Highlights in multiple myeloma

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1 3 CONGRESS HIGHLIGHTS Highlights in multiple myeloma P. Vlummens, MD SUMMARY Multiple myeloma (MM) remains a devastating disease, even in the era of novel agents. As such, the search for new treatment modalities, alongside optimization of those already available, boldly continues. Each year, the ASH congress offers us the opportunity to learn about the latest developments in the MM field. This text aims to provide a brief summary of some of the latest insights presented at ASH this year. (BELG J HEMATOL 207;8():3-7) CONSOLIDATION THERAPY DEMYSTIFIED? Sonneveld et al. presented data from a multicenter study addressing the role of consolidation therapy in newly diagnosed multiple myeloma patients (NDMM) who are transplant eligible. This trial consisted of 2 subsequent randomizations, which were presented separately. The first randomization (R) compared 4 cycles of melphalan/ prednisone/bortezomib versus high-dose melphalan and autologous stem cell transplantation (ASCT, single or double transplant) as an intensification therapy after bortezomib/cyclophosphamide/dexamethasone (VCD) induction but will not be discussed in further detail.2 Subsequently, a second randomization (R2), comparing consolidation using 2 cycles of bortezomib/lenalidomide/ dexamethasone (VRD) versus no consolidation therapy, was performed. All patients received 0mg of lenalidomide continuously as maintenance therapy. A total of 903 patients were randomized to consolidation (N=459), or no consolidation (N=444) with a median follow-up of 25 months. After adjusting for R, a significant decrease in the risk of progression was seen in the consolidation arm at the 3-year time point (HR: 0.78; p= 0.045). Looking into specific subgroups, it became clear that this benefit was mostly present in patients with low-risk cytogenetics (HR: 0.68; p= 0.03). No significant difference (HR:.03; p= 0.9) was seen in patients with high-risk cytogenetics (del(7p) and/or t(4;4) and/or t(4;6)).2 Although this study shows results favoring consolidation therapy after ASCT/intensification therapy, the exact role of consolidation still remains unclear when considering the results of the STAMiNA-trial.3 This large phase III study randomly assigned transplant-eligible patients :: to receive melphalan/asct and 4 cycles of VRD consolidation (ACM), versus single (AM) or tandem ASCT (TAM). All patients were subsequently treated with lenalidomide maintenance therapy. A total of 758 patients were enrolled (ACM, N=254; TAM, N=247; AM, N=257) and the median follow-up was 38 months. Interestingly, the 38-month probabilities for progression did not differ between subgroups (ACM 57%, TAM 56% and AM 52%; ACM versus TAM p= 0.75, ACM versus AM p= 0.2, TAM versus AM p= 0.37). The median overall survival (OS) was not reached in all subgroups. These results show that the addition of VRD consolidation or a second autologous transplant was not superior to single transplant and lenalidomide maintenance.3 RESPONSE ADAPTED INDUCTION TREATMENT LEADS TO AUGMENTATION OF RESPONSE RATES IN NDMM PATIENTS The Myeloma XI study is the first randomized controlled trial in NDMM patients investigating a response driven induction strategy.4 Patients were randomized between thalidomide or lenalidomide in triplet combination with cyclophosphamide and dexamethasone for 4 (transplant-eligible, TE) or 6 cycles (transplant-ineligible, TIE). Response assessment was performed after termination of treatment and patients with a minor (MR) or partial Ghent University Hospital. Please send all correspondence to: Philip Vlummens, MD, Department of Hematology, Ghent University Hospital, De Pintelaan Gent, Tel: 09/ , philip.vlummens@uzgent.be. Conflict of interest: The author has nothing to declare and indicates no potential conflict of interest. VO LU M E8 F E B R U A R Y 2 07

2 4 response (PR) were randomized between subsequent therapy with VCD versus no further induction therapy. Patients having a very good partial or complete response (VGPR/CR) were transplanted if eligible, whilst refractory patients (stable or progressive disease) went on to receive the VCD scheme. MR/PR was seen in 58 patients (TE N= 366; TIE N= 25), who went on to VCD treatment. Sequential use of VCD significantly improved PFS from a median of 20 to 30 months (HR: 0.60; p< 0.00) in this patient population. This effect was mainly due to the significant benefit in TE patients with a median PFS 48 months versus 28 months (HR: 0.50; p< 0.00). No difference was seen in TIE patients. An important upgrade in response was seen in the VCD-treated group with 4% of evaluable patients (N= 8/289) moving from MR/PR to VGPR/CR. The improved depth of response was maintained in transplanted patients with post-asct VGPR/CR responses of 65% in the VCD-treated group versus 38%. As such, a sequential strategy in patients with suboptimal response after first induction therapy seems to be worth exploring in further studies. 4 MINIMAL RESIDUAL DISEASE IN TRANSPLANT-INELIGIBLE PATIENTS Minimal residual disease (MRD) remains a powerful predictor of outcome in MM as was already demonstrated in TE patient cohorts. Data on the benefit of MRD in TIE patients is however more limited. To address this de Tute et al. analyzed the impact of MRD in these patients in the Myeloma XI trial. 5 The impact of MRD on PFS was analyzed in patients included in the non-intensive arm, receiving either thalidomide or lenalidomide combined with cyclophosphamide and dexamethasone, with responding patients being subsequently randomized to lenalidomide maintenance or follow-up. MRD was assessed using 6-colour flow cytometry at the end of induction therapy (sensitivity 0-4 ). Overall MRD-negativity was 3.8% (N= 4/297) with no significant difference between induction regimens. MRD-negativity was associated with a significant PFSbenefit with a median PFS of 34 versus 8 months in MRD-positive patients (HR: 0.44; p< 0.000). No significant difference was seen between both induction therapies. OS data were not yet mature at the time of the presentation. 5 These data suggest that MRD-negativity is also clinically important in TIE patients and could be a valuable prognostic tool even when high-dose treatment is not feasible. DARATUMUMAB: AN UPDATE ON CASTOR AND POLLUX AND THE ROLE OF MRD IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) PATIENTS The further importance of MRD was underlined by the impressive results obtained with daratumumab. Daratumumab has been shown to be a potent therapeutic weapon in MM and was recently added to standard of care regimens in 2 randomized controlled phase III trials in RRMM: POLLUX (lenalidomide/dexamethasone +/- daratumumab; Rd/DRd) and CASTOR (bortezomib/dexamethasone +/- daratumumab; Vd/ DVd). Both studies showed that combination therapy led to a significant PFS benefit in RRMM. 6-7 An update on PFS in both studies was given at this conference alongside the first prospective data on MRD in RRMM patients. 8 In POLLUX the median PFS was not reached (DRd) versus 7.5 months (Rd) with a median follow-up of 7.3 months (HR: 0.37; p< 0.000) and at 3.0 months of median follow-up in CASTOR, PFS was shown to be not reached (DVd) versus 7. months (Vd) (HR: 0.33; p< 0.000). MRD was assessed using nextgeneration sequencing in POLLUX at time of suspected CR and at 3 and 6 months. In CASTOR, MRD was assessed at the time of suspected CR and at 6 and 2 months after the first dose. The analysis showed that the addition of daratumumab to Rd/Vd resulted in an impressive gain in MRD-negativity rates, which were approximately 4-times higher in both POLLUX (24.8 versus 5.7%, p< 0.000) and CASTOR (0.4 versus 2.4%, p< 0.005). Patients with MRD-negativity also had a lower risk of progression, suggesting that the deep clinical responses induced by daratumumab may lead to improved survival in RRMM patients. VENETOCLAX AS A NOVEL TREATMENT IN RRMM In this day and age the search for novel therapies goes on relentlessly. One of these interesting molecules is venetoclax, a selective and orally available, BCL-2 inhibitor. Kumar et al. presented the data on a phase I trial investigating venetoclax monotherapy in RRMM patients. 9 A total of 66 patients were enrolled in this study (30 in dose escalation cohorts and 36 in safety expansion). All patients were heavily pretreated with a median number of 5 prior therapies (range to 5) and 70%/77% being refractory to bortezomib and lenalidomide, respectively. Thirty (46%) patients had the t(;4) translocation and were suspected to respond better to venetoclax based on pre-clinical data. Median

3 CONGRESS HIGHLIGHTS 5 treatment duration was 2.5 months and 5 patients (77%) discontinued treatment, mainly due to disease progression. The most common grade 3-4 adverse events were thrombocytopenia (26%), neutropenia (20%), lymphopenia (5%) and anemia (4%). The overall response rate (ORR) for all patients was 2% (4/66) and 5% (0/66) obtained a VGPR or better. Patients having a t(;4) indeed seemed to benefit more, as the ORR in this group was 40% with 8 patients (27%) achieving a VGPR or better (Figure ). The median time to progression (TTP) for patients with or without/ undetermined t(;4) was 6.6 and.9 months, respectively. These data supports the single agent activity of venetoclax, especially in t(;4) positive RRMM patients. In another oral abstract, Moreau et al. presented the results of the phase Ib study investigating treatment with venetoclax combined with bortezomib and dexamethasone in RRMM. 0 This combination was chosen as it was shown that venetoclax enhances the activity of bortezomib in MM cell lines and xenograft models. Sixty-six patients were enrolled with 54 in the dose escalation cohort and 2 in the expansion cohort with the recommended dose of 800 mg daily. Patients had a median of 3 prior lines (range - 3) and 39%/ 5 were refractory to prior treatment with bortezomib and lenalidomide, respectively. More than half (59%) of the patients had received a prior ASCT. The ORR was 67% in the total cohort and 4 achieved a VGPR or better. The median duration of response was 8.8 months and with a median TTP of 8.6 months. In a subgroup of patients who were bortezomib non-refractory and had received to 3 prior lines, the ORR was how-ever higher at 97%. Responses were also seen to be more durable in patients not refractory to prior bortezomib (median TTP.3 versus.8 months) and those who had received -3 prior lines (median TTP.6 months versus 4.3 months). In contrast to venetoclax monotherapy, no clear benefit from t(;4) was seen in this patient population as responses were comparable between both groups. 0 These data indicate the promising efficacy of this novel combination and results from the ongoing phase 3 trial are eagerly awaited. SELINEXOR-DEXAMETHASONE HAS IMPRESSIVE ANTI-DISEASE ACTIVITY IN QUAD- AND PENTA-REFRACTORY MM PATIENTS Another interesting molecule with potential benefit in MM patients is selinexor, a selective XPO inhibitor Percentage of Patients FIGURE. ORR by t(;4) status in a phase I study assessing venetoclax monotherapy for relapsed/refractory multiple myeloma. 9 0 scr CR VGPR PR ORR 2% 9% 6% All Patients (n=66) ORR 40% t(;4) (n=30) ORR 6% Non-t(;4) or undetermined (n=36) inducing the accumulation of tumor suppressor proteins in the nucleus. Vogl et al. presented their data of the phase II clinical trial evaluating the selinexor-dexamethasone combination in MM patients refractory to bortezomib, carfilzomib, lenalidomide and pomalidomide (quad-refractory) or additionally refractory to anti- CD38 antibody treatment (penta-refractory). In total, 79 patients (48 quad-refractory, 3 penta-refractory) were enrolled. In both groups patients had received a median of 7 prior therapy lines. At the time of analysis 70 patients had discontinued therapy, mainly due to progression (7) or adverse events (7%). Most common grade 3-4 treatment-related adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (7%), fatigue (5%) and hyponatremia (22%). An impressive ORR of 2% in quad-refractory and 20% in pentarefractory patients was seen. The PFS was 5.5 months in responding patients versus 2.3 months in non-responders. Median OS was not reached in responders versus 9.3 months in non-responders. As such, selinexor-dexamethasone displays anti-tumor activity in heavily pretreated patients with RRMM and responses are associated with a benefit in terms of OS in these patients with a dismal prognosis. 7% 7%

4 6 KEY MESSAGES FOR CLINICAL PRACTICE The potential benefit of consolidation therapy or second ASCT after induction therapy remains unclear, especially in patients receiving lenalidomide maintenance therapy. 2 Response adapted induction therapy can lead to improvement of disease response and improves PFS. 3 MRD is an important marker of response and leads to better disease control and prolonged PFS, even in elderly and RRMM patients. The interplay between MRD and OS looks promising and will hopefully be further elucidated in the near future. 4 Agents such as selinexor and venetoclax exhibit noteworthy single-agent activity in heavily pretreated RRMM and results of larger clinical trials are eagerly awaited. 5 Maintenance therapy with IMiDs is well tolerated and should be considered in the future treatment of MM patients. LENALIDOMIDE MAINTENANCE SEEMS SAFE AND FEASIBLE IN MM PATIENTS OF ALL AGES Lenalidomide is an effective treatment for MM and a recent meta-analysis has shown that prolonged exposure is important to improve outcomes post-transplant. As part of the larger Myeloma XI trial, risks and benefits of lenalidomide maintenance were compared to no maintenance. 2 A total of,550 patients (828 TE and 722 TIE) were randomized to either receive lenalidomide (857 patients) versus no therapy (693 patients). The analysis showed that maintenance therapy consisting of lenalidomide 0 mg 2/28 days resulted in a median PFS of 37 months versus 9 months (HR: 0.45; p< 0.000) in the non-maintenance group. This benefit was maintained in TE patients (median PFS 60 versus 28 months, HR: 0.46; p< 0.000) as well as in TIE patients (median PFS 26 versus 2 months, HR: 0.44; p< 0.000). Interestingly, this benefit persisted across risk subgroups and was independent of induction therapy and response. The therapy was well tolerated overall and, although 72 second primary malignancies were observed, the authors state that this observation doesn t outweigh the benefits of continuous treatment. 2 As such, they propose lenalidomide maintenance as standard of care in patients of all ages. CONCLUSION This year s ASH meeting once again showed that the MM community goes on relentlessly to investigate novel molecules and new combinations to battle this disease. Interesting and novel therapies, including CAR-T or BiTE-based strategies, are being actively investigated but unfortunately abstracts were in too abundant a number to be all discussed in detail here. Selected molecules such as selinexor and venetoclax show promising results in terms of ORR and PFS in heavily pretreated patients. The importance of maintenance therapy and MRD has been confirmed in large studies. Also, the combination of monoclonal antibodies with already validated standard of care regimens has been shown to be safe and led to some of the best responses ever reported in this setting. Pertinent questions, such as the exact role of consolidation therapy or second ASCT considering maintenance therapy, remain unanswered nonetheless. REFERENCES. Sonneveld P., Beksac M., van der Holt B. et al. Consolidation followed by maintenance therapy versus maintenance alone in newly diagnosed, transplant eligible patients with multiple myeloma (MM): A randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). Blood 206;28(22): abstract Cavo M., Beksac M., Dimopoulos M. et al. Intensification therapy with bortezomib-melphalan-prednisone versus autologous stem cell transplantation for newly diagnosed multiple myeloma: An intergroup, multicanter phase III study of the European Myeloma Network (EMN02/HO95 MM trial). Blood 206;28(22): abstract Stadtmauer E., Pasquini M., Blackwell B. et al. Comparison of autologous hematopoietic cell transplant (autohct), bortezomib, lenalidomide (len) and dexa- methasone (RVD) consolidation with len maintenance (ACM), tandem autohct with len maintenance (TAM) and autohct with len maintenance (AM) for up-front

5 CONGRESS HIGHLIGHTS 7 treatment of patients with multiple myeloma (MM): Primary pesults from the randomized phase III Trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 StaMINA Trial). Blood 206;28(22): abstract LBA-. 4. Jackson G., Davies F., Pawlyn C. et al. Response adapted induction treatment improves outcomes for myeloma patients; Results of the phase III Myeloma XI study. Blood 206;28(22): abstract de Tute R., Rawstron A., Cairns D. et al. Impact of minimal residual disease in transplant ineligible myeloma patients: results of from the UK NCRI Myeloma XI trial. Blood 206;28(22): abstract Palumbo A., Chanan-Khan A., Weisel K. et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 206;375(8): Dimopoulos M., Oriol A., Nahi H. et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med 206;375(4): Avet-Loiseau H., Casneuf T., Chiu C. et al. Evaluation of minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) patients treated with daratumumab in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone. Blood 206;28(22): abstract Kumar S., Vij R., Kaufman J. et al. Venetoclax monotherapy for relapsed/ refractory multiple myeloma: Safety and efficacy results from a phase I study. Blood 206;28(22): abstract Moreau P., Chanan-Khan A., Roberts A. et al. Venetoclax combined with bortezomib and dexamethasone for patients with relapsed/refractory multiple myeloma. Blood 206;28(22) : abstract Vogl D., Dingli D., Cornell R. et al. Selinexor and low dose dexamethasone (Sd) in patients with lenalidomide, pomalidomide, bortezomib, carfilzomib and anti-cd38 ab refractory multiple myeloma (MM): STORM study. Blood 206; 28(22): abstract Jackson G., Davies F., Pawlyn C. et al. Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; results of the phase III myeloma XI study. Blood 206;28(22): abstract 43.