Retrospective Analysis of Outcome and Survival of Patients with Multiple Myeloma who Relapse post Autologous Stem Cell Transplant

Multiple myeloma (MM) is the prototype of all plasma cell dyscrasias. It is the second most common hematological malignancy with increasing incidence across the world. Induction therapy with a triplet [incorporating a proteasome inhibitor (Bortezomib), immunomodulatory drug (lenalidomide), and steroid (dexamethasone)] or quadruplet [triplet + monoclonal antibody (daratumumab)] regimen is the standard upfront treatment. After 4-6 cycles of induction, high dose melphalan followed by autologous stem cell rescue / transplant (ASCT) is the standard treatment in young and fit patients with this disease. ASCT results in increased CR rates, prolongs progression free survival and can cure a fraction of patients. The role of ASCT for prolonging disease-free survival remains even in the era of novel agents and long term lenalidomide maintenance. In contrast to our western counterparts, the median age of MM patients in India is a decade younger i.e., in 4th -5th decade.

MM accounts for 20% of all hematopoietic stem cell transplants and approximately 50% of all autologous transplants done in India. Across major studies of ASCT from India, 5-year disease free survival varies from 35-55% [1]. This means that atleast 50-60% MM patients relapse within 5 years of ASCT in India. As per International Myeloma Working group (IMWG) guidelines, a relapse of MM is defined as recurrence of disease after prior response on the basis of objective laboratory and radiological criteria. It includes either of the following - ≥25% increase of the monoclonal protein (M-protein) in serum (absolute increase ≥ 0.5 g/dL) or urine (absolute increase ≥ 200 mg/d) or ≥25% difference between involved and uninvolved serum-free light chains (absolute increase > 10 mg/dL) or >10% increase of the absolute percentage of bone marrow plasma cells or development of new (extramedullary) plasmacytomas or hypercalcemia. Similarly, relapsed/refractory MM (RRMM) is defined as disease that becomes nonresponsive or progressive on therapy or within 60 days of last treatment in patients who had achieved a minimal response or better on prior therapy.

The decision to treat a patient who has relapsed post ASCT will depend on the type of relapse (biochemical versus clinical). Moreover, the treatment for a post ASCT relapse will also be dictated by multiple factors – comorbidities, duration of response to first line treatment or ASCT, refractoriness to prior therapy, presence of any extramedullary disease or high-risk cytogenetics at relapse. The French group have reported that early relapse (within 18 months of initial diagnosis which equates to within 12 months of ASCT) is a poor prognostic factor post ASCT, irrespective of cytogenetic risk. Data available from randomised clinical trials (RCTs) have shown that while treating at relapse, triplets should be preferred and continuous treatment or maintenance prolongs PFS. Following triplet regimens have shown improvement in survival in RCTs which included 50-60% subjects with prior ASCT – KRd (Carfilzomib-Lenalidomide-dexamethasone), DRd (Daratumumab-Lenalidomide-dexamethasone), Elo-Rd (Elotuzumab-Lenalidomide-dexamethasone), Ixa-Rd (Ixazomib-Lenalidomide-dexamathasone), DVd (Daratumumab-Bortezomib-dexamethasone), VPd (Bortezomib-Pomalidomide-dexamethasone), DKd (Daratumumab-carfilzomib-dexamethasone), SVd (Selenexor-Bortezomib-dexamethasone). However, in majority of patients, it is not possible to use daratumumab owing to its exorbitant costs, and carfilzomib too due to its cardiotoxicity, need for weekly intravenous infusions and financial burden in long term. There is paucity of data from India pertaining to outcomes and survival of post ASCT relapses in MM. Hence, it would be prudent to know the response rates and outcomes with various treatment regimens given for post ASCT relapses.