Selected Abstracts From 2015 ASH Annual Meeting: Part 3


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Syed A. Abutalib, MD

Here are several more abstracts selected from the proceedings of the 2015 American Society of Hematology (ASH) Annual Meeting and Exposition, focusing on newly diagnosed multiple myeloma, relapsed/refractory multiple myeloma, and amyloid light-chain (AL) amyloidosis. For other selected abstracts from this conference, see the December 25, 2015, and the February 10, 2016, issues of The ASCO Post. For full details of these study abstracts, visit https://ash.confex.com/ash/2015/webprogram/start.html.

Newly Diagnosed Multiple Myeloma

Abstract 27: Bortezomib induction and maintenance in patients with newly diagnosed multiple myeloma: Long-term follow-up of the HOVON-65/GMMG-HD4 trial1

Question Asked: Does addition of bortezomib (Velcade) in the treatment platform, induction (bortezomib, doxorubicin, dexamethasone), and 2 years of maintenance after autologous hematopoietic stem cell transplant (single or double) result in improvement in progression free survival compared with standard treatment?

Abstract Conclusion: Yes; bortezomib given at 1.3 mg/m2 twice weekly for 2 years leads to a significant and lasting improvement of progression-free survival and overall survival. Response rates with bortezomib/doxorubicin/dexamethasone induction, transplant, and bortezomib maintenance were complete response, 37%; ≥ very good partial response, 76%; ≥ partial response, 91% vs complete response, 25%; ≥ very good partial response, 56%; ≥ partial response, 83% with standard treatment (vincristine, doxorubicin, dexamethasone, then transplant, then thalidomide [Thalomid]). Interestingly, their data show that bortezomib treatment combined with double autologous hematopoietic stem cell transplant significantly improves progression-free and overall survival in patients with del(17p) and almost abrogates the negative impact of this cytogenetic abnormality.

Abstract 393: Randomized phase III investigation of four cycles of VTD (bortezomib/thalidomide/dexamethasone) vs VCD (bortezomib/cyclophosphamide/dexamethasone) prior to autologous hematopoietic stem cell transplant in patients with newly diagnosed multiple myeloma. This trial is the first prospective randomized comparison of VTD vs VCD administered as induction therapy prior to transplant2

Question Asked: Is VTD superior to VCD with regard to achieving a very good partial response?

Abstract Conclusion: Very good partial and partial responses were significantly higher in the VTD arm, with P values of .04 and .02, respectively. The very good partial response was 66.7% vs 56.2% in the VTD and VCD arms, respectively.

Abstract 25: Results of phase III SWOG (S0777) trial comparing two induction therapies (bortezomib, lenalidomide, dexamethasone [VRD] vs lenalidomide/dexamethasone) in newly diagnosed multiple myeloma3

Question Asked: Does VRD result in better progression-free survival than lenalidomide/dexamethasone?

Abstract Conclusion: VRD results in a statistically significant and clinically meaningful improvement in progression-free survival (43 vs 31 months) as well as better overall survival (not reached vs 63 months) relative to lenalidomide/dexamethasone. The stratified hazard ratio was 0.742 (96% Wald confidence interval: 0.579–0.951), and the one-sided stratified log rank P value for progression-free survival (VRD vs lenalidomide/dexamethasone) was .0066. The overall survival was improved for VRD vs lenalidomide/dexamethasone, with a hazard ratio of 0.666 and a two-sided log-rank P value of .0114.

Abstract 191: Evaluation of minimal residual disease by next-generation sequencing (and its comparison with seven-color flow-cytometry) is highly predictive of progression-free survival in patients treated on IFM/DFCI 2009 trial4

Question Asked: What is the utility of performing next-generation sequencing and flow cytometry at predefined time points, pre- and postmaintenance, in patients treated with triple-agent therapy during induction?

Abstract Conclusion: Briefly, this trial enrolled 700 patients under 66 years of age to receive either eight cycles of VRD (arm A) or three cycles of VRD, high-dose melphalan, and auto-hematopoietic cell transplant, followed by two consolidation VRD cycles (arm B). All patients received lenalidomide maintenance for 12 months.

A total of 246 patients have been evaluated by next-generation sequencing before maintenance and 178, after maintenance. Patients were classified in three categories: negative (< 10-6), low-positive (between 10-4 and 10-6), and positive (> 10-4). At premaintenance, 87 patients were negative, 80 were low-positive, and 79 were positive. At postmaintenance, these numbers improved and were respectively 86, 52, and 40, favoring maintenance therapy.

Using a cutoff at 10-6, patients below 10-6 at premaintenance had a 3-year progression-free survival of 83%, vs 53% for patients > 10-6; at postmaintenance, these results were 90% and 59%, respectively, in favor of maintenance therapy. When restricted to patients in complete response, the 3-year progression-free survival was 87% and 63% at premaintenance, and 92% and 64% at postmaintenance, favoring maintenance therapy.

Second, the investigators compared two minimal residual disease techniques (next-generation sequencing vs flow cytometry). Using a seven-color flow cytometry strategy, the sensitivity level was 10-4. Among the 163 patients testing negative with the flow-cytometry approach, 84 (51%) were positive, and the remaining 79 patients were “true” negative using next-generation sequencing and among 72 patients positive with flow cytometry, 67 (93%) were also positive using next-generation sequencing. In the subgroup of patients with negative minimal residual disease using flow cytometry, the 3-year progression-free survival was 86% for next-generation sequencing–negative patients vs 66% for next-generation sequencing–positive at premaintenance and 91% vs 65% at postmaintenance. The final results of this trial will unveil answers to many controversial and debated questions and will construct the foundation for future clinical trials in multiple myeloma.

Abstract 391: Autologous hematopoietic stem cell transplant for patients with newly diagnosed multiple myeloma treated with VRD induction therapy: A phase III study of the Intergroup Francophone Du Myelome (IFM/DFCI 2009 trial)5

Question Asked: What is the impact on progression-free survival of patients who undergo upfront autologous hematopoietic stem cell transplant after conventional VRD induction therapy?

Abstract Conclusions: The 3-year postrandomization progression-free survival rate was 61% in the transplant arm vs 48% in the VRD arm (stratified P value for log-rank test < .0002; HR = 1.5, 95% CI = 1.2–1.9). The progression-free survival benefit observed in the transplant arm was uniform across all the following subgroups: age (≤ or > 60 years), sex, Ig isotype (IgG or others), International Staging System stage (I or II or III), cytogenetics (standard- or high-risk), and response after the first three cycles of VRD (complete response or not).

The complete response rate was significantly higher in the transplant arm than in the VRD arm: 58% vs 46%, respectively (P < .01). The 3-year postrandomization rate of overall survival was extremely high (88%) and similar between the two study groups (stratified P value for log rank test = .25). In the transplant arm, 93% of patients underwent autologous hematopoietic stem cell transplant, and five toxic deaths occurred during mobilization or in the actual transplant phase (1.4%). Finally, it is important to note that these data are from 700 patients treated in France and Belgium. The parallel U.S. trial is ongoing, and results are awaited.

Abstract 3155: Phase II study of the combination of ixazomib (3 mg) with lenalidomide as maintenance therapy following autologous hematopoietic stem cell transplant in patients with newly diagnosed multiple myeloma (n = 65)6

Question Asked: Is “all oral therapy” convenient, safe, and efficacious in the prevention of relapse after autologous hematopoietic stem cell transplant in patients with newly diagnosed multiple myeloma?

Abstract Conclusion: Long-term administration of combination of lenalidomide/ixazomib (Ninlaro) as maintenance therapy after autologous hematopoietic stem cell transplant is feasible, with patients ongoing at 30+ cycles. The incidence of adverse events was similar to the historical experience with lenalidomide alone; hematologic adverse events were manageable with dose reductions. The incidence of peripheral neuropathy was limited to grade 1/2 events and one grade 3 event, with no other unexpected toxicity. The median progression-free survival has not been reached; however, the estimated 2-year progression-free survival was 83%.

Relapsed and Refractory Multiple Myeloma

Abstract 3051: Recapturing disease response: A phase II study of high-dose carfilzomib in patients with relapsed or refractory multiple myeloma who have progressed on standard-dose carfilzomib 7

Question Asked: Can the response of patients who progressed on carfilzomib at 27 mg/m2 be recaptured by dose escalation to 56 mg/m2 (with only 16 mg of dexamethasone weekly)?

Abstract Conclusion: Of the 12 patients evaluable for efficacy, responses include 1 very good partial response, 4 partial responses, and 6 stable diseases, for overall response rates of 42% and a median duration of response of 6.5 months, with manageable side effects. The median progression-free survival was 3.5 months. Interestingly, two of the three patients who progressed on carfilzomib-based triplet regimens prior to study entry achieved a partial response with dose escalation. These findings support enrollment to the ongoing SWOG S1304 randomized study comparing carfilzomib at 27 and 56 mg/m2.

Abstract 731: Subgroup analysis from the phase III Aspire study evaluating the efficacy and safety of carfilzomib, lenalidomide, and dexamethasone (KRd) vs lenalidomide/dexamethasone in patients with relapsed multiple myeloma based on cytogenetic risk status8

Question being asked: What are the benefits of adding carfilzomib to lenalidomide/dexamethasone across high- and standard-risk cytogenetic groups in patients with relapsed multiple myeloma?

Abstract Conclusion: In patients with high-risk cytogenetics (defined as the presence of t[4;14] or t[14;16] or with deletion 17p in ≥ 60% of plasma cells), treatment with KRd resulted in a median progression-free survival of nearly 2 years, a 9-month improvement over lenalidomide/dexamethasone. Treatment with KRd also led to a 10-month improvement in median progression-free survival in patients with standard-risk cytogenetics over lenalidomide/dexamethasone. KRd had a favorable benefit-risk profile.

Abstract 4221: Phase I study of ixazomib in combination with panobinostat and dexamethasone in patients with relapsed/refractory multiple myeloma9

Question Asked: What is the safety (and preliminary efficacy data) for an all-oral regimen that uses ixazomib and every-other-week dosing of panobinostat (Farydak) in extensively pretreated patients with progressive multiple myeloma on proteasome/immunomodulatory combinations?

Abstract Conclusion: Addition of panobinostat at 20 mg three times a week every other week to ixazomib at a target of 4 mg weekly, three weeks on, one week off, with dexamethasone at20 mg on the day of and after ixazomib was well tolerated and demonstrated activity.

AL Amyloidosis

Abstract 732: Treatment with doxycycline in combination with chemotherapy significantly improves overall survival in patients with advanced cardiac stage IIIa AL amyloidosis but not in those with advanced, stage IIIb disease10

Question Asked: Does the addition of doxycycline during and following induction therapy improve outcomes of patients (n = 30) with cardiac AL amyloidosis?

Abstract Conclusion: The median overall survival was 13 months in the control group and not reached in the doxycycline group. The 12- and 24-month survival in the doxycycline-treated group was 82% and 82%, respectively, compared with 53% and 40% in the control group (log rank P < .0001). The survival advantage was marked in stage IIIa patients, but there was no impact of doxycycline in the stage IIIb patients. On an intent-to-treat basis, 60% of the doxycycline group and 18% of the control group achieved cardiac responses by NT-proBNP criteria (chi square P < .0001).

This study confirms the previous preliminary results11 of using adjuvant doxycycline in AL amyloidosis and strongly supports the rationale to proceed with a randomized trial. Doxycyline was given orally at 100 mg twice daily until completion of treatment and continued as long as tolerated without unacceptable toxicity or patient preference. In the doxycycline group, 56% achieved a complete response, 10% had a very good partial response, 30% had a partial response (compared with 35% complete response), 8% had a very good partial response, and 37% had a partial response in the control group. ■

Disclosure: Dr. Abutalid reported no potential conflicts of interest.

References

1. Sonneveld P, Salwender H-J, Van Der Holt B, et al: Bortezomib induction and maintenance in patients with newly diagnosed multiple myeloma. 2015 ASH Annual Meeting. Abstract 27.

2. Moreau P, Hulin C, Macro M, et al: Bortezomib, thalidomide and dexamethasone is superior to bortezomib, cyclophosphamide and dexamethasone prior to autologous stem cell transplantation for patients with de novo multiple myeloma. 2015 ASH Annual Meeting. Abstract 393.

3. Durie B, Hoering A, Rajkumar SV, et al: Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant. 2015 ASH Annual Meeting. Abstract 25.

4. Avet-Loiseau H, Corre J, Lauwers-Cances V, et al: Evaluation of minimal residual disease by next generation sequencing is highly predictive of progression free survival in the IFM/DFCI 2009 trial. 2015 ASH Annual Meeting. Abstract 191.

5. Attal M, Lauwers-Cances V, Hulin C, et al: Autologous transplantation for multiple myeloma in the era of new drugs. 2015 ASH Annual Meeting. Abstract 391.

6. Shah JJ, Feng L, Weber D, et al: Phase II study of the combination of ixazomib with lenalidomide as maintenance therapy following autologous stem cell transplant in patients with multiple myeloma. 2015 ASH Annual Meeting. Abstract 3155.

7. Chari A, Cho HJ, Parekh S, et al: Recapturing disease response. 2015 ASH Annual Meeting. Abstract 3051.

8. Avet-Loiseau H, Fonseca R, Siegel D, et al: Efficacy and safety of carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients with relapsed multiple myeloma based on cytogenetic risk status. 2015 ASH Annual Meeting. Abstract 731.

9. Reu FJ, Valent J, Malek E, et al: A phase I study of ixazomib in combination with panobinostat and dexamethasone in patients with relapsed or refractory multiple myeloma. 2015 ASH Annual Meeting. Abstract 4221.

10. Wechalekar A, Whelan C, Lachmann H, et al: Oral doxycycline improves outcomes of stage III AL amyloidosis. 2015 ASH Annual Meeting. Abstract 732.

11. Wechalekar A, Whelan C, Sachchithanantham S, et al: A matched case control study of doxycycline added to chemotherapy for reducing early mortality in patients with advanced cardiac AL amyloidosis from the Alchemy study cohort. 2014 ASH Annual Meeting. Abstract 3485.



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