Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group

Moreau, Philippe; Kumar, Shaji; Miguel, Jesús F. San; Davies, Faith E.; Zamagni, Elena; Bahlis, Nizar J.; Ludwig, Heinz; Mıkhael, Joseph; Terpos, Evangelos; Schjesvold, Fredrik; Martin, Thomas; Yong, Kwee; Durie, Brian G.M.; Façon, Thierry; Jurczyszyn, Artur; Sidana, Surbhi; Raje, Noopur; Donk, Niels W.C.J. van de; Lonial, Sagar; Cavo, Michèle; Kristinsson, Sigurður Y.; Lentzsch, Suzanne; Hájek, Roman; Anderson, Kenneth C.; João, Cristina; Einsele, Hermann; Sonneveld, Pieter; Engelhardt, Monika; Fonseca, Rafaël; Vangsted, Annette Juul; Weisel, Katja; Baz, Rachid; Hungria, Vânia; Berdeja, Jesús G.; Costa, Fernando Leal da; Maiolino, Ângelo; Waage, Anders; Vesole, David H.; Ocio, Enrique M.; Quach, Hang; Driessen, Christoph; Bladé, Joan; Leleu, Xavier; Riva, Eloísa; Bergsagel, P. Leif; Hou, Jian; Chng, Wee Joo; Mellqvist, Ulf Henrik; Dytfeld, Dominik; Harousseau, Jean Luc; Goldschmidt, Hartmut; Laubach, Jacob P.; Munshi, Nikhil C.; Beksaç, Meral; Costa, Luciano J.; Kaiser, Martin; Hari, Parameswaran; Boccadoro, Mario; Usmani, Saad Z.; Zweegman, Sonja; Holstein, Sarah A.; Sezer, Orhan; Harrison, Simon; Nahi, Hareth; Cook, Gordon; Mateos, María Victoria; Rajkumar, S. Vincent; Dimopoulos, Meletios A.; Richardson, Paul G.

doi:10.1016/s1470-2045(20)30756-7

Cited by 153 publications

(172 citation statements)

References 66 publications

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“…[21][22][23][24] Consequently, translation of PFS benefit into OS benefit and interpretation of OS has become increasingly confounded by more extensive use of subsequent therapies with optimized sequencing. 2 In TOURMALINE-MM1, approximately 70% of patients received subsequent therapy, and imbalances were seen between arms. Patients progressed earlier on placebo-Rd, received a higher number of subsequent therapies than those on the ixazomib-Rd arm (median 3 v 2), and received subsequent PIs, daratumumab, and other treatments more frequently.…”

Section: Discussionmentioning

confidence: 99%

“…An increasing number of treatment options are becoming available for patients with relapsed or refractory (RR) multiple myeloma (MM). 1,2 Although these advances have led to marked improvements in overall survival (OS), 3 there remains a need for effective and tolerable therapies for patients who continue to relapse or are refractory to treatment, as well as for hard-to-treat subgroups such as the elderly and/or frail, and those with high disease burden or highrisk cytogenetics. 2 Other studies have shown that premature discontinuation of antimyeloma therapy may negatively affect outcomes, being associated with reduced duration of response 8 and poorer OS.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 Although these advances have led to marked improvements in overall survival (OS), 3 there remains a need for effective and tolerable therapies for patients who continue to relapse or are refractory to treatment, as well as for hard-to-treat subgroups such as the elderly and/or frail, and those with high disease burden or highrisk cytogenetics. 2 Other studies have shown that premature discontinuation of antimyeloma therapy may negatively affect outcomes, being associated with reduced duration of response 8 and poorer OS. 9 Notably, longer-term use of parenteral PIs, particularly in routine clinical practice, may be limited because of the associated treatment burden, including toxicities and the need for patients to visit the clinic or hospital for treatment.…”

Section: Introductionmentioning

confidence: 99%

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Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Richardson

Kumar

Masszi

et al. 2021

JCO

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PURPOSE The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Richardson

Kumar

Masszi

et al. 2021

JCO

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“…Multiple myeloma (MM) represents a life-threatening hematological disorder, being the second most common blood cancer diagnosis, with over 12,000 deaths estimated per year and a 5-year survival rate around 54% ( , accessed on 7 May 2021). Notwithstanding the introduction of novel therapeutic approaches that have led to steadily increased survival rates over the last decade, a complete eradication has not been obtained so far, and MM remains an incurable disease [ 1 , 2 ].…”

Section: Introductionmentioning

confidence: 99%

Pentraxin 3 Inhibits the Angiogenic Potential of Multiple Myeloma Cells

Ronca

Taranto

Corsini

et al. 2021

Cancers

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During multiple myeloma (MM) progression the activation of the angiogenic process represents a key step for the formation of the vascular niche, where different stromal components and neoplastic cells collaborate and foster tumor growth. Among the different pro-angiogenic players, Fibroblast Growth Factor 2 (FGF2) plays a pivotal role in BM vascularization occurring during MM progression. Long Pentraxin 3 (PTX3), a natural FGF antagonist, is able to reduce the activation of stromal components promoted by FGF2 in various in vitro models. An increased FGF/PTX3 ratio has also been found to occur during MM evolution, suggesting that restoring the “physiological” FGF/PTX3 ratio in plasma cells and BM stromal cells (BMSCs) might impact MM. In this work, taking advantage of PTX3-inducible human MM models, we show that PTX3 produced by tumor cells is able to restore a balanced FGF/PTX3 ratio sufficient to prevent the activation of the FGF/FGFR system in endothelial cells and to reduce the angiogenic capacity of MM cells in different in vivo models. As a result of this anti-angiogenic activity, PTX3 overexpression causes a significant reduction of the tumor burden in both subcutaneously grafted and systemic MM models. These data pave the way for the exploitation of PTX3-derived anti-angiogenic approaches in MM.

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“…Despite the development of novel therapeutic strategies, including proteasome inhibitors, drug resistance occurs with frequent disease relapse and fatal outcome [2]. Therefore, there is a crucial need to design more effective anti-myeloma therapies by discovering novel bioactive compounds and combination strategies [3,4].…”

Section: Introductionmentioning

confidence: 99%

5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells

Jaouadi

Limam

Abdelkarim

et al. 2021

Cancers

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Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent patient relapse due to innate or acquired drug resistance. Cholesterol metabolism is reported to be altered in MM; therefore, we investigated the potential anti-myeloma activity of two cholesterol derivatives: the 5,6 α- and 5,6 β-epoxycholesterol (EC) isomers. To this end, viability assays were used, and isomers were shown to exhibit important anti-tumor activity in vitro in JJN3 and U266 human myeloma cell lines (HMCLs) and ex vivo in myeloma patients’ sorted CD138+ malignant cells. Moreover, we confirmed that 5,6 α-EC and 5,6 β-EC induced oxiapoptophagy through concomitant oxidative stress and caspase-3-mediated apoptosis and autophagy. Interestingly, in combination treatment a synergistic interaction was observed between 5,6 α-EC and 5,6 β-EC on myeloma cells. These data highlight a striking anti-tumor activity of 5,6 α-EC and 5,6 β-EC bioactive molecules against human myeloma cells, paving the way for their potential role in future therapeutic strategies in MM.

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Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group

Cited by 153 publications

References 66 publications

Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

Pentraxin 3 Inhibits the Angiogenic Potential of Multiple Myeloma Cells

5,6-Epoxycholesterol Isomers Induce Oxiapoptophagy in Myeloma Cells

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