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E-KRd Vs. KRd in Multiple Myeloma

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KRd triple induction regimen should result in an even higher rate of deep (MRD neg-at least very good partial response [VGPR]

Hello David- I’m 44 years old and from Germany. I was diagnosed in 11/19 and completed 6 cycles of E-KRd in german trial (Elotuzumab in Combination With Carfilzomib, Lenalidomide and Dexamethasone).

I was diagnosed quite early because of pain one of my three lessions was causing. My counts where quite low, My only CRAB criteria were bone lesions.
I’m scheduled for an autologous stem cell transplant (ASCT) in September and don’t want to put my body through this if it doesn’t help me.
At the moment I’m considered CR ( not 100% sure as there is a strange wording in my electrophoresis report “we cannot say with definite certainty that there is no Band any more”) and i’m waiting for my mdr result.
The trial would so an ASCT and another 4 cycles followed by Revlimid + Elo untill progression.
My plan was to go straight to maintainance If i should be mrd negative.
Obviously i want to be in remission as long as possible but i read a lot of stuff including the Landgren and Richardson paper from this summer.
Europe is still very pro ASCT and my docs doing the trial think i should tolerate it well think i should worry to much about the long side term effects.
What’s your take on fear in missing out in treatment vs. worry about (long term) asct side effects?
Best regards Bernie-

Hi Bernie, 

Your situation is interesting so I won’t worry about you not asking any specific questions. I will use your situation to explain several basic MM concepts. Let me first list my assumptions. 
  • You are young (44) and otherwise healthy
  • You were “early stage” MM at diagnosis. No CRAB symptoms other than high blood calcium indicating bone involvement. 
  • You are currently in Complete Remission. Your m-spike and other diagnostic criteria are normal or close to normal. 
  • Lastly, after completing 6 (six) cycles of e-KRd, you have undergone a lot of toxicity. While your body may not show it, you have absorbed a lot of chemo. 
I should mention my most important assumption. And that is that your highest priority is overall survival aka OS. Meaning you goal is to live as long as you possibly can. This goal can be quite different between, say, the 44 year old NDMM and the 74 year old NDMM. 
I am not being trying to be flippant or sarcastic when I list OS as your main priority. When I was diagnosed, I assumed that my oncologist and I thought the same way. I was wrong. You may assume that you and your oncologist agree on OS as your main goal. You may be wrong. 
By enrolling you in this trial, I believe that your oncologist would tell you that e-KRd followed by an ASCT and low-dose maintenance therapy, will give you a deep response, hopefully MRD and that this deep response is your best possible outcome. 
I disagree with this thinking, this logic. 
First of all, there are no studies that cite MRD leading to longer OS. At least none that I know of. I think oncology believes there is a link between MRD and OS but there has been no “evidence” proving that relationship. I have read about many MM patients who achieve MRD only to relapse a year or two later. 
I think it is reasonable to think that a “deep response” will lead to a long OS. But I think it is unreasonable to expose a young, healthy, early stage MM patient to a great deal of toxicity unless you know for certain, that a deep response translates to the patient’s best chance for the longest OS. 
Secondly, undergoing six rounds of a quadruplet (e-KRd) is more chemo, more toxicity than, say undergoing just low-dose maintenance Revlimid or Velcade would be. Once oncology thinks long-term survival, NOT about a deep response, then a therapy plan with low-dose therapies begins to make more sense. 
Thirdly, let me take the goal of OS a step further. Two things. I work with MM patients who have spent years undergoing just enough low dose therapy to put them into remission when they discontinue therapy. This low-dose approach is standard for elderly MM patients. I work with other MM patients who simply don’t like toxic therapies…
If the patient combines low-dose chemo with evidence-based integrative therapies, a case can be made for enhancing the efficacy of the low-dose chemo, while reducing toxicity further. 
Lastly is the concept of MDR aka multi-drug resistance. In general, the more chemo the MM patient undergoes, the faster his/her MM will develop resistance to ALL chemotherapies. 
Please confirm this reasoning with your oncologist. Even if you achieve a long remission from your e-KRd, ASCT and maintenance therapy, you will relapse in say 12-15 years, best case scenario. If you enjoyed a 12-15 year remission and then underwent several more years of survival as a RR MM survivor, again, best case scenario, you would his your 64th birthday as an end stage MM survivor. 
My assumption is that even a 20 year MM survival is not your goal. I think a low-dose approach coupled with integrated therapies provides a longer OS possibility.
Yes, harvest your stem cells now. But no, I wouldn’t recommend an ASCT at this time. Harvest enough stem cells for two ASCT. Just in case. 
I covered a lot of information Bernard. Let me know if you have any questions. 
Good luck, 
David Emerson
  • MM Survivor
  • MM Cancer Coach
  • Director PeopleBeatingCancer

Recommended Reading:

Elotuzumab in Combination With Carfilzomib, Lenalidomide and Dexamethasone (E-KRd) Versus KRd in MM

Brief Summary:

Of the next-generation compounds, the monoclonal antibodies (moAbs) have recently attracted a lot of interest in MM. The anti-SLAMF7 directed moAb elotuzumab has completed phase III trials in MM patients. One phase III trial in MM patients with one to three prior lines of therapy compared elotuzumab-Rd with standard Rd.

The triple combination was shown to significantly prolong PFS in this patient cohort with a greater proportion of patients in at least very good partial response (VGPR) when compared to subjects on Rd.

Notably, the rate of infusion-related reactions with this specific moAb was very low, with an overall rate of 10% in premedicated patients and only 1% of Grade 3 severity. Grades 4/5 infusion-related reactions were absent and only 1% of patients on elotuzumab discontinued for infusion-related reactions.

Of particular interest is the observation in this trial, that response and PFS were independent of cytogenetic high-risk features, i.e., deletion of chromosome 17p and translocation t(4;14). This effect distinguishes elotuzumab from most, if not all, other drug-based approaches.

The investigators assume that incorporating the moAb into the KRd triple induction regimen should result in an even higher rate of deep (negative for MRD in conjunction with at least very good partial response [VGPR] as defined by the International Myeloma Working Group [IMWG]) with these responses occurring independently of cytogenetic risk. Due to potential interference of elotuzumab with serum immune fixation, the investigators chose VGPR rather than complete response (CR) to exclude false-positive immunofixation results. Furthermore the investigators hypothesize that combining elotuzumab with lenalidomide should prolong PFS further.”

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