Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group
This comprehensive review provides a detailed analysis of the management of relapsed multiple myeloma (MM) based on the recommendations of the International Myeloma Working Group. It highlights the importance of managing relapsed MM, as nearly all patients eventually experience relapse despite initial therapy. The review discusses the diagnostic evaluation of relapsed disease, including the use of serum protein electrophoresis, urine protein electrophoresis, serum-free light chain assay, and bone marrow evaluation. It emphasizes the significance of imaging techniques such as skeletal survey, magnetic resonance imaging, and fluorodeoxyglucose-positron emission tomography in assessing disease progression and extramedullary involvement.
The review provides detailed recommendations on the determinants of therapy, including disease characteristics, prior or ongoing therapy, transplant eligibility, and patient-specific factors. It identifies high-risk disease features such as adverse cytogenetic abnormalities, extramedullary disease, short remission duration, aggressive clinical features, and high lactate dehydrogenase levels. The review emphasizes the importance of considering the response and duration of response to prior therapy, as well as the eligibility for autologous stem cell transplantation (ASCT) or allogeneic SCT (Allo-SCT).
General treatment principles for managing relapsed MM are outlined, including the timing of treatment initiation based on symptomatic relapse, rapidly rising paraprotein levels, or extramedullary disease. The review emphasizes the importance of individualized treatment approaches, considering factors such as prior treatment history and response, disease aggressiveness, and patient characteristics. It discusses the use of immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide, as well as proteasome inhibitors like bortezomib, in various treatment regimens. The efficacy and safety of these agents, both as monotherapy and in combination with dexamethasone, are evaluated based on clinical trial data.
The review also addresses the role of autologous stem cell transplantation (ASCT) and allogeneic SCT (Allo-SCT) in the management of relapsed MM. It provides recommendations for ASCT eligibility and discusses the potential benefits and risks of Allo-SCT in selected patients. The review highlights the need for ongoing research and clinical trials to evaluate novel agents and treatment strategies for relapsed MM.
In conclusion, this comprehensive review serves as a valuable guide for clinicians and researchers involved in the management of relapsed MM. It provides evidence-based recommendations for diagnostic evaluation, determinants of therapy, and general treatment principles. By considering disease characteristics, prior therapy, transplant eligibility, and patient-specific factors, clinicians can make informed decisions to optimize outcomes for patients with relapsed MM.
Important Points:
- Different drug combinations for relapsed MM have varying overall response rates (ORR) and progression-free survival (PFS) and overall survival (OS) outcomes.
- Prednisone and lower doses of bendamustine combination resulted in an ORR of 76% with 5% CR and 71% PR.
- Pomalidomide, cyclophosphamide, and dexamethasone combination showed a PR or better rate of 39%.
- Thalidomide, liposomal doxorubicin, and dexamethasone combination resulted in an ORR of 76% with 26% CR.
- Lenalidomide, adriamycin, and dexamethasone combination yielded an ORR of 73%.
- Bortezomib, oral cyclophosphamide, and prednisone combination showed an ORR of 95%.
- Bortezomib, bendamustine, and dexamethasone combination resulted in an ORR of 77%.
- Bortezomib, doxorubicin, and dexamethasone combination achieved a PR or better in 67% of patients.
- Bortezomib plus pegylated liposomal doxorubicin combination showed superiority in terms of median time to progression (TTP) and OS rate.
- Bortezomib, thalidomide, and dexamethasone combination resulted in longer median TTP and higher CR plus near CR rate.
- Lenalidomide plus bortezomib combination achieved an ORR of 61%.
- Carfilzomib, lenalidomide, and dexamethasone combination showed improved PFS compared to lenalidomide and dexamethasone alone.
- Carfilzomib, pomalidomide, and dexamethasone combination achieved an ORR of 64%.
- Bortezomib, cyclophosphamide, thalidomide, and dexamethasone combination showed an ORR of 88% with 46% CR.
- Salvage therapy with high-dose dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide (DT-PACE) achieved an ORR of 49%.
- Salvage therapy with bortezomib, dexamethasone, and thalidomide (VDT-PACE) achieved an ORR of 63%.
- Second ASCT for relapsed MM after an interval of 18 months or more from the first ASCT showed improved OS.
- Allo-SCT is a possible option for relapsed MM patients younger than 65-70 years.
- Myeloablative conditioning is associated with excessive non-relapse mortality.
- Reduced-intensity conditioning before Allo-SCT (RICallo) can reduce non-relapse mortality.
- Clinical trial participation should be offered for first and second relapse.
- Re-treatment can be considered for patients with high-quality, prolonged response to initial therapy.
- Lenalidomide, bortezomib, or both drugs can be used in regimens based on response and tolerability.
- Carfilzomib and pomalidomide are recommended for patients refractory and/or intolerant to both bortezomib and lenalidomide.
- Allo-SCT should be discussed in eligible patients with poor prognostic features, preferably in the context of a clinical trial.
- Monoclonal antibody therapy, pan-histone deacetylase inhibitors, and small molecule inhibitors show promising results in relapsed MM.
- Next generation novel agents, such as kinesin spindle protein inhibitors and CDK inhibitors, show encouraging activity in RR MM.
- The role of allogeneic stem cell transplant may be revisited in the future for selected high-risk patients with RR MM.
- Other immuno-oncologic strategies, including checkpoint inhibitors, vaccines, and CAR-T therapy, are of interest in MM treatment.
- The survival of patients progressing after treatment with the IMiDs and bortezomib remains poor.
- Continued efforts are needed to better understand disease biology at the time of relapse and develop effective treatment options.
- Multiple novel agents have been approved for relapsed and refractory MM in 2015, providing hope for improved patient outcomes.
Authors:
J Laubach, L Garderet, A Mahindra, G Gahrton, J Caers, O Sezer, P Voorhees, X Leleu, H E Johnsen, M Streetly, A Jurczyszyn, H Ludwig, U-H Mellqvist, W-J Chng, L Pilarski, H Einsele, J Hou, I Turesson, E Zamagni, C S Chim, A Mazumder, J Westin, J Lu, T Reiman, S Kristinsson, D Joshua, M Roussel, P O’Gorman, E Terpos, P McCarthy, M Dimopoulos, P Moreau, R Z Orlowski, J S Miguel, K C Anderson, A Palumbo, S Kumar, V Rajkumar, B Durie and P G Richardson
Citation:
Leukemia (2016) 30, 1005–1017
doi:10.1038/leu.2015.356