Sequential or Combination Therapy for Multiple Myeloma

Ajay Nooka; Sagar Lonial


Expert Rev Hematol. 2012;5(5):533-545. 

In This Article

Importance of Complete Remission in Myeloma

Historical data on the relative importance of obtaining a complete remission (CR) following either induction therapy or salvage therapy for relapsed myeloma are quite variable. As the definitions of CR have come to better reflect residual tumor burden, the relative importance of this end point has gained more prominence. Data using both younger transplant-eligible patients and older nontransplant-eligible patients have clearly demonstrated that patients who achieve a deeper response have improved outcomes, as measured by PFS and OS. Although this is not uniformly the case, in most instances, this approach of deeper response having better long-term outcomes generally applies. To induce deep responses, it is critically important to treat with multiple drugs as part of the combination approach. The current uniform response criteria by the International Myeloma Working Group describes the category as 'stringent CR' (sCR), which requires normalization of the free light chain ratio and the absence of clonality by immunohistochemistry or immunofixation.[4] It is important to realize that with this current definition of sCR, achieving an immunofixation negativity and normalization of free light chains does not predict a cure. Even at this level, there is still significant tumor burden remaining. In other words, the present definition of sCR represents a threshold to the limit of detection. The use of more sophisticated techniques below this limit of detection is necessary if our goal is to significantly lower disease burden or to eliminate any evident disease. A Spanish study demonstrated that negativity for minimal residual disease (MRD) as a measure of CR by multiplanar flow cytometry (MFC) at day 100 following autologous stem-cell transplant (ASCT) was an independent prognostic factor for PFS and OS.[5] With other studies corroborating that MRD has better predictive value of long-term remission, development of standardized MFC techniques with defined specificity and sensitivity could be a potential method for monitoring and even identifying patients at risk for progression.[6,7] Molecular techniques such as PCR have greater sensitivity than MFC. Ladetto et al. reported that consolidation with combination therapy of bortezomib, thalidomide and dexamethasone (VTD) following ASCT resulted in the induction of persistent molecular remissions in a higher proportion of myeloma patients.[8] Among a group of 39 patients who underwent ASCT, 3% patients were noted to have a quantitative PCR (qPCR)-negative bone marrow post-ASCT (molecular response). Following treatment with four cycles of VTD, 18% of patients converted from qPCR-positivity to qPCR-negativity, suggesting that combination therapies may be able to induce molecular responses, where conventional agents failed to achieve similar responses. At a median follow-up of 42 months, no relapses occurred in patients with qPCR-negative bone marrow.

Thus, although induction to achieve currently definable CR is important, further consolidation and maintenance is clearly needed to achieve deeper molecular remissions. This is particularly important among patients with high genetic risk for disease: where it is known that they can achieve deep responses, but if unmaintained, they rapidly relapse. This concept of inhibition of multiple different signaling pathways to circumvent resistance and suppress multiple different tumor clones is another real advantage of combination therapy, and one which provides the strongest approach to date for leading to cure for myeloma.

In the preclinical and clinical testing arena, there are a number of combinations that induce major responses (very good partial remission [VGPR] and CR) and are based upon preclinical rationale. These will be discussed in detail.