Response Adapted Induction Therapy for Multiple Myeloma
Authors: Valent Jason , Samaras Christy , Hastings Debbie , Faiman Beth M , Hamilton Kimberly , Bolwell Brian J. , Reed Janice , Karam Mary Ann , Cummings Chad , Tullio Katherine , Smith Mitchell R. , Liu Hien K. , Reu Frederic J 
Published: October 2019

Abstract
Background: Bortezomib (bort), lenalidomide (len), cyclophosphamide (cy), and dexamethasone (dex) combinations are acceptable initial treatment options for multiple myeloma (MM). At least 2 of these agents are generally used in initial treatment. Continuous len /dex treatment in older patients (pts) may be superior to shorter courses of 3 drug therapy (Benboubker L et al. N Engl J Med 2014; 371:906-917). Standardized treatment programs for cancer pts are important in a changing healthcare reimbursement system. Response adapted therapy for multiple myeloma has the potential to reduce toxicity, limit multi-drug resistant subclone development thus improving survival, and provide cost savings.
Methods: The Cleveland Clinic multiple myeloma carepath initiates 2 drug response adapted therapy with len/dex (bort/dex if there is evidence of myeloma related kidney disease or unacceptable len cost to pt). This is an update to preliminary data of Narkhede et al 2014 ASH abstract 2620. Response assessment per current IMWG criteria is obtained with each cycle of therapy, although bone marrow biopsy is not required to confirm complete response. Pts with progressive disease (PD) after one cycle or lack of partial response (PR) after 2 cycles have either bort or len added to the initial 2 drug therapy. If needed, sequential addition of cy and liposomal doxorubicin occurs until at least PR is obtained. Pts achieving PR after 2 cycles are continued on 2 drug therapy. All transplant eligible pts are offered high dose melphalan and autologous stem cell transplant if they achieve PR followed by maintenance therapy. Pts not eligible for transplant are continued on effective therapy for up to 3 years as tolerated. Supportive care with bisphosphonates, vaccinations, zoster prophylaxis, and thromboembolism prophylaxis are outlined in this carepath.
Results: From October 2012 to March 2015 carepath therapy was used in 53 pts not eligible for or unwilling to participate in clinical trials. Outcome data was attained through July 31, 2015 and median follow up was 16 months. 10 pts are off carepath treatment due to death (n=4), drug induced anorexia (n=1), or disease progression (n=5). 5 of these 10 pts were treated with ≥ 3 drugs. 3 of the 4 deaths occurred in pts high risk by FISH or MyPRS analysis. For all pts, response rates of VGPR or better were 55% in pts treated with 2 drugs and 41% in pts treated with ≥ 3 drugs. Of the 43 pts remaining on carepath based therapy, 26 pts have required only 2 drugs during the induction phase of treatment with 58% achieving at least very good partial response (VGPR) prior to either transplant or consolidation maintenance therapy. 17 pts required 3 or more drugs during the induction phase with 35% achieving at least VGPR prior to transplant or consolidation maintenance. Grade 3 or higher toxicity included hyperglycemia (n=4) due to dex, neutropenia (n=4) due to len, febrile neutropenia (n=2) due to len, insomnia (n=2) due to dex, and upper respiratory infection (n=2). One episode each of acute coronary syndrome due to dex (pt not on len), pancreatitis due to dex, anorexia due to len, sensory peripheral neuropathy due to bort, and tumor lysis syndrome due to len/dex occurred.
Conclusion: Response adapted carepath based therapy provides effective disease control for the majority of MM pts treated while limiting cost due to the lower utilization of 3 drug therapy. While overall survival data is immature, the primary goal of response adapted therapy is to improve overall survival of MM pts by limiting early development of multi-drug resistant subclones. 55% of our pts required only 2 drug induction therapy to achieve a VGPR or better and 84% of these patients remain on carepath based therapy. Estimated cost savings on drug alone is over $4000 per cycle in the 2 drug treated pts. Cost savings may be underestimated as 73% of pts received len/dex as induction therapy and thus incurring less infusion related cost.

Disclosures
Valent: Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Off Label Use: cyclophosphamide for the treatment of multiple myeloma. Faiman:Amgen/Onyx: Consultancy; Celgene: Consultancy, Speakers Bureau; Takeda/Millennium: Consultancy. Hamilton:Takeda/Millennium: Speakers Bureau. Smith:celegene, spectrum, genentech: Honoraria. Reu:Takeda/Millennium: Research Funding; Novartis: Research Funding; Celgene: Research Funding.