Outcomes of Multiple Myeloma Patients Refractory to Standard Dose Vs Low Dose Lenalidomide

Background: Lenalidomide (Len) containing regimens are extensively used as first line therapy in multiple myeloma (MM). Since most patients (pts) eventually relapse while on these regimens or on Len maintenance, refractoriness to Len is an important factor in determining the choice of therapy at first relapse. It remains debatable if resistance to Len varies between pts who progress on a standard dose of Len (e.g., 25 mg daily, in combination with other agents or otherwise), and those who progress on single agent low dose Len (e.g., 10 mg daily). To this extent, often pts progressing on standard doses are considered refractory to Len, while pts progressing on maintenance doses are considered Len sensitive. In this study, we sought to assess the impact of refractoriness to standard dose vs low dose Len on outcomes with subsequent therapies in MM pts.

Methods: We retrospectively reviewed MM pts diagnosed from January 2004 to December 2018, who progressed on/ after receiving first line therapy with Len containing regimens. We divided pts into 3 groups based on refractoriness to Len at first relapse- 1. Pts progressing on or within 60 days of receiving 25 mg Len (Standard Dose Refractory), 2. Pts progressing on or within 60 days of receiving 5-15 mg Len (Low Dose Refractory), and 3. Pts who received Len as a part of first line therapy but progressed after 60 days of stopping Len (Not Refractory). In addition to Len, we classified pts as refractory to proteasome inhibitors (PI) or daratumumab (Dara) at first relapse. We classified salvage regimens into Dara, PI, immunomodulatory drug (IMiD), PI+IMiD, elotuzumab, and VDT PACE like regimens. We used the International Staging System (ISS) and mSMART criteria for risk stratification. We assessed progression free survival (PFS) and overall survival (OS) on next line therapy, as well as for next Len containing line of therapy using Kaplan Meier and Cox models.

Results: A total of 312 pts were included. Median age at diagnosis was 65 years and 60% pts were male. Overall, 30%, 33%, and 23% pts were ISS stage I, II, and III respectively; 33% pts had a high-risk FISH abnormality. At first relapse, 54 (17 %) pts were Standard Dose Refractory, 124 (40 %) were Low Dose Refractory, and 134 (43 %) were Not Refractory.

For next line of therapy, no PFS difference was found between Standard Dose Refractory and Low Dose Refractory pts (14.5 months vs 12.6 months, p=0.76, Figure 1). As compared to Not Refractory pts (median PFS 29 months), the median PFS was inferior for both Standard Dose Refractory (PFS 14.5 months, p=0.002) and Low Dose Refractory pts (PFS 12.6 months, p<0.001). Using the Cox model to adjust for ISS, high risk FISH, refractoriness to other drugs, type of salvage regimen, and receipt of ASCT at relapse; the Not Refractory group had a better PFS (Hazard Ratio (HR)= 0.37, 95% CI: 0.24-0.57), while no difference was seen in the Standard Dose Refractory group (HR= 0.95, 95% CI: 0.59-1.51) as compared to the Low Dose Refractory group.

Among the 312 pts, 124 (39.7 %) pts had received another Len containing regimen after the first line regimen at any time during the disease course. For this line of therapy, when compared to Not Refractory pts (median PFS 37 months), the median PFS for the Standard Dose Refractory group was 6 months (p<0.001) and for the Low Dose Refractory group was 10 months (p<0.001). Again, no PFS difference was found between Standard Dose vs Low Dose Refractory groups (p=0.79, Figure 1). On adjusting for parameters as above, the Not Refractory group had a better PFS (HR= 0.24, 95% CI: 0.13-0.44), while no difference was seen in the Standard Dose Refractory group (HR= 1.26, 95% CI: 0.6-2.63) when compared to the Low Dose Refractory group.

In terms of OS, no differences were seen among Low Dose Refractory, Standard Dose Refractory, and Not Refractory groups, both from the time of first relapse (HR= 1 vs 1.03 (0.57-1.85) vs 0.62 (0.36-1.07) respectively), and from start of next Len containing regimen (HR= 1 vs 2.3 (0.78-6.74) vs 1.2 (0.45-3.18) respectively); after adjusting for above listed characteristics.

Conclusions: The PFS for next line therapy and next Len containing line of therapy did not differ between pts refractory to standard dose vs low dose Len, and both were significantly inferior to pts who were not refractory to Len. These data suggest that resistance to Len is not dose dependent, and definition of Len refractoriness should not depend on the dose of Len to which the pts were considered refractory.

Kapoor:Sanofi: Honoraria, Research Funding; X4 Pharmaceuticals: Honoraria; Regeneron: Research Funding; Amgen: Research Funding; Ichnos: Research Funding; Loxo: Research Funding; Karyopharma: Research Funding; BMS: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Research Funding; Casma: Honoraria; Pharmacyclics: Honoraria; Imedex: Honoraria; GSK: Honoraria; Cellectar: Honoraria; Oncopeptides: Honoraria. Dingli:Alexion Pharmaceuticals: Consultancy; Apellis Pharmaceuticals: Consultancy; Bristol Meyers Squibb Global Pharmaceutical Company: Consultancy; Novartis Pharmaceuticals: Consultancy; Roche: Consultancy; Sanofi: Consultancy; Regeneron Pharmaceuticals: Research Funding. Dispenzieri:Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides, and Sorrento: Other: Data monitoring safety committee; Alynlam, Pfizer, Takeda, and BMS: Research Funding. Gertz:Sorrento: Other: personal fees; i3Health: Other: Development of educational materials for i3Health; Research to Practice: Other: personal fees; Celgene: Other: personal fees; Johnson & Johnson: Other: personal fees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: personal fees from Data Safety Monitoring Board; Physicians Education Resource: Other: personal fees; Juno: Other: personal fees; Ashfield: Other: personal fees; Aptitude Healthgrants: Other: personal fees; Janssen: Other: personal fees; Sanofi: Other: personal fees; Prothena: Other: personal fees; Ionis/Akcea: Other: personal fees. Kourelis:Novartis: Research Funding. Lacy:Celgene: Research Funding. Leung:Takeda Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Lin:Juno: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Legend: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Kumar:AbbVie,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive,: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE,: Research Funding; MedImmune/Astra Zeneca,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck,: Research Funding; Novartis,: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee.