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Previous line IMiD-based


Previous line PI-based


Is the patient in a clinically symptomatic relapse?


Consider delay initiation of therapy until symptoms development

Switch drugs Re-treatment

ASCT eligible No

Previous line IMiD-based

Previous line PI-based

VMP, TD, VD, FRd, Bz-PegLD


Considerations ASCT: No previous auto-SCT or PFS>18–24 months from previous ASCT Allo-SCT: high-risk disease or PFS<18 months Renal impairment: bortezomib-based Recent thrombosis: bortezomib-based

Poor risk cytogenetics: bortezomib- or lenalidomide-based Neuropathy: lenalidomide-based

Plasmacytomas: bortezomib-based and radiotherapy

Allo-SCT: Allogenic stem cell transplantation; ASCT: Autologous stem cell transplantation; CTD: Cyclophosphamide, thalidomide, dexamethasone; CyBorD: Cyclophosphamide, bortezomib, dexamethasone; KRd: Carfilzomib, lenalidomide, dexamethasone; Bz-PegLD: Bortezomib, pegylated liposomal doxorubicin; MPT: melphalan, prednisone, thalidomide; PAD: Bortezomib, doxorubicin, dexamethasone; Rd: Lenalidomide, dexamethasone; TD: Thalidomide, dexamethasone; VD: Bortezomib, dexamethasone; VMP: Bortezomib, melphalan, prednisone; VTD: Bortezomib, thalidomide, dexamethasone. IMiD: Immunomodulatory drugs; PI: Proteasome inhibitor; PFS: Progression-free survival.

Figure 1: Treatment alternatives for patients with relapsed/refractory multiple myeloma algorithm for patients in first relapse.

Treatment based on IMiD Thalidomide as single agent was the first IMiD tested in RRMM with response rates >25% in heavily pre-treated patients.8


combination with bortezomib, it has been associated with up to 63% of partial responses and four-year overall survival (OS) of 23%9

whereas other more

aggressive thalidomide-based combinations have been associated with an overall response rate (ORR) of 50%.10 Lenalidomide is a better-tolerated second-generation IMiD, with up to 60% response rate when combined with dexamethasone.11,12

As with thalidomide,

several lenalidomide-based combinations for MMRR patients have been tested with ORR ranging from 64% to 73%.13–16 Pomalidomide is the last IMiD to be incorporated in the therapeutic armamentarium for patients with MM beyond second line. When combined with low-dose dexamethasone in double refractory patients to lenalidomide and bortezomib, it has shown an ORR of 33% with a significantly longer progression-free survival (PFS) and OS than high-dose dexamethasone.17

Preliminary data also

show promising results of this regimen in patients with high-risk cytogenetics, especially del17p.18


different pomalidomide-based combinations have been tested in clinical trials with encouraging results and this As with the other IMiDs,

drug is likely to be a valuable option for patients with RRMM in the near future.

Treatment based on proteasome inhibitors

Bortezomib as single agent for patients with MM in relapse is associated with an ORR of 34%.19

The most common toxicities of bortezomib are thrombocytopenia, fatigue and peripheral neuropathy. The recently available subcutaneous formulation of this drug has been associated with a significant reduction in the incidence of severe neuropathy without any impact on clinical outcomes.20


and several bortezomib-based combinations have been successfully used in clinical practice, making this drug a backbone of the majority of the currently available schemes in patients with RRMM.9,23–25

A novel proteasome inhibitor –

carfilzomib – has been recently incorporated into clinical practice. Carfilzomib is a selective member of the epoxyketone class that differs from bortezomib both structurally and mechanistically.26

Carfilzomib has a

favourable risk–benefit profile as a single agent in patients with RRMM but is especially active when combined with lenalidomide, and dexamethasone (KRd) in patients with up to three previous lines of therapy. Notably, the median PFS observed

regimens improve outcome in patients with renal impairment21 profiles22

and adverse genetic

Transplant-eligible patients The three general approaches to management of symptomatic relapse after initial autologous stem cell transplantation (ASCT) are: re-induction followed by salvage ASCT; re-induction followed by allogeneic SCT (AlloSCT); or, most commonly, re-induction with continuation of conventional dose chemotherapy using rational combinations of novel therapies for relapsed/refractory disease. It is generally accepted that the most important predictor of benefit from salvage ASCT is the time to progression from the first ASCT and multiple studies have demonstrated that those patients who relapse early after the first ASCT derive less benefit from salvage ASCT and have worse outcomes. However, a cut-off time after relapse from first ASCT for considering patients for salvage ASCT is a matter of debate and has ranged from

with KRd (26.3 months) has been unprecedented in randomised Phase III trials in patients with relapsed MM and this regimen may represent a new standard of care for patients with relapsed MM.27 Numerous ongoing studies are evaluating other carfilzomib-based regimens and alternative doses and schedules. In this regard, preliminary results of the combination of carfilzomib with pomalidomide and dexamethasone show a high activity in heavily pretreated patients, with an ORR of 50% and an overall survival of 90% at one year.28

Rd, CTD, KRd


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