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High-dose chemotherapy plus autologous hematopoietic cell transplantation ( AHCT ) has long been a standard treatment of multiple myeloma ( MM ), but the associated toxicity risks and the introduction of effective immunomodulatory drugs and proteasome inhibitors raise questions about the role and timing of AHCT in MM patients . In an analysis from the Intergroupe Francophone du Myélome ( IFM ) 2009 study published in the New England Journal of Medicine , the combination of lenalidomide , bortezomib , and dexamethasone ( RVD ) followed by AHCT led to deeper and longer responses than high-dose chemotherapy alone in patients with newly diagnosed MM .

The authors , led by Michel Attal , MD , PhD , from the University Institute Cancer Toulouse Oncopole in France , also noted that the survival benefits must be weighed against the increased toxicity risks of both high-dose chemotherapy and AHCT .

This randomized , open-label , phase III trial included 700 adult patients enrolled from 69 sites in France , Belgium , and Switzerland between November 2010 and November 2012 . Patients with grade ≥2 peripheral neuropathy or a history of other cancers were excluded .

All patients received induction therapy consisting of three 21-day cycles of RVD :

• lenalidomide 25 mg orally on days 1-4

• bortezomib 1.3 mg / m 2 intravenously on days 1 , 4 , 8 , and 11

• dexamethasone 20 mg orally on days 1 , 2 , 4 , 5 , 8 , 9 , 11 , and 12

During consolidation , patients were randomized 1:1 according to International Staging System disease stage and cytogenetic risk profile to receive either :

• five additional cycles of RVD with dexamethasone reduced to 10 mg ( RVD-alone group ; n = 350 ; median age = 59 years ; range = 29-66 years )

• melphalan 200 mg / m 2 plus AHCT followed by two cycles of RVD with dexamethasone reduced to 10 mg ( RVD plus AHCT group ; n = 350 ; median age = 60 years ; range = 30-66 years )

Both groups then received maintenance therapy with lenalidomide for one year or until disease progression , toxicity , or patient withdrawal . Patients in the RVD-alone group were eligible for salvage AHCT at the time of disease progression .

During study follow-up , 368 patients had progressive disease or died : 211 in the RVD-alone group and 157 in the RVD plus AHCT group .

There were no significant between-group differences in the rates of treatment-related deaths , second primary cancers , thromboembolic events , or peripheral neuropathy . Grade 3 / 4 adverse events were more common with RVD plus AHCT , compared with RVD alone ( 97.1 % vs . 83.4 %; p value not provided ). Grade 3 / 4 neutropenia was significantly higher in the transplant group than in the RVD-alone group ( 92 % vs . 47 %; p < 0.001 ), as were rates of grade 3 / 4 gastrointestinal disorders ( 28 % vs . 7 %; p < 0.001 ) and infections ( 20 % vs . 9 %; p < 0.001 ).

After a median follow-up of 44 months in the RVD-alone group and 43 months in the RVD plus AHCT group , the median progression-free survival ( PFS ; the study ’ s primary endpoint ) was 36 months and 50 months , respectively ( hazard ratio [ HR ] adjusted for disease progression or death = 0.65 ; 95 % CI 0.53-0.80 ; p < 0.001 ). Patients

TABLE . Response to Treatment

Complete response ( CR )

Very good partial response ( VGPR )

169 ( 48 %)

101 ( 29 %)

PR 70 ( 20 %)

Stable disease 10 ( 3 %)

CR 169 ( 48 %)

CR or VGPR 270 ( 77 %)

MRD not detected

171 / 265 during the study * ( 65 %)

205 ( 59 %)

102 ( 29 %)

37 ( 11 %)

6 ( 2 %)

205 ( 59 %)

307 ( 88 %)

220 / 278 ( 79 %)

0.03

0.001

< 0.001

* Represents number of patients with MRD out of the total number of patients with CR or VGPR . RVD = lenalidomide , bortezomib , and dexamethasone ; MRD = minimal residual disease

in the RVD plus AHCT group also had higher rates of complete response and lower rates of MRD positivity ( TABLE ).

However , overall survival ( OS ) was similar between the two groups : 82 percent in the RVD-alone group and 81 percent in the RVD plus AHCT group ( HR adjusted for death = 1.16 ; 95 % CI 0.80- 1.68 ; p = 0.87 ). The similarity in OS results could be attributed to “ the high level of activity of the new agents that were used to treat relapses ,” the researchers explained .

The successful use of salvage transplantation may also have led to the comparable OS rates ; of the 207 patients in the RVD-alone group who experienced progressive disease , 136 ( 79 %) went on to receive salvage transplantation , which suggests that “ delayed transplantation is feasible and is associated with no decrement in OS ,” the authors noted .

Patients with undetectable MRD after consolidation and maintenance therapy had longer PFS and OS , compared with those who had MRD ( HRs adjusted for disease progression or death = 0.30 and 0.34 ; p < 0.001 for both ). “ These findings confirm that the absence of MRD is an important treatment target in myeloma ,” the authors noted , “ and suggest that the use of high-dose chemotherapy plus transplantation after induction therapy with RVD specifically among patients in whom MRD is detected could be … one approach to tailoring therapy and further improving clinical benefit .”

However , the MRD implications are limited by the sensitivity of the MRD detection method ; more sensitive methods , such as next-generation flow cytometry , could have revealed more subtle differences , according to the researchers . Study results also could have been influenced by therapies received subsequent to study conduct . The study was supported by grants from Celgene and Janssen . Contributing authors report financial relationships with Celgene , Janssen , Takeda Oncology , and Millennium Pharmaceuticals .

REFERENCE

Attal M , Lauwers-Cances V , Hulin C , et al . Lenalidomide , bortezomib , and dexamethasone with transplantation for myeloma . N Engl J Med . 2017 ; 376:1311-20 .

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