Program DHC-Virtual
20 - 21 January 2021
Clinical Abstracts session 3
Abstract
HOVON143: Ixa-Dara-dex in intermediate fit and frail multiple myeloma patients
20 January
11:30 11:42
C. Stege
Paper

IXAZOMIB, DARATUMUMAB AND LOW-DOSE DEXAMETHASONE IN INTERMEDIATE FIT AND FRAIL NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS

Claudia Stege (1), Ellen van der Spek (3), Yavuz Bilgin (4), Alain Kentos (5), Maaike Sohne (6), Roel van Kampen (7), Inge Ludwig (8), Noortje Thielen (9), Nazik Durdu-Rayman (10), Nicole de Graauw (11), Niels van de Donk (1), Esther de Waal (12), Marie-Christine Vekemans (13), Gert Jan Timmers (14), Marjolein van der Klift (15), Savita Soechit (16), Paul Geerts (17), Matthijs Silbermann (18), Margriet Oosterveld (19), Inger Nijhof (1), Pieter Sonneveld (20), Saskia Klein (21), Mark-David Levin (22), Sonja Zweegman (1)
(1) Amsterdam UMC, Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Hematology, Amsterdam, (2) HOVON data center, Erasmus MC Cancer Institute, Hematology, Rotterdam, (3) Rijnstate Hospital, Internal medicine, Arnhem, (4) Admiraal de Ruijter Hospital, Internal medicine, Goes, (5) Centre Hospitalier Jolimont, Hematology, Haine-Saint-Paul, (6) St Antonius Hospital, Internal medicine/hematology, Nieuwegein, (7) Zuyderland Medical Center, Internal medicine, Sittard-Geleen, (8) Bernhoven Hospital, Hematology, Uden, (9) Diakonessenhuis, Internal Medicine, Utrecht, (10) Franciscus Hospital location Vlietland, Internal medicine/hematology, Schiedam, (11) Bravis Hospital, Internal medicine, Roosendaal, (12) Medisch Centrum Leeuwarden, Internal medicine, Leeuwarden, (13) St Luc Hospital, Hematology, Bruxelles, (14) Amstelland Hospital, Internal medicine, Amstelveen, (15) Amphia Hospital, Internal medicine, Breda, (16) Reinier de Graaf Groep, Hematology, Delft, (17) Deventer Hospital, Internal medicine, Deventer, (18) Tergooi Hospital, Internal medicine, Hilversum, (19) Canisius-Wilhelmina Hospital, Internal medicine, Nijmegen, (20) Erasmus MC Cancer Institute, Hematology, Rotterdam, (21) Meander Medical Center, Internal medicine, Amersfoort, (22) Albert Schweitzer Hospital, Internal medicine, Dordrecht
No potential conflicts of interest
Introduction

Intermediate fit and frail patients with newly diagnosed multiple myeloma (NDMM) have an inferior outcome as compared to fit patients, mainly because of high discontinuation rates due to toxicity. We designed a prospective trial specifically for intermediate fit and frail patients, evaluating the efficacy and tolerability of the novel triplet ixazomib-daratumumab-low-dose-dexamethasone (Ixa-Dara-dex).

Methods

The multicenter, non-randomized, phase II HOVON 143-trial included NDMM patients who were intermediate fit or frail according to the IMWG frailty index. Patients were treated with 9 induction cycles Ixa-Dara-dex followed by maintenance with Ixa-Dara for a maximum of 2 years. The primary endpoint was overall response rate (ORR) on induction treatment. Per-protocol, intermediate fit and frail patients were analyzed separately.         

Results

A total of 65 intermediate fit and 65 frail patients were eligible. Median follow-up was 18.1 (range 9.5-27.8) and 22.9 (12.7-31.0) months, respectively. The ORR during induction was 71% in intermediate fit and 78% in frail patients. Median PFS rates were 17.4 months (95% confidence interval [CI] 10.4-22.6) and 13.8 months (95%CI 9.2-17.7), and 12-months OS rates were 92% (95%CI 82-97%) and 78% (95%CI 57-99), respectively. Global health status/quality of life improved statistically significant and clinically meaningful during induction in both intermediate fit and frail patients.

In frail patients, median PFS and 12-months OS rates were superior in patients who were frail based on age >80 years only (not reached and 92%) versus patients who were frail because of comorbidities and/or impairments in (instrumental) activities of daily living either ≤80 years (13.8 months and 78%) or >80 years (10.1 months and 70%).

Thirty/65 (46%) intermediate fit and 33/65 (51%) frail patients did not proceed to maintenance. Main reasons for treatment discontinuation were progressive disease (29% and 19%), toxicity (6% and 9%), incompliance (5% and 6%) and intercurrent death (2% and 9%), respectively. In addition, 6 (9%) intermediate fit and 12 (18%) frail patients discontinued ixazomib, while continuing with daratumumab, mainly due to peripheral neuropathy (6/6 and 10/12). Of those, 2/6 and 7/10 had PNP grade ≤2 only.      
Cumulative hematological toxicity grade ≥3 during induction was reported in 8 (12%) intermediate fit and 20 (31%) frail patients, and non-hematological toxicity grade ≥3 in 33 (51%) and 48 (74%) patients. Early death (<2 months) occurred in 1 (1.5%) intermediate fit patient, and 5 (8%) frail patients.
  

Conclusion

Ixa-Dara-dex lead to high response rates and improvement in quality of life. However, treatment discontinuation due to toxicity and (early) mortality, negatively influencing PFS and OS remains a concern, especially in frail patients. Improving frailty risk stratification in order to select those patients in whom treatment is beneficial and additional frailty-adjusted treatment regimens are urgently needed. 

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