy (58 VDD and 79 VD).ResultsIn bortezomib-containing regimens, the complete response rate (48.3 vs. 30.4%, p = 0.033) and very good partial response or better rate (74.1 vs. 57.0%, p = 0.038) of VDD were significantly higher than those of VD subgroup. While no superior survival was found between VDD and VD subgroup. In vindesine-containing regimens, no statistical significance was identified between vDD and vAD in terms of response rate and survival. The occurrence rates of all cardiac AEs were similar between VDD and VD.ConclusionsThe vDD regimen was similar with vAD in the aspect of response rate, survival, and toxicity in NDMM patients. The addition of PLD to VD brought deeper response without increased toxicity, while no superior survival was found.

Carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) as induction therapy for transplant-eligible, newly diagnosed multiple myeloma patients (Myeloma XI+): Interim analysis of an open-label randomised controlled trial

Background Carfilzomib is a second-generation irreversible proteasome inhibitor that is efficacious in the treatment of myeloma and carries less risk of peripheral neuropathy than first-generation proteasome inhibitors, making it more amenable to combination therapy. Methods and findings The Myeloma XI+ trial recruited patients from 88 sites across the UK between 5 December 2013 and 20 April 2016. Patients with newly diagnosed multiple myeloma eligible for transplantation were randomly assigned to receive the combination carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide (KRdc) or a triplet of lenalidomide, dexamethasone, and cyclophosphamide (Rdc) or thalidomide, dexamethasone, and cyclophosphamide (Tdc). All patients were planned to receive an autologous stem cell transplantation (ASCT) prior to a randomisation between lenalidomide maintenance and observation. Eligible patients were aged over 18 years and had symptomatic myeloma. The co-primary endpoints for the study were progression-free survival (PFS) and overall survival (OS) for KRdc versus the Tdc/Rdc control group by intention to treat. PFS, response, and safety outcomes are reported following a planned interim analysis. The trial is registered (ISRCTN49407852) and has completed recruitment. In total, 1,056 patients (median age 61 years, range 33 to 75, 39.1% female) underwent induction randomisation to KRdc (n = 526) or control (Tdc/Rdc, n = 530). After a median follow-up of 34.5 months, KRdc was associated with a significantly longer PFS than the triplet control group (hazard ratio 0.63, 95% CI 0.51–0.76). The median PFS for patients receiving KRdc is not yet estimable, versus 36.2 months for the triplet control group (p < 0.001). Improved PFS was consistent across subgroups of patients including those with genetically high-risk disease. At the end of induction, the percentage of patients achieving at least a very good partial response was 82.3% in the KRdc group versus 58.9% in the control group (odds ratio 4.35, 95% CI 3.19–5.94, p < 0.001). Minimal residual disease negativity (cutoff 4 × 10−5 bone marrow leucocytes) was achieved in 55% of patients tested in the KRdc group at the end of induction, increasing to 75% of those tested after ASCT. The most common adverse events were haematological, with a low incidence of cardiac events. The trial continues to follow up patients to the co-primary endpoint of OS and for planned long-term follow-up analysis. Limitations of the study include a lack of blinding to treatment regimen and that the triplet control regimen did not include a proteasome inhibitor for all patients, which would be considered a current standard of care in many parts of the world. Conclusions The KRdc combination was well tolerated and was associated with both an increased percentage of patients achieving at least a very good partial response and a significant PFS benefit compared to immunomodulatory-agent-based triplet therapy. Trial registration ClinicalTrials.gov ISRCTN49407852.

Day 21 serum Free Light Chain (FLC) levels as a predictor of response to therapy in symptomatic multiple myeloma

Introduction: Serum Free Light Chain (sFLC) assay has a major role in the screening, diagnosis and monitoring in patients with Multiple Myeloma (MM). Measuring involved Free Light Chain (iFLC) has a proven advantage due to the short half-life compared to that of M-protein, thus useful as a prognostic tool for the assessment of response to therapy. It is established that achieving VGPR (very good partial response) or better after induction chemotherapy is associated with better OS (overall survival) and PFS (progression free survival) in myeloma patients. Few studies have shown that early reduction in iFLC during treatment is associated with achievement of VGPR or better. Objective: To study the predictive value of reduction of involved free light chain level on Day 21 of chemotherapy for achievement of VGPR after 4 cycles of induction chemotherapy. Methods: We conducted a prospective observational study in twenty eight patients of newly diagnosed Multiple Myeloma with iFLC ≥ 100mg/L. Serum FLC assay was done at baseline and on day 21 of therapy. All patients were followed up till the end of induction therapy for response assessment based on the IMWG criteria. Receiver Operator Characteristic (ROC) curve analysis was done to determine the cut off value of percent reduction in day 21 iFLC for achievement of VGPR or better. Results: After the induction chemotherapy, out of 28 patients, 13 patients achieved CR, 8 patients achieved VGPR, 4 patients achieved PR and 2 patients had stable disease (≥ VGPR = 21 patients, < VGPR = 6 patients). One patient expired after 2nd cycle of chemotherapy. The mean per cent reduction in day 21 iFLC level as compared to baseline was 91.5% and 57.1% in patients achieving ≥ VGPR and < VGPR (P < 0.0001), respectively. No other baseline parameter was found to be significantly different between the 2 groups. ROC curve analysis demonstrated a cut off of 84% reduction in iFLC value on day 21 (AUC of 0.937) had a sensitivity of 85.7% and a specificity of 100% in predicting the achievement of VGPR after four cycles of induction chemotherapy. Conclusion: Monitoring iFLC levels on Day 21 can be used as an important tool for early identification of responders/non responders to myeloma therapy. We recommend serum FLC assay to be done on day 21 as a real time assessment of treatment response in newly diagnosed myeloma patients. Key words- Multiple Myeloma, involved Free Light Chain (iFLC), Very Good Partial Response (VGPR)

Efficacy of Venetoclax and Dexamethasone in Refractory IgM Primary Plasma Cell Leukemia with t(11;14) and TP53 Mutation: A Case Report and Literature Review

Primary plasma cell leukemia (pPCL) is an uncommon disease. IgM multiple myeloma (MM) is an infrequent subtype that accounts for less than 1 percent of MM cases. IgM pPCL is quite rare with only a few cases published to date. We describe a case of a patient with IgM pPCL who initially presented with hyperviscosity syndrome requiring urgent plasma exchange. His bone marrow biopsy demonstrated t(11;14). He progressed on proteasome inhibitors, immunomodulating agents, and other chemotherapy medications but later achieved very good partial response (VGPR) to venetoclax and dexamethasone. Given the poor prognosis of pPCL, further studies using venetoclax alone or in combination with other novel agents as first-line treatment options are warranted particularly in patients with t(11;14).

Pembrolizumab as Consolidation Strategy in Patients with Multiple Myeloma: Results of the GEM-Pembresid Clinical Trial

PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43, p = 0.007; 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly lower expression of PD1 in CD8+ effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23.

Pomalidomide and dexamethasone in myelomatous pleural effusion

Myelomatous pleural effusion (MPE) is an uncommon clinical entity and occurs in less than 1% of all patients with multiple myeloma. MPE indicates a progression of disease, therefore is associated with a poor prognosis and estimated median survival of <3 months. Treatment of MPE is challenging, and the data regarding the role of novel agents lack in the literature. Herein, we report a relapsed IgA myeloma case of a patient presenting with MPE, who was treated with pomalidomide with a very good partial response.