Myeloma Treatment Sequencing |
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A Brief Look at Maintenance Therapy A significant milestone in MM treatment is the shift from induction to maintenance therapy . The optimal choice in this stage will differ based on a patient ’ s risk level and disease-specific genetic profile .
“ When we get into the maintenance phase , we really begin to tailor treatments ,” Sagar Lonial , MD , professor and chair of the Department of Hematology and Medical Oncology at Emory University , said , adding that experience with induction therapies can truly inform treatment decisions . “ In high-risk patients , one drug is probably not sufficient to maintain their response , whereas standard-risk patients may be able to ‘ get away ’ with single-drug therapy .”
Below are a few maintenance therapy sequencing options for transplant-ineligible patients with new or relapsed disease :
• lenalidomide without dexamethasone ( 10-15 mg for 21 of 28 days )
• bortezomib every 3 months with prednisone or thalidomide ( a 21-day cycle )
• bortezomib ( weekly for 4 of 5 weeks , or every other week )
• pomalidomide with low-dose dexamethasone ( 2-5 mg / day for 21 of 28 days ) 1 , 2
At the 2016 ASH Annual Meeting , results from the phase III Myeloma XI trial confirmed that lenalidomide maintenance therapy significantly improved PFS , compared with no lenalidomide maintenance in a mixed population of transplant-eligible and -ineligible patients with newly diagnosed MM . However , an analysis of Myeloma XI data found that patients receiving lenalidomide maintenance had a significantly higher risk of developing secondary primary malignancies ( SPMs ) – though the SPMs reported were largely non-invasive . 3
SOURCES
1 . Jackson GH , Davies FE , Pawlyn C , et al . Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages ; results of the phase III Myeloma XI Study . Abstract # 1143 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , California .
2 . Abonour R , Durie BGM , Jagannath S , et al . Health-related quality of life of patients with newly diagnosed multiple myeloma receiving any or lenalidomide maintenance after autologous stem cell transplant in the Connect ® MM Disease Registry . Abstract # 537 . Presented at the 2016 ASH Annual Meeting , December 4 , 2016 ; San Diego , California .
3 . Jones JR , Cairns DA , Gregory WM , et al . Second malignancies in the context of lenalidomide treatment : an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial . Blood Cancer J . 2016 ; 6 : e506 .
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or even quadruplet , combinations does not necessarily translate to a corresponding exponential increase in the risk of AEs because “ each drug in a combination regimen has a unique mechanism of action and should ideally have non-overlapping toxicities ,” he said .
“ Today , in the first-in-human trials in MM , it ’ s not uncommon for us to have patients who have undergone seven or eight prior lines of treatment ,” Dr . Harvey added . “ If a drug candidate in a phase I trial is going to be effective , it has a higher bar to clear .”
For instance , a phase I trial that adds and escalates another agent to an RVD sequence would examine the optimal dosing for all four agents before evaluating the sequence in a large set of patients . “ From a sequencing perspective , that information might help you determine how to get to a four-drug induction regimen ,” he noted .
The horizon of treatment sequencing continues to expand with new indications for the BCL2 inhibitor venetoclax , which is approved to treat chronic lymphocytic leukemia with del17p . At the 2016 ASH Annual Meeting , researchers reported that adding venetoclax to bortezomib and dexamethasone led to an overall response rate of 68 percent among all patients with relapsed / refractory MM . 13 The triplet was particularly effective in patients who were not refractory to bortezomib and who had been treated with one to three lines of prior therapy , who experienced an overall response rate of 94 percent .
“ Cure Versus Control ”
Dr . Rajkumar detailed the “ fundamental clash of philosophies ” of MM treatment in a 2011 Perspective article in Blood ; six years later , that clash has taken center stage in debates over treatment sequencing . 13
“ If you think you can cure a disease , then you are guided by hope and are likely to give aggressive therapy to reach that goal ,” he said , alluding to clinics that take this approach and may use seven- or eight-drug sequences . “ In turn , telling a patient that you are going to cure them may make them more willing to turn their lives upside down and agree to all those therapies .”
On the other hand , if the clinician and patient agree that the current goal is disease control and not cure , a patient may opt to start with less aggressive treatment , escalating treatment intensity only when it becomes necessary . “ In that scenario , we are able to adjust our approach based on the patient ’ s wishes , and , if the disease is not curable , many patients will go that route ,” he said .
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Other factors unrelated to treatment can guide sequencing , such as financial concerns , geographic hardships , or even the ability to tolerate a multi-drug treatment course .
If a patient is scheduled to start an RVD regimen , for instance , he or she would also be put on thromboembolic and herpes zoster prophylaxis ; if any treatment-related AEs emerge , then the patient would receive medication to manage those . “ So , it ’ s not just the three agents for treatment we have to consider ; it ’ s also the addition of these other drugs and the supportive care needed during treatment ,” Dr . Harvey said . This can be challenging , particularly for older patients who are already receiving treatment for comorbidities , he continued . “ As clinicians , we have to factor all of those aspects into how we deliver treatment .”
Dr . Rajkumar recalled a recent patient who declined to make the weekly 45-mile drive to the nearest hospital to receive subcutaneous bortezomib . “ She took two doses and then stopped because of the travel burden , so , as a reasonable alternative , she took oral ixazomib instead ,” he said . “ We have to be willing to fine-tune the treatment to address those kinds of patient hardships .”
Financial circumstances also play a large part in patients ’ prescription drug usage , and high costs force many cancer patients to skip medication doses , take less medicine , use alternative therapies , or take other cost-saving actions , according to an analysis from the American Cancer Society . 14
“ This type of financial toxicity has been shown to decrease compliance with treatment ,” Daniel A . Goldstein , MD , a senior physician at the Davidoff Cancer Center in Petach Tikvah , Israel , wrote in an editorial accompanying the report . 15 “ All physicians must recognize that financial toxicity is a serious issue , not to be denied or ignored ,” he stated . “ Although financial toxicity has become accepted by most , there remain subsections of the medical community that deny its existence . ... We must avoid unnecessary testing and treatments ; if a test or treatment will not impact management , then it should not be done .”
“ The treatment schedule also may play a role , depending on the patient ’ s ability to travel for treatment , which in turn may be influenced by the patient ’ s level of fitness and performance status ,” Drs . Yee and Raje added .
Ultimately , clinicians need to treat the patient in front of them , rather than relying on a one-size-fitsall
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regimen . For Dr . Rajkumar , that means first knowing the “ default ” treatment sequence . “‘ If all things were equal , what would my standard treatment option be ?’” he posed . “ Then from there , you can ask yourself , ‘ Under what circumstances would I vary from that default ?’”
“ It ’ s hard to create a flowchart that outlines simply , ‘ First , do this ; if that regimen doesn ’ t work , do this …’ because there are questions that need to be answered during treatment ,” Dr . Lonial offered . “ What were some of the patient ’ s side effects from the first therapy ? How far away from the clinic does he or she live ? What ’ s the co-pay for oral drugs ? All those answers factor into making drug-sequencing decisions .”— By Shalmali Pal ●
REFERENCES
1 . Kyle RA , Rajkumar SV . Multiple myeloma . Blood . 2008 ; 111:2962-72 .
2 . Yee AJ , Raje NS . Sequencing of nontransplant treatments in multiple myeloma patients with active disease . Hematology Am Soc Hematol Educ Program . 2016 ; 1:495-503 .
3 . Palumbo A , Bringhen S , Mateos MV , et al . Geriatric assessment predicts survival and toxicities in elderly myeloma patients : an International Myeloma Working Group report . Blood . 2015 ; 125:2068-74 .
4 . Durie BG , Hoering A , Abidi MH , et al . Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stemcell transplant ( SWOG S0777 ): a randomised , open-label , phase 3 trial . Lancet . 2017 ; 389:519-27 .
5 . O ’ Donnell EK , Laubach JP , Yee AJ , et al . A phase II study of modified lenalidomide , bortezomib , and dexamethasone ( RVD-lite ) for transplant-ineligible patients with newly diagnosed multiple myeloma . Abstract # 4217 . Presented at the 2015 ASH Annual Meeting , December 8 , 2015 ; Orlando , Florida .
6 . Rajkumar SV , Kyle RA . Progress in myeloma – a monoclonal breakthrough . N Engl J Med . 2016 ; 375:1390-2 .
7 . Lonial S , Dimopoulos M , Palumbo A , et al . Elotuzumab therapy for relapsed or refractory multiple myeloma . N Engl J Med . 2015 ; 373:621-31 .
8 . Dimopoulos M , Oriol A , Nahi H , et al . Daratumumab , lenalidomide , and dexamethasone for multiple myeloma . N Engl J Med . 2016 ; 375:1319-31 .
9 . Shah JJ , Stadtmauer EA , Abonour R , et al . Carfilzomib , pomalidomide , and dexamethasone for relapsed or refractory myeloma . Blood . 2015 ; 126:2284-90 .
10 . Voorhees PM , Mulkey F , Hassoun H , et al . Alliance A061202 . A phase I / II study of pomalidomide , dexamethasone , and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor based therapy : phase I results . Abstract # 375 . Presented at the 2015 ASH Annual Meeting , December 5 , 2015 ; Orlando , Florida .
11 . Mayo Clinic . Welcome to mSMART : the Risk Adapted Approach to Management of Multiple Myeloma and Related Disorders . Accessed March 6 , 2017 , from https :// www . msmart . org / home . html .
12 . Moreau P , Chanan-Khan AA , Roberts AW , et al . Venetoclax combined with bortezomib and dexamethasone for patients with relapsed / refractory multiple myeloma . Abstract # 975 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , California .
13 . Rajkumar SV , Gahrton G , Bergsagel PL . Approach to the treatment of multiple myeloma : a clash of philosophies . Blood . 2011 ; 118:3205-11 .
14 . Zheng Z , Han X , Guy , Jr GP , et al . Do cancer survivors change their prescription drug use for financial reasons ? Findings from a nationally representative sample in the United States . Cancer . 2017 February 20 . [ Epub ahead of print ]
15 . Goldstein DA . Financial toxicity in cancer care — edging toward solutions . Cancer . 2017 February 20 . [ Epub ahead of print ]
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