Second Generation 3-Drug Combination Found Safe & Effective for Newly Diagnosed Multiple Myeloma Interview with:

Ola Landgren, MD, PhD Professor of Medicine  Chief, Myeloma Service  Department of Medicine  Memorial Sloan Kettering Cancer Center New York, NY 10065

Dr. Landgren

Ola Landgren, MD, PhD
Professor of Medicine
Chief, Myeloma Service
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, NY 10065 What is the background for this study? What are the main findings?

Response: Meta-analysis show that minimal residual disease (MRD) negativity is a strong predictor of longer progression-free survival (PFS). Emerging data show that an increasing proportion of newly diagnosed multiple myeloma patients obtain MRD negativity after modern combination therapy, even in the absence of bone marrow transplant. The first generation of 3-drug combination therapy (RVd) was associated with quite high rates of peripheral neuropathy which may be life-long.

The current study was designed to define the rates of peripheral neuropathy in newly diagnosed multiple myeloma treated with the second generation of 3-drug combination therapy (KRd), and per default delayed transplant (i.e. collection of stem cells which were stored for potential future use).

This single arm, phase 2 study found no cases of grade 3 peripheral neuropathy. The rates of MRD negativity wereunprecedented; 28 of 45 patients achieved MRD-negative CR (62%). The durability of MRD-negative CR has been observed up to 70 months (median duration 52.4 months). Patients who achieved MRD negativity by the end of cycle 8 had a 78% reduced risk of progression. The results were regardless of age or cytogenetic risk category.

The results from this second generation of 3-drug combination therapy (KRd) without transplant,  compare favorably to first generation of 3-drug combination therapy (RVd) followed by stem cell transplant. What should readers take away from your report? 

Response: The second generation 3-drug combination KRd is safe and highly efficacious. The results stress the importance of using highly efficacious triplet-based regimens for all newly diagnosed multiple myeloma patients who are in clinical shape allowing them to received effective therapy; clinicians should avoid de-escalation of triplet regimen and dosage based on patient age or other factors.

Emerging data show that patients who achieve MRD negativity, independent of therapy, has similar PFS. Given the high rate of MRD negativity after KRd alone (62%), and with a durability of MRD-negative CR being observed up to 70 months (median duration 52.4 months) this challenges the old paradigm. In countries with access to modern combination therapies, and, importantly, with access to reliable and validated MRD assays, it seems logical to conjecture that the future standard of care will become MRD-driven: patients who become MRD negative after modern combination therapy may collect stem cells and move straight forward with maintenance therapy, while patients who remain MRD positive after combination therapy may benefit from an upfront transplant before they move forward with maintenance therapy. Ongoing studies are investigating these important questions. Is there anything else you would like to add?

Response: The treatment field for multiple myeloma is moving very fast forward. The modern 3-drug combination used in the present study is currently being investigated in combination with a 4th drug, a monoclonal CD38 antibody ( See link:

In that ongoing study, the primary endpoint is set very high: the study aims to reach up to 80% MRD negativity in newly diagnosed multiple myeloma patients treated with KRd-daratumumab, in the absence of a bone marrow transplant. The results are anticipated to be available within the coming 12-18 months.


Kazandjian D, Korde N, Mailankody S, et al. Remission and Progression-Free Survival in Patients With Newly Diagnosed Multiple Myeloma Treated With Carfilzomib, Lenalidomide, and Dexamethasone  Five-Year Follow-up of a Phase 2 Clinical Trial. JAMA Oncol. Published online November 21, 2018. doi:10.1001/jamaoncol.2018.5457

Nov 26, 2018 @ 1:09 pm




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